ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Gastrointestinal (GI) complications are common in the patients undergoing anticancer treatment and, especially, upon allogeneic hematopoietic cell transplantation (allo-HSCT). They are associated with the development of acute protein-energy malnutrition, deficiency and imbalance of macro- and micronutrients, vitamins, thus affecting basic energy supply, as well as cellular regenerative processes, recovery of donor hematopoiesis and immune functions [1]. The malnutrition is known to make a great impact on overall survival, frequency of infectious and immune complications, delayed graft engraftment post-transplant [2]. Severe intestinal dysfunction is among the most dramatic complications in the HSCT setting. Its severity is scored by the degree of diarrhea, dehydration, systemic intoxication due to bacterial toxins, biomarkers of cytokine storm, imbalance of both innate and adaptive immunity, being, generally, associated with altered integrity of gut/blood barrier, thus causing septicemia and bloodstream infections. According to the generally accepted WHO determination, ‘Diarrhoea is the passage of 3 or more loose or liquid stools per day, or more frequently than is normal for the individual’ (https://www.who.int/ru/news-room/fact-sheets/detail/diarrhoeal-disease).

In neutropenic patients, e.g., following HSCT, the situation is complicated by restrictions of low-microbial diet primarily based on infectious safety of the nutrition with minimal contents of microorganisms (<500 CFU per 1 gram of meal) as proposed by several study groups [3, 4]. However, there are no convincing data on proven efficiency of a low-microbial diet for prevention of infectious complications in the neutropenic patients [5, 6]. Moreover, an increasing body of evidence shows a negative impact of a restrictive diet on the risk of infectious episodes and graft-versus-host disease (GvHD) [7]. These trends are based on decreased ability of such balanced diet to protect and maintain the vital activity of intestinal microbiota, like as anatomical and functional integrity of the GI tract [8].

GI complications may occur at different terms after HSCT, from the beginning of cytostatic (conditioning) therapy to the late posttransplant period. Upon the stem cell engraftment (1st month post-HSCT), the diarrhea may be also ascribed to acute GvHD (aGvHD), causing immune damage to the skin and GI mucosal epithelium [9]. However, if diarrhea in GvHD occurs as an isolated intestinal dysfunction, the other possible causes must be excluded before initiating the GvHD treatment, especially, infectious factors [10].

Any type of early or late GI complications, especially, GvHD, is always associated with overgrowth or suppression of viral, bacterial, and fungal pathogens inhabiting GI system. Toxic effects of antitumor, anti-infectious and immunosuppressive drugs may also predispose for intestinal dysfunction post-HSCT, thus determining its proper diagnostics and management.

Hence, the distinct time periods should be considered for intestinal dysfunction, in order to specify their possible causes. Four post-transplant periods may be discerned, with respect to prevailing pathogenic factors:

• Pre-transplant period of conditioning therapy (Day -7 to D0): acute toxic effects of cytostatic therapy causing loss of appetite, nausea and vomiting, severe oral mucositis and initial damage of intestinal crypt associated with dysbiosis of microbiota;

• Posttransplant period: cytopenia and engraftment (D0 to D+15): profound cytopenia, massive anti-infectious treatment and start of immunosuppressive therapy; prolonged intestinal crypt damage, profound dysbiosis (exhaustion) of intestinal microbiota; enhanced risk of bloodstream infections;

• Post-engraftment period (D+16 to D+100): immune/toxic damage of intestinal epithelium (GvHD), established immunosuppressive therapy; continuing bacterial dysbiosis; endogenous viruses activated; mixed microbial and viral infections;

• Late posttransplant period (D+100>): autoimmune tissue disorders; failure of gut/blood barrier; high risk of viral and fungal invasions (Fig. 1).

Goloshchapov-fig01.jpg

Figure 1. Time course of gross microbiota changes (top line) after chemotherapy and following hematopoietic stem cell transplantation. Pre- and posttransplant terms (days) are shown at the straight arrow. Bottom lines show the sequence of common posttransplant complications.

1. Conditioning regimen and early posttransplant period

Acute mucosal damage

Early GI toxicity (a week before and after HSCT) is a common complication of conditioning regimen prior to bone marrow transplantation [11]. Intensive chemotherapy causes severe tissue damage, like as high-dose total body irradiation (TBI). Biological effects include oral mucositis, necrosis of intestinal cells, degeneration of epithelial mucosal crypts and flattening of rectal epithelium. Therefore, diarrhea often quite often during the conditioning treatment and over the posttransplant cytopenic phase. The early diarrhea is caused by the cytotoxic chemotherapy or TBI which inflict deadly insult to hematopoietic, intestinal and other dividing cell populations. Moreover, the evolving immune suppression allows activation of opportunistic and enteropathogenic microbiota. Hence, initial affection of intestinal cells may be readily exacerbated by superposing infection, mainly, by the microorganisms of oral and gut origin.

HSCT procedure was first tested in classical experimental studies [12]. E.g., the dogs given cyclophosphamide at myeloablative doses followed by autologous HSCT developed pronounced leukopenia and severe GI toxicity. Early clinical studies with busulphan and melphalan as a preparative regimen for autologous HSCT have also shown pronounced GI toxicity with nausea, vomiting and diarrhea, in most cases combined with severe oral mucositis [13]. Early GI complications were observed with other chemotherapeutic regimens in autologous HSCT settings [14, 15]. Rapoport et al. [16] registered clinical signs of posttransplant myelosuppression, oral mucositis as well as profuse diarrhea after completion of high-dose conditioning therapy in a large mixed group of patients (n=202) subjected to auto- or allogeneic HSCT. The authors found significant associations between oral mucositis, blood cytopenia and bacterial complications over early posttransplant period, but no correlations between the cytotoxicity of conditioning therapy and diarrhea, probably, due to overall high-dose treatment.

Intestinal mucositis and pre-transplant microbiota

Immunocompromised state develops in all patients prior to HSCT as a part of previous cytostatic treatment. Early programmed death of enterocytes and resulting denudation of intestinal mucosa were documented in heterogenous group of cancer patients subjected to different cytostatic therapies [17]. Intestinal mucositis is a common side effect of chemotherapy also leading to diarrhea, abdominal pain and increased risk of infections. The general epitheliala damage leads to impairment of the intestine/blood barrier, thus potentially causing higher risk of microbial migration into the bloodstream, bacterial endotoxemia and systemic inflammatory responses which are potentially life-threatening conditions [18].

Impaired intestinal barrier integrity may be confirmed by neutrophil detection in gut lumen, as shown in murine mo-dels with different conditioning treatment schedules [19]. Influx of neutrophil granulocytes to the intestinal lamina propria (LP), reflecting an innate immune response to translocation of microbes and their products, showed distinct correlation with severe intestinal damage caused by TBI or chemotherapy.

Decreased levels of plasma citrulline may be another marker of intestinal damage resulting from toxic death and loss of enterocytes, with nadir values of ca. D+7 after conditioning therapy and HSCT [20]. The authors have tested five myeloablative conditioning regimens (MAC) which caused severe inflammatory response associated with dose-dependent loss of intestinal epithelium.

Meanwhile, the frequency and incidence of distinct pathogens are only poorly studied in these groups. E.g., a prospective cohort study of 112 allogeneic and autologous HCT recipients was conducted by Kubiak et al. [21]. Fecal samples were collected within a week before HSCT, and tested for 22 diarrheal pathogens using the BioFire FilmArray PCR diagnostic panel. Different GI pathogens were detected in 37% of cases. In particular, pretransplant detection of C. difficile and diarrhea-provoking E. coli was frequently associated with post-transplant diarrhea.

General biodiversity of gut microbiota before HSCT seem not to influence clinical outcomes in HSC recipients, as suggested by Doki et al. [22]. The authors analyzed fecal samples before conditioning in 107 allo-HSCT recipients. Composition of intestinal microbiota was evaluated by next-generation sequencing (NGS) of bacterial 16S rRNA gene. The patients were classified into three groups based on the low, intermediate, or high biodiversity indexes. No significant differences were revealed in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups as well as grade II-IV GvHD. The only finding was higher abundance of phylum Firmicutes in the patients who later developed aGvHD (p<0.01).

The novel approaches to assessment of bacterial diversity using the 16S rRNA gene variability allowed to follow the time-dependent changes of gut microbiota after anticancer therapy [23]. The authors showed an association of intestinal microbiota with enterocyte loss and systemic inflammation when treating pediatric patients with lymphoblastic leukemia (ALL) by means of high-dose induction chemotherapy. Several plasma inflammation markers (CRP), citrulline levels (marker of functional enterocytes mass) were tested on days 1, 8, 15, 22 and 29 of therapy. Bacterial DNA in fecal samples of patients and their healthy siblings was subject to 16S rRNA gene sequencing (V3-V4 region). The study has shown a substantial decrease in bacterial alpha diversity in the treated patients within first 20 days. The abundance of unclassified Lachnospiraceae spp. was correlated with citrulline on days 8-15 thus suggesting an association between enterocyte damage and microbiota exhaustion.

The issues of chemotherapy and intestinal microbiota were considered in details by the Chinese group [24]. Analysis of literature data concerned changes in composition and biodiversity of gut microbiota in acute myeloid leukemia and ALL during chemotherapy. They have summarized a number of heterogeneous studies on impaired microbiota, with changingratios of Bacteroides, Akkermansia as well as biodiversity indexes prior to treatment and in the course of cytostatic chemotherapy. These data are not equivocal, showing quite different shifts in gut bacterial microbiota at distinct steps of therapy. Moreover, the authors discuss possible correlation between post-treatment restoration of intestinal microbiota and development of late complications, thus affecting clinical outcomes.

2. Cytopenic period and posttransplant engraftment

The early engraftment period (7-15 days post HSCT) is accompanied by exhaustion of all leukocyte and platelet populations, thus being a reason for massive preventive anti-infectious therapy. Along with prevention of early infectious complications, this treatment causes a pronounced suppression of multiple bacterial species at different sites (including oral cavity and intestines), as revealed by classic bacteriology and modern high-throughput NGS techniques [25]. Therefore, normal intestinal microbiota is exhausted within first month after HSCT, with partial reconstitution of dominant bacteria at later terms. However, selection and colonization with antibiotic-resistant bacterial strains, e.g., Klebsiella spp., Pseudomonas spp., Acinetobacter spp., pathogenic E.coli, etc., may occur within this time period [26]. Nevertheless, local bacterial dysbiosis may persist for long terms, thus promoting the intestinal dysfunction post-transplant.

Malnutrition factors associated with diarrhea

Along with abovementioned microbiota changes, the reasons for posttransplant diarrhea include toxic effects of conditioning regimen on the endocrine organs, oral mucositis caused by GI mucosal damage, intoxication and inflammatory effect due to local overgrowth of resistant bacteria. There are no detailed data about pathophysiology of posttransplant diarrhea. However, if comparing the known stages of the diarrhea pathogenesis and the mechanisms of action for different cytostatic agents, antibiotics and other toxic drugs, pathogenic microorganisms, the secretory-osmotic form of diarrhea seems to be the most likely in HSCT, at least until additional provoking factors are added [27]. In this case, a disturbed breakdown, digestion and assimilation of nutrients are observed in these patients, thus promoting the malnutrition states [28]. For example, with the development of neutropenic colitis characterized by swelling of the intestinal mucosa and increased intra-abdominal pressure, the risk of septicemia significantly increases due to the translocation of pathogenic microorganisms into the systemic circulation [29]. The development of infectious complications, in particular, those associated with toxigenic C.difficile infection, activation of cytomegalovirus, Epstein-Barr virus, Candida spp., Aspergillus species also leads to the diarrhea manifestation [30]. Hence, toxic chemotherapy and immune damage to the pancreas, liver, along with the generally accepted use of anti-ulcer therapy (usually with proton pump inhibitors), along with higer infectious risk leads to a decrease in the functional activity of digestive system, i.e., its inability to adequately absorb nutrients from the intestinal lumen. The above conditions contribute negatively to the rapid depletion of the body's nutrient depot, the development of malnutrition and require timely correction with the by means of pathogenetic anti-infective treatment, nutritional support, liver protection and pancreatic enzyme replacement therapy.

A positive effect in the context of damaged intestinal microbiota restoration can be provided by prebiotics therapy, mainly consisting of oligo- and polysaccharides, peptides, fatty acids and a number of other substances, the main function of which is to stimulate common to the certain organism microorganisms strains growth by participating in their physiological metabolic processes. At the same time, there is evidence of the prebiotics therapy efficacy not only directly on the state of the intestinal microbiota, but also on reducing the risk of aGvHD [31].

Probiotic microbial strains, i.e., different preparations of Lactobacilli and Bifidobacteria are widely used in order to prevent and treat a number of intestinal disorders [32]. Given the uncertain therapeutic effect and safety profile of classical commercially provided probiotics in the period of cytopenia and immunodeficiency after HSCT, until sufficient immune reconstruction, the routine probiotics therapy is not currently applied in immunocompromised patients, and further studies are required [33]. Promising results are obtained with clinical isolates of autologous probiotic microorganisms, e.g., non-toxigenic enterococci from the patients’ microbiota, aiming for treatment of intestinal bowel syndromes, both in experiment and in clinical settings. These data are also reviewed elsewhere in literature [34].

3. Post-engraftment period (D+16 – D+21 to D+100)

Acute intestinal GvHD

Following engraftment and proliferation of donor stem cells, the intestinal mucosa, alike skin epithelium, may be affected by aggressive donor T-cells, as well as targeted by commensal microbes that reside within the intestinal lumen leukocytes [35]. Over this time period, the clinical pattern of GI aGvHD is determined by several pathogenic factors: (1) residual cytotoxic damage to intestinal cells, (2) additional enterocyte lesions induced by donor T cells; (3) intestinal dysbiosis with exhaustion of microbial species promoting host survival; (4) proliferation of pathogenic antibiotic-resistant microbial strains. Therefore, severe intestinal aGvHD (grade 3-4) is considered a life-threatening condition with high mortality rates.

Some data on bacterial diversity with NGS of 16S rRNA gene were performed after chemotherapy of acute leukemia in children [23]. E.g., bacterial alpha diversity was lower in patients compared to healthy siblings, being increased on Day 29. Shannon alpha diversity index was correlated with CRP levels on Days 15-29 (r=-0.33 to -0.49; p < 0.05) and with citrulline on Days 15 and 29 (although at p<0.06, r=0.32-0.34). The abundance of unclassified Enterococcus species (spp.) was correlated with CRP on Days 22-29 (r=0.42-0.49; p < 0.009). In conclusion, restoration of intestinal microbiota seems to be associated with changed markers of systemic inflammation after the therapy.

The NGS studies of bacterial microbiota yielded new vision of intestinal microbiota composition and its changes after chemotherapy and HSCT, showing exhaustion of unculturable anaerobic bacteria thus being associated with severe immune disorders posttransplant [36] However, the disadvantage of 16S rRNA gene sequencing is the lack of taxonomic resolution at species and strain-specific levels. Whole-genome metagenomic sequencing of bacterial and viral sequences may be more effective in detailed evaluation of the whole microbiome. These studies revealed a sufficiently decreased biodiversity of bacterial microbiota post-HSCT correlating with increased aGvHD mortality. Among exhausting "favorable" bacteria are the SCFA-producing members of the families Lachnospiraceae and Ruminococcaceae, which may have a protective effect protection against aGvHD. Hence, correction of the gut microbiota posttransplant is a perspective direction in transplantology.

Differential diagnostics of intestinal aGvHD

Intestinal crypt loss and enterocyte apoptosis are key signs of acute intestinal damage [37]. Melson et al. [38] have also performed basic studies in aGvHD pathology. The authors have taken colonic biopsies in 23 patients with aGvHD after HSCT. The crypt loss was present in most cases, and in 11 cases, contiguous areas of crypt loss were observed which associated with severe diarrhea. The patients with severe crypt loss had a pathologic appearance at endoscopy, steroid-refractory disease and worse prognosis for survival. Hence, aberrant mucosal architecture and apoptotic colonic crypt cells seem to be typical to GvHD [39].

The three adopted histopathological scales of gut aGvHD assessment were compared by Kreft et al. [40]. A group of 157 patients with sufficient intestinal samples (>3 biopsies) was studied within 20-200 days after allo-HSCT. The grade of aGvHD was evaluated in serial H&E stained preparations using Lerner, Sale, or and Melson grades of morphological changes, then correlating with clinically approved Glucksberg GvHD grading. A significant association was found between non-relapse mortality, mean Lerner grade, minimum Melson grade, Glucksberg organ staging. In brief, the best correlation with clinical GvHD was obtained with Lerner grading system. It includes: Normal mucosa (Grade 0); Crypt cell apoptosis (Grade 1); Crypt destruction (Grade 2); Focal mucosa denudation (Grade 3); Diffuse mucosa denudation (Grade 4). Therefore, exact diagnosis of acute intestinal GvHD is largely based on histopathological studies of intestinal biopsies while detecting specific signs typical to autoaggressive inflammatory lesions. Once the diagnosis of aGvHD is established, systemic therapy with corticosteroids is administered, and non-responders can be treated with a wide range of second-line therapies (ruxolitinib etc.). In view of gastroenterologists, one should perform extensive management of its complications, especially, profuse diarrhea, malnutrition, and intestinal bleedings [41].

4. Late posttransplant period (D+100>)

By the existing NIH criteria for chronic GvHD, the respective incidence rates of esophageal, upper GI, and lower GI involvement are 16%, 20%, and 13%, according to a cross-sectional analysis from the Chronic GvHD (cGvHD) Consortium [42]. In general, intestinal syndrome at later terms (>100 days) after HSCT is relatively uncommon and may be ascribed to cGvHD. However, histopathological results are difficult to interpret in these cases. The main histological features of late or cGvHD of intestinal mucosa are summarized in a review by Mourad et al. [43], as follows: apoptotic bodies, glandular destruction, ulceration, and features of chronic course such as architectural, distortion, Paneth cell metaplasia, lymphoplasmacytic inflammation, and lamina propria fibrosis, being, however, unspecific for cGvHD. Submucosal and subserosal fibrosis of the intestines are rare in cGvHD, with intact muscularis propria. Hence, making a proper histopathological conclusion needs integration of clinical and histological findings with exclusion of other potential causes of the disorder.

Differentiation between morphological features of acute and chronic gut GvHD was attempted in an early study by Akpek et al. [44]. A cohort of 40 patients with clinically suspected cGvHD (diarrhea, abdominal pains, dysphagia, weight loss) underwent endoscopic examination. Four groups were defined based on the following histological criteria: (1) consistent with GI aGvHD (marked apoptosis with or without cryptitis); (2) suggestive of acute GI GvHD (scattered apoptosis with or without cryptitis; (3) suspected cGvHD (fibrosis and significant crypt distortion). Acute GvHD or overlap syndrome were diagnosed in vast majority of this group (86%), whereas a suspected cGvHD was revealed in only 14% of the patients.

A special large study concerned late GI complications (100 days post-HSCT) in allo-HSCT adult recipients at Duke University observed over a 6-year period [45]. The study included 392 patients who survived for at least 100 days post-transplant. The late GI symptoms required endoscopic evaluation in 71 cases. The endoscopy revealed GI GvHD in 45 cases (63%), i.e., late aGvHD in 39 cases (87%), and 5 patients (11%) had the overlap disease (a combination of acute and chronic GvHD). Of the patients free of GvHD, the symptoms were mostly related to infectious and inflammatory causes. In a multivariate analysis the factors most indicative of GI GvHD were histological findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P=.015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P=.024). In general, up to 20% of allogeneic transplant recipients experienced late GI complications.

Moreover, during last decades, the so-called cord colitis syndrome was described after umbilical cord blood transplantation (UCBT) manifesting with late-onset diarrhea, absence of infection or GvHD, chronic active colitis and granulomatous inflammation [39]. The authors made a blinded histological review of 153 colon biopsies taken in UCBT recipients and 45 matched allografted controls (D+70 to day +365 post-transplant). Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. The comparative study did not show any histological differences between UCBT and control HSCT with diarrhea. Hence, this type of colitis proved to be histological similar to aGvHD and colitis in other allograft recipients.

Goloshchapov-fig02.jpg

Figure 2. Classic aerobic cultures in clinical bacteriological laboratories detect <10% of intestinal human microbiota. Most fecal bacteria, being strict anaerobes, are detectable by means of nucleic acid-based diagnostics (multiple PCR, or next-generation DNA sequencing).

5. Bacterial microbiota following cytostatic therapy and HSCT

Possible clinical role of early intestinal dysbiosis

Routine bacteriological techniques used in the hospital cli-nical laboratories (microscopy and cultural methods) reveal a number of pathogenic microorganisms. However, recent studies show that, e.g., 90% of intestinal bacteria are strict anaerobes which require very special cultural conditions. They are detectable mostly by DNA diagnostics, i.e. PCR or, more recently, with next-generation sequencing. Moreover, one should take a plethora of eukaryotic cell viruses and bacteriophages shaping the intestinal microbiota (Fig. 2).

In general, the intestinal viral microbiome (virome) is much less studied than bacterial microbiota (bacteriome). Meanwhile, the infectious pathogenic viruses, as well as latent endogenous viruses (e.g., herpesviruses) and bacterial viruses (bacteriophages) still dominate in the microbiome. Today, a lot of viral infections seem to affect bacterial gut microbiota. So far, however, the gut virome is insufficiently studied, especially, its interactions with intestinal bacteriome [46]. Interactions between the intestinal mucosa and local microbiota are yet poorly understood. However, the interactions between host epithelium and gut microbiota may be of importance for searching novel tools of prevention and treatment of aGvHD [35, 47].

Early intestinal syndrome due to conditioning therapy may be somewhat connected with subsequent aGvHD, as shown by Goldberg et al. [48]. The authors used diarrhea as a marker of early gut damage in HSCT in CML patients in order to assess relation of conditioning therapy to aGvHD risk grade. The study showed a significant correlation between the sum of diarrhea on days 4 to 7 after SCT and acute GvHD. Such correlation between early diarrhea and risk of aGvHD was later confirmed by Liu et al. [49]. Duration of diarrhea (>5.5 days), and its high volume over days -3 to 0 proved to be risk factors of grade II to IV aGvHD. Thus, early diarrhea, increased TNF-α and IL-6 during the conditioning regimen could be potentially effective predictors for aGvHD, allowing preventive therapy, e.g., with low-dose glucocorticoids.

A recent study by van Praet et al. [50] was based on multiple PCR assessment by Taqman Array Card technology detecting 9 bacterial pathogens, 8 protozoan pathogens, and 8 viral pathogens in diarrheal syndromes in 140 patients post-transplant. The authors searched for intestinal pathogens in diarrheal episodes post-HSCT. Most affected patients (82%) had only one episode of infectious diarrhea within 1 year after HSCT with a cumulative incidence of 32%, mostly as bacterial infections in the pre-engraftment phase. C.difficile, adenovirus, enteropathogenic E.coli, and C. jejuni proved to be most common pathogens.

6. Potential interactions between viral and bacterial microbiota in severely Immunocompromised patients

Viral microbiota is an important component of intestinal mucosal cells and surface. The viruses affecting eukaryotic cells may persist in enterocytes lifelong (e.g., adenoviruses, or Epstein-Barr herpes virus), or may be transported from other organs and tissues (e.g., with migrating blood cells), or behave as a foodborne infection (rota-, noro-, astroviruses etc). Meanwhile, practical and ethical constraints limit functional studies of the virome in humans with enteric and bowel disorders. Therefore, a large body of information on intestinal virome is obtained in animal models [51]. This approach allows tracing the interplay between viruses, bacteria, and the animal host in health and disease.

There are several recent reviews concerning relative roles of eukaryotic cell viruses and bacteriophages in different disorders affecting gastrointestinal system [52, 53]. E.g., sufficient attention is drawn to the inflammatory bowel disorders [54] which may be promoted by common viral infections, e.g., by noro- and rotavirus. Their pathogenetic role may also depend on genetic variants of specific intestinal receptors. Therefore, future studies using new techniques such as metagenomic analysis of intestinal microbiome could further specify the exact relations between bacteriome and virome in health and disease.

Possible interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. E.g. a special study was performed to search for potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of GI aGvHD [55]. Among 121 allo-HSCT patients, acute diarrhea has been registered in 71% of cases thus requiring PCR testing for the primary GI pathogens. One or more GI pathogens were detected in 31% of diarrhea cases, especially, enteropathogenic viruses (12.7%) including Astrovirus, Norovirus, Sapovirus, Adenovirus, and Rotavirus. Thirty patients were diagnosed with all grade GI aGvHD by histopathology. Enteric viruses were found in 8 out of 30 patients with GvHD. In sum, the detection of enteric viruses was not significantly associated with subsequent GI aGvHD development in this unselected cohort.

Moreover, some endogenous herpes viruses may be also activated in the intestinal wall (CMV, EBV, HSV, etc.) at various time periods after HSCT and show a definite time dynamics in the patients with posttransplant intestinal syndromes [56].

Potential interactions of bacteria and viruses in the infectious conditions

Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies show that microbiota actively participates in host-viral interactions and determining the final outcomes of various disorders [57]. The authors illustrate these relations by mutual impact of bacteria and viruses (rotavirus, reovirus) during infectious processes. These effects may occur as direct bacterial-viral interactions or mediated through the innate and/or adaptive host immunity.

In the course of infectious diseases, the viruses may have substantial and intimate interactions with the commensal microbiota [58]. Ample evidence indicates that commensal microbiota regulates the invading viruses through diverse mechanisms, thereby having stimulatory or suppressive roles in viral infections. Vice versa, the integrity of the commensal microbiota can be altered by invading viruses, causing bacterial dysbiosis in the host.

The interplay between commensal and pathogenic bacteria is now better elucidated, with studying the effects of intestinal microbiota on viral pathogenesis [59]. It has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination.

Competitive or symbiotic relations of intestinal bacteria and viruses and studies on their pathogenic mechanisms tend to focus on one pathogen alone. Bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly [60]. The bacterial-viral-gut interactions involve multiple aspects of inflammatory and immune signaling, nutritional immunity, and shaping the gut microbiome. Possible regulatory mechanisms of bacterial/viral co-infections at the host intestinal mucosal surfaces may create a specialized immune interface.

Conclusion

Current advances in microbiology, especially, DNA sequencing of multiple bacterial species have revealed hundreds of microbial species living in human intestines. Normal gut microbiome is mostly presented by anaerobic bacteria which provide stable metabolism of nutrients in symbiosis with the host organism. They exist in a well-coordinated network which largely depends on the type of diet consumed.

The normal balance of gut microbiota may be, however, disturbed by several factors, e.g., changes in diet, microbial or viral infections, immune-related damage to intestinal mucosa, or effects of medicinal drugs. All these pathogenic factors are acrtual in blood cancer patients subjected to cytostatic therapy and, finally, to bone marrow transplantation which provide a chance for radical cure of the disease.

Intestinal microbiota at different terms of HSCT is modified by several disease- and therapy-related factors: 1) acute toxicity to enterocytes and suppression of gut microbiota by preventive antibacterial treatment; 2) pronounced lympho- and neutropenia caused by conditioning treatment and immunosuppressive drugs; 3) immune damage to intestinal epithelium during early engraftment of donor cells; 4) significant depletion changes and restriction in the diet, according to requirements of a low-microbial nutritional regimen; 5) Deficiency of macro- and micronutrients essential for enterocyte metabolism and cellular regeneration. All these pathogenic factors cause imbalance of intestinal microbiota and promote selection of antibiotic-resistant bacterial strains. Due to damage of intestinal crypts and suppressed local immunity, the intestinal pathogens migrate to blood, lymph nodes causing septicemia and infection in secondary sites. Hence, the management of the post-transplant patients with intestinal complications requires distinct approaches to repair of intestinal epithelium and microbiota, dependent on the stage of underlying pathogenetic events at early and *late phases of posttransplant period.

In order to increase protective potential of intestinal microbiota, the attempts were made to systematize the nutritional support therapy in HSCT patients. In particular, the EBMT working group proposed updated nutrition principles, in which a greater emphasis is placed on compliance with the rules of personal hygiene, rules for food storage and cooking, the so-called food safety-based diet, rather than on rigid dietary restrictions [61].

As seen from the data discussed, different pathogenic factors prevail at distinct periods of host and microbiota impairment after HSCT. In clinical terms, however, it manifests as an intestinal dysfunction proceeding with diarrhea, dehydration, intoxication and high risk of septicemia.

To manage these intestinal complications, one should try some clinical measures aimed for prevention and reduction of these conditions, as follows:
1. Less intensive conditioning regimens associated with reduced epithelial damage;
2. Rational preventive antibiotic therapy with broad-spectrum antibacterial drugs in order to spare normal intestinal microbiota;
3. Effective prevention and treatment of aGvHD, and optimization of immunosuppressive therapy, aiming for alleviation of immune-mediated enterocyte damage.
4. Correction of impaired intestinal microbiota by means of common and novel probiotics, autologous probiotics, or fecal microbiota transplantation.
5. Timely detection of the evolving bacterial strains resistant to antibiotics using bacteriological and DNA-based diagnostics.
6. Rational approach to dietary restrictions, timely nutritional support and usage of prebiotics to increase the functional microbiota activity.

Acknowledgement

This study was supported by a research grant from Russian Science Foundation No. №22-15-00149 of 18.05.2022.

Conflict of interest

None reported.

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Introduction

Gastrointestinal (GI) complications are common in the patients undergoing anticancer treatment and, especially, upon allogeneic hematopoietic cell transplantation (allo-HSCT). They are associated with the development of acute protein-energy malnutrition, deficiency and imbalance of macro- and micronutrients, vitamins, thus affecting basic energy supply, as well as cellular regenerative processes, recovery of donor hematopoiesis and immune functions [1]. The malnutrition is known to make a great impact on overall survival, frequency of infectious and immune complications, delayed graft engraftment post-transplant [2]. Severe intestinal dysfunction is among the most dramatic complications in the HSCT setting. Its severity is scored by the degree of diarrhea, dehydration, systemic intoxication due to bacterial toxins, biomarkers of cytokine storm, imbalance of both innate and adaptive immunity, being, generally, associated with altered integrity of gut/blood barrier, thus causing septicemia and bloodstream infections. According to the generally accepted WHO determination, ‘Diarrhoea is the passage of 3 or more loose or liquid stools per day, or more frequently than is normal for the individual’ (https://www.who.int/ru/news-room/fact-sheets/detail/diarrhoeal-disease).

In neutropenic patients, e.g., following HSCT, the situation is complicated by restrictions of low-microbial diet primarily based on infectious safety of the nutrition with minimal contents of microorganisms (<500 CFU per 1 gram of meal) as proposed by several study groups [3, 4]. However, there are no convincing data on proven efficiency of a low-microbial diet for prevention of infectious complications in the neutropenic patients [5, 6]. Moreover, an increasing body of evidence shows a negative impact of a restrictive diet on the risk of infectious episodes and graft-versus-host disease (GvHD) [7]. These trends are based on decreased ability of such balanced diet to protect and maintain the vital activity of intestinal microbiota, like as anatomical and functional integrity of the GI tract [8].

GI complications may occur at different terms after HSCT, from the beginning of cytostatic (conditioning) therapy to the late posttransplant period. Upon the stem cell engraftment (1st month post-HSCT), the diarrhea may be also ascribed to acute GvHD (aGvHD), causing immune damage to the skin and GI mucosal epithelium [9]. However, if diarrhea in GvHD occurs as an isolated intestinal dysfunction, the other possible causes must be excluded before initiating the GvHD treatment, especially, infectious factors [10].

Any type of early or late GI complications, especially, GvHD, is always associated with overgrowth or suppression of viral, bacterial, and fungal pathogens inhabiting GI system. Toxic effects of antitumor, anti-infectious and immunosuppressive drugs may also predispose for intestinal dysfunction post-HSCT, thus determining its proper diagnostics and management.

Hence, the distinct time periods should be considered for intestinal dysfunction, in order to specify their possible causes. Four post-transplant periods may be discerned, with respect to prevailing pathogenic factors:

• Pre-transplant period of conditioning therapy (Day -7 to D0): acute toxic effects of cytostatic therapy causing loss of appetite, nausea and vomiting, severe oral mucositis and initial damage of intestinal crypt associated with dysbiosis of microbiota;

• Posttransplant period: cytopenia and engraftment (D0 to D+15): profound cytopenia, massive anti-infectious treatment and start of immunosuppressive therapy; prolonged intestinal crypt damage, profound dysbiosis (exhaustion) of intestinal microbiota; enhanced risk of bloodstream infections;

• Post-engraftment period (D+16 to D+100): immune/toxic damage of intestinal epithelium (GvHD), established immunosuppressive therapy; continuing bacterial dysbiosis; endogenous viruses activated; mixed microbial and viral infections;

• Late posttransplant period (D+100>): autoimmune tissue disorders; failure of gut/blood barrier; high risk of viral and fungal invasions (Fig. 1).

Goloshchapov-fig01.jpg

Figure 1. Time course of gross microbiota changes (top line) after chemotherapy and following hematopoietic stem cell transplantation. Pre- and posttransplant terms (days) are shown at the straight arrow. Bottom lines show the sequence of common posttransplant complications.

1. Conditioning regimen and early posttransplant period

Acute mucosal damage

Early GI toxicity (a week before and after HSCT) is a common complication of conditioning regimen prior to bone marrow transplantation [11]. Intensive chemotherapy causes severe tissue damage, like as high-dose total body irradiation (TBI). Biological effects include oral mucositis, necrosis of intestinal cells, degeneration of epithelial mucosal crypts and flattening of rectal epithelium. Therefore, diarrhea often quite often during the conditioning treatment and over the posttransplant cytopenic phase. The early diarrhea is caused by the cytotoxic chemotherapy or TBI which inflict deadly insult to hematopoietic, intestinal and other dividing cell populations. Moreover, the evolving immune suppression allows activation of opportunistic and enteropathogenic microbiota. Hence, initial affection of intestinal cells may be readily exacerbated by superposing infection, mainly, by the microorganisms of oral and gut origin.

HSCT procedure was first tested in classical experimental studies [12]. E.g., the dogs given cyclophosphamide at myeloablative doses followed by autologous HSCT developed pronounced leukopenia and severe GI toxicity. Early clinical studies with busulphan and melphalan as a preparative regimen for autologous HSCT have also shown pronounced GI toxicity with nausea, vomiting and diarrhea, in most cases combined with severe oral mucositis [13]. Early GI complications were observed with other chemotherapeutic regimens in autologous HSCT settings [14, 15]. Rapoport et al. [16] registered clinical signs of posttransplant myelosuppression, oral mucositis as well as profuse diarrhea after completion of high-dose conditioning therapy in a large mixed group of patients (n=202) subjected to auto- or allogeneic HSCT. The authors found significant associations between oral mucositis, blood cytopenia and bacterial complications over early posttransplant period, but no correlations between the cytotoxicity of conditioning therapy and diarrhea, probably, due to overall high-dose treatment.

Intestinal mucositis and pre-transplant microbiota

Immunocompromised state develops in all patients prior to HSCT as a part of previous cytostatic treatment. Early programmed death of enterocytes and resulting denudation of intestinal mucosa were documented in heterogenous group of cancer patients subjected to different cytostatic therapies [17]. Intestinal mucositis is a common side effect of chemotherapy also leading to diarrhea, abdominal pain and increased risk of infections. The general epitheliala damage leads to impairment of the intestine/blood barrier, thus potentially causing higher risk of microbial migration into the bloodstream, bacterial endotoxemia and systemic inflammatory responses which are potentially life-threatening conditions [18].

Impaired intestinal barrier integrity may be confirmed by neutrophil detection in gut lumen, as shown in murine mo-dels with different conditioning treatment schedules [19]. Influx of neutrophil granulocytes to the intestinal lamina propria (LP), reflecting an innate immune response to translocation of microbes and their products, showed distinct correlation with severe intestinal damage caused by TBI or chemotherapy.

Decreased levels of plasma citrulline may be another marker of intestinal damage resulting from toxic death and loss of enterocytes, with nadir values of ca. D+7 after conditioning therapy and HSCT [20]. The authors have tested five myeloablative conditioning regimens (MAC) which caused severe inflammatory response associated with dose-dependent loss of intestinal epithelium.

Meanwhile, the frequency and incidence of distinct pathogens are only poorly studied in these groups. E.g., a prospective cohort study of 112 allogeneic and autologous HCT recipients was conducted by Kubiak et al. [21]. Fecal samples were collected within a week before HSCT, and tested for 22 diarrheal pathogens using the BioFire FilmArray PCR diagnostic panel. Different GI pathogens were detected in 37% of cases. In particular, pretransplant detection of C. difficile and diarrhea-provoking E. coli was frequently associated with post-transplant diarrhea.

General biodiversity of gut microbiota before HSCT seem not to influence clinical outcomes in HSC recipients, as suggested by Doki et al. [22]. The authors analyzed fecal samples before conditioning in 107 allo-HSCT recipients. Composition of intestinal microbiota was evaluated by next-generation sequencing (NGS) of bacterial 16S rRNA gene. The patients were classified into three groups based on the low, intermediate, or high biodiversity indexes. No significant differences were revealed in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups as well as grade II-IV GvHD. The only finding was higher abundance of phylum Firmicutes in the patients who later developed aGvHD (p<0.01).

The novel approaches to assessment of bacterial diversity using the 16S rRNA gene variability allowed to follow the time-dependent changes of gut microbiota after anticancer therapy [23]. The authors showed an association of intestinal microbiota with enterocyte loss and systemic inflammation when treating pediatric patients with lymphoblastic leukemia (ALL) by means of high-dose induction chemotherapy. Several plasma inflammation markers (CRP), citrulline levels (marker of functional enterocytes mass) were tested on days 1, 8, 15, 22 and 29 of therapy. Bacterial DNA in fecal samples of patients and their healthy siblings was subject to 16S rRNA gene sequencing (V3-V4 region). The study has shown a substantial decrease in bacterial alpha diversity in the treated patients within first 20 days. The abundance of unclassified Lachnospiraceae spp. was correlated with citrulline on days 8-15 thus suggesting an association between enterocyte damage and microbiota exhaustion.

The issues of chemotherapy and intestinal microbiota were considered in details by the Chinese group [24]. Analysis of literature data concerned changes in composition and biodiversity of gut microbiota in acute myeloid leukemia and ALL during chemotherapy. They have summarized a number of heterogeneous studies on impaired microbiota, with changingratios of Bacteroides, Akkermansia as well as biodiversity indexes prior to treatment and in the course of cytostatic chemotherapy. These data are not equivocal, showing quite different shifts in gut bacterial microbiota at distinct steps of therapy. Moreover, the authors discuss possible correlation between post-treatment restoration of intestinal microbiota and development of late complications, thus affecting clinical outcomes.

2. Cytopenic period and posttransplant engraftment

The early engraftment period (7-15 days post HSCT) is accompanied by exhaustion of all leukocyte and platelet populations, thus being a reason for massive preventive anti-infectious therapy. Along with prevention of early infectious complications, this treatment causes a pronounced suppression of multiple bacterial species at different sites (including oral cavity and intestines), as revealed by classic bacteriology and modern high-throughput NGS techniques [25]. Therefore, normal intestinal microbiota is exhausted within first month after HSCT, with partial reconstitution of dominant bacteria at later terms. However, selection and colonization with antibiotic-resistant bacterial strains, e.g., Klebsiella spp., Pseudomonas spp., Acinetobacter spp., pathogenic E.coli, etc., may occur within this time period [26]. Nevertheless, local bacterial dysbiosis may persist for long terms, thus promoting the intestinal dysfunction post-transplant.

Malnutrition factors associated with diarrhea

Along with abovementioned microbiota changes, the reasons for posttransplant diarrhea include toxic effects of conditioning regimen on the endocrine organs, oral mucositis caused by GI mucosal damage, intoxication and inflammatory effect due to local overgrowth of resistant bacteria. There are no detailed data about pathophysiology of posttransplant diarrhea. However, if comparing the known stages of the diarrhea pathogenesis and the mechanisms of action for different cytostatic agents, antibiotics and other toxic drugs, pathogenic microorganisms, the secretory-osmotic form of diarrhea seems to be the most likely in HSCT, at least until additional provoking factors are added [27]. In this case, a disturbed breakdown, digestion and assimilation of nutrients are observed in these patients, thus promoting the malnutrition states [28]. For example, with the development of neutropenic colitis characterized by swelling of the intestinal mucosa and increased intra-abdominal pressure, the risk of septicemia significantly increases due to the translocation of pathogenic microorganisms into the systemic circulation [29]. The development of infectious complications, in particular, those associated with toxigenic C.difficile infection, activation of cytomegalovirus, Epstein-Barr virus, Candida spp., Aspergillus species also leads to the diarrhea manifestation [30]. Hence, toxic chemotherapy and immune damage to the pancreas, liver, along with the generally accepted use of anti-ulcer therapy (usually with proton pump inhibitors), along with higer infectious risk leads to a decrease in the functional activity of digestive system, i.e., its inability to adequately absorb nutrients from the intestinal lumen. The above conditions contribute negatively to the rapid depletion of the body's nutrient depot, the development of malnutrition and require timely correction with the by means of pathogenetic anti-infective treatment, nutritional support, liver protection and pancreatic enzyme replacement therapy.

A positive effect in the context of damaged intestinal microbiota restoration can be provided by prebiotics therapy, mainly consisting of oligo- and polysaccharides, peptides, fatty acids and a number of other substances, the main function of which is to stimulate common to the certain organism microorganisms strains growth by participating in their physiological metabolic processes. At the same time, there is evidence of the prebiotics therapy efficacy not only directly on the state of the intestinal microbiota, but also on reducing the risk of aGvHD [31].

Probiotic microbial strains, i.e., different preparations of Lactobacilli and Bifidobacteria are widely used in order to prevent and treat a number of intestinal disorders [32]. Given the uncertain therapeutic effect and safety profile of classical commercially provided probiotics in the period of cytopenia and immunodeficiency after HSCT, until sufficient immune reconstruction, the routine probiotics therapy is not currently applied in immunocompromised patients, and further studies are required [33]. Promising results are obtained with clinical isolates of autologous probiotic microorganisms, e.g., non-toxigenic enterococci from the patients’ microbiota, aiming for treatment of intestinal bowel syndromes, both in experiment and in clinical settings. These data are also reviewed elsewhere in literature [34].

3. Post-engraftment period (D+16 – D+21 to D+100)

Acute intestinal GvHD

Following engraftment and proliferation of donor stem cells, the intestinal mucosa, alike skin epithelium, may be affected by aggressive donor T-cells, as well as targeted by commensal microbes that reside within the intestinal lumen leukocytes [35]. Over this time period, the clinical pattern of GI aGvHD is determined by several pathogenic factors: (1) residual cytotoxic damage to intestinal cells, (2) additional enterocyte lesions induced by donor T cells; (3) intestinal dysbiosis with exhaustion of microbial species promoting host survival; (4) proliferation of pathogenic antibiotic-resistant microbial strains. Therefore, severe intestinal aGvHD (grade 3-4) is considered a life-threatening condition with high mortality rates.

Some data on bacterial diversity with NGS of 16S rRNA gene were performed after chemotherapy of acute leukemia in children [23]. E.g., bacterial alpha diversity was lower in patients compared to healthy siblings, being increased on Day 29. Shannon alpha diversity index was correlated with CRP levels on Days 15-29 (r=-0.33 to -0.49; p < 0.05) and with citrulline on Days 15 and 29 (although at p<0.06, r=0.32-0.34). The abundance of unclassified Enterococcus species (spp.) was correlated with CRP on Days 22-29 (r=0.42-0.49; p < 0.009). In conclusion, restoration of intestinal microbiota seems to be associated with changed markers of systemic inflammation after the therapy.

The NGS studies of bacterial microbiota yielded new vision of intestinal microbiota composition and its changes after chemotherapy and HSCT, showing exhaustion of unculturable anaerobic bacteria thus being associated with severe immune disorders posttransplant [36] However, the disadvantage of 16S rRNA gene sequencing is the lack of taxonomic resolution at species and strain-specific levels. Whole-genome metagenomic sequencing of bacterial and viral sequences may be more effective in detailed evaluation of the whole microbiome. These studies revealed a sufficiently decreased biodiversity of bacterial microbiota post-HSCT correlating with increased aGvHD mortality. Among exhausting "favorable" bacteria are the SCFA-producing members of the families Lachnospiraceae and Ruminococcaceae, which may have a protective effect protection against aGvHD. Hence, correction of the gut microbiota posttransplant is a perspective direction in transplantology.

Differential diagnostics of intestinal aGvHD

Intestinal crypt loss and enterocyte apoptosis are key signs of acute intestinal damage [37]. Melson et al. [38] have also performed basic studies in aGvHD pathology. The authors have taken colonic biopsies in 23 patients with aGvHD after HSCT. The crypt loss was present in most cases, and in 11 cases, contiguous areas of crypt loss were observed which associated with severe diarrhea. The patients with severe crypt loss had a pathologic appearance at endoscopy, steroid-refractory disease and worse prognosis for survival. Hence, aberrant mucosal architecture and apoptotic colonic crypt cells seem to be typical to GvHD [39].

The three adopted histopathological scales of gut aGvHD assessment were compared by Kreft et al. [40]. A group of 157 patients with sufficient intestinal samples (>3 biopsies) was studied within 20-200 days after allo-HSCT. The grade of aGvHD was evaluated in serial H&E stained preparations using Lerner, Sale, or and Melson grades of morphological changes, then correlating with clinically approved Glucksberg GvHD grading. A significant association was found between non-relapse mortality, mean Lerner grade, minimum Melson grade, Glucksberg organ staging. In brief, the best correlation with clinical GvHD was obtained with Lerner grading system. It includes: Normal mucosa (Grade 0); Crypt cell apoptosis (Grade 1); Crypt destruction (Grade 2); Focal mucosa denudation (Grade 3); Diffuse mucosa denudation (Grade 4). Therefore, exact diagnosis of acute intestinal GvHD is largely based on histopathological studies of intestinal biopsies while detecting specific signs typical to autoaggressive inflammatory lesions. Once the diagnosis of aGvHD is established, systemic therapy with corticosteroids is administered, and non-responders can be treated with a wide range of second-line therapies (ruxolitinib etc.). In view of gastroenterologists, one should perform extensive management of its complications, especially, profuse diarrhea, malnutrition, and intestinal bleedings [41].

4. Late posttransplant period (D+100>)

By the existing NIH criteria for chronic GvHD, the respective incidence rates of esophageal, upper GI, and lower GI involvement are 16%, 20%, and 13%, according to a cross-sectional analysis from the Chronic GvHD (cGvHD) Consortium [42]. In general, intestinal syndrome at later terms (>100 days) after HSCT is relatively uncommon and may be ascribed to cGvHD. However, histopathological results are difficult to interpret in these cases. The main histological features of late or cGvHD of intestinal mucosa are summarized in a review by Mourad et al. [43], as follows: apoptotic bodies, glandular destruction, ulceration, and features of chronic course such as architectural, distortion, Paneth cell metaplasia, lymphoplasmacytic inflammation, and lamina propria fibrosis, being, however, unspecific for cGvHD. Submucosal and subserosal fibrosis of the intestines are rare in cGvHD, with intact muscularis propria. Hence, making a proper histopathological conclusion needs integration of clinical and histological findings with exclusion of other potential causes of the disorder.

Differentiation between morphological features of acute and chronic gut GvHD was attempted in an early study by Akpek et al. [44]. A cohort of 40 patients with clinically suspected cGvHD (diarrhea, abdominal pains, dysphagia, weight loss) underwent endoscopic examination. Four groups were defined based on the following histological criteria: (1) consistent with GI aGvHD (marked apoptosis with or without cryptitis); (2) suggestive of acute GI GvHD (scattered apoptosis with or without cryptitis; (3) suspected cGvHD (fibrosis and significant crypt distortion). Acute GvHD or overlap syndrome were diagnosed in vast majority of this group (86%), whereas a suspected cGvHD was revealed in only 14% of the patients.

A special large study concerned late GI complications (100 days post-HSCT) in allo-HSCT adult recipients at Duke University observed over a 6-year period [45]. The study included 392 patients who survived for at least 100 days post-transplant. The late GI symptoms required endoscopic evaluation in 71 cases. The endoscopy revealed GI GvHD in 45 cases (63%), i.e., late aGvHD in 39 cases (87%), and 5 patients (11%) had the overlap disease (a combination of acute and chronic GvHD). Of the patients free of GvHD, the symptoms were mostly related to infectious and inflammatory causes. In a multivariate analysis the factors most indicative of GI GvHD were histological findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P=.015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P=.024). In general, up to 20% of allogeneic transplant recipients experienced late GI complications.

Moreover, during last decades, the so-called cord colitis syndrome was described after umbilical cord blood transplantation (UCBT) manifesting with late-onset diarrhea, absence of infection or GvHD, chronic active colitis and granulomatous inflammation [39]. The authors made a blinded histological review of 153 colon biopsies taken in UCBT recipients and 45 matched allografted controls (D+70 to day +365 post-transplant). Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. The comparative study did not show any histological differences between UCBT and control HSCT with diarrhea. Hence, this type of colitis proved to be histological similar to aGvHD and colitis in other allograft recipients.

Goloshchapov-fig02.jpg

Figure 2. Classic aerobic cultures in clinical bacteriological laboratories detect <10% of intestinal human microbiota. Most fecal bacteria, being strict anaerobes, are detectable by means of nucleic acid-based diagnostics (multiple PCR, or next-generation DNA sequencing).

5. Bacterial microbiota following cytostatic therapy and HSCT

Possible clinical role of early intestinal dysbiosis

Routine bacteriological techniques used in the hospital cli-nical laboratories (microscopy and cultural methods) reveal a number of pathogenic microorganisms. However, recent studies show that, e.g., 90% of intestinal bacteria are strict anaerobes which require very special cultural conditions. They are detectable mostly by DNA diagnostics, i.e. PCR or, more recently, with next-generation sequencing. Moreover, one should take a plethora of eukaryotic cell viruses and bacteriophages shaping the intestinal microbiota (Fig. 2).

In general, the intestinal viral microbiome (virome) is much less studied than bacterial microbiota (bacteriome). Meanwhile, the infectious pathogenic viruses, as well as latent endogenous viruses (e.g., herpesviruses) and bacterial viruses (bacteriophages) still dominate in the microbiome. Today, a lot of viral infections seem to affect bacterial gut microbiota. So far, however, the gut virome is insufficiently studied, especially, its interactions with intestinal bacteriome [46]. Interactions between the intestinal mucosa and local microbiota are yet poorly understood. However, the interactions between host epithelium and gut microbiota may be of importance for searching novel tools of prevention and treatment of aGvHD [35, 47].

Early intestinal syndrome due to conditioning therapy may be somewhat connected with subsequent aGvHD, as shown by Goldberg et al. [48]. The authors used diarrhea as a marker of early gut damage in HSCT in CML patients in order to assess relation of conditioning therapy to aGvHD risk grade. The study showed a significant correlation between the sum of diarrhea on days 4 to 7 after SCT and acute GvHD. Such correlation between early diarrhea and risk of aGvHD was later confirmed by Liu et al. [49]. Duration of diarrhea (>5.5 days), and its high volume over days -3 to 0 proved to be risk factors of grade II to IV aGvHD. Thus, early diarrhea, increased TNF-α and IL-6 during the conditioning regimen could be potentially effective predictors for aGvHD, allowing preventive therapy, e.g., with low-dose glucocorticoids.

A recent study by van Praet et al. [50] was based on multiple PCR assessment by Taqman Array Card technology detecting 9 bacterial pathogens, 8 protozoan pathogens, and 8 viral pathogens in diarrheal syndromes in 140 patients post-transplant. The authors searched for intestinal pathogens in diarrheal episodes post-HSCT. Most affected patients (82%) had only one episode of infectious diarrhea within 1 year after HSCT with a cumulative incidence of 32%, mostly as bacterial infections in the pre-engraftment phase. C.difficile, adenovirus, enteropathogenic E.coli, and C. jejuni proved to be most common pathogens.

6. Potential interactions between viral and bacterial microbiota in severely Immunocompromised patients

Viral microbiota is an important component of intestinal mucosal cells and surface. The viruses affecting eukaryotic cells may persist in enterocytes lifelong (e.g., adenoviruses, or Epstein-Barr herpes virus), or may be transported from other organs and tissues (e.g., with migrating blood cells), or behave as a foodborne infection (rota-, noro-, astroviruses etc). Meanwhile, practical and ethical constraints limit functional studies of the virome in humans with enteric and bowel disorders. Therefore, a large body of information on intestinal virome is obtained in animal models [51]. This approach allows tracing the interplay between viruses, bacteria, and the animal host in health and disease.

There are several recent reviews concerning relative roles of eukaryotic cell viruses and bacteriophages in different disorders affecting gastrointestinal system [52, 53]. E.g., sufficient attention is drawn to the inflammatory bowel disorders [54] which may be promoted by common viral infections, e.g., by noro- and rotavirus. Their pathogenetic role may also depend on genetic variants of specific intestinal receptors. Therefore, future studies using new techniques such as metagenomic analysis of intestinal microbiome could further specify the exact relations between bacteriome and virome in health and disease.

Possible interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. E.g. a special study was performed to search for potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of GI aGvHD [55]. Among 121 allo-HSCT patients, acute diarrhea has been registered in 71% of cases thus requiring PCR testing for the primary GI pathogens. One or more GI pathogens were detected in 31% of diarrhea cases, especially, enteropathogenic viruses (12.7%) including Astrovirus, Norovirus, Sapovirus, Adenovirus, and Rotavirus. Thirty patients were diagnosed with all grade GI aGvHD by histopathology. Enteric viruses were found in 8 out of 30 patients with GvHD. In sum, the detection of enteric viruses was not significantly associated with subsequent GI aGvHD development in this unselected cohort.

Moreover, some endogenous herpes viruses may be also activated in the intestinal wall (CMV, EBV, HSV, etc.) at various time periods after HSCT and show a definite time dynamics in the patients with posttransplant intestinal syndromes [56].

Potential interactions of bacteria and viruses in the infectious conditions

Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies show that microbiota actively participates in host-viral interactions and determining the final outcomes of various disorders [57]. The authors illustrate these relations by mutual impact of bacteria and viruses (rotavirus, reovirus) during infectious processes. These effects may occur as direct bacterial-viral interactions or mediated through the innate and/or adaptive host immunity.

In the course of infectious diseases, the viruses may have substantial and intimate interactions with the commensal microbiota [58]. Ample evidence indicates that commensal microbiota regulates the invading viruses through diverse mechanisms, thereby having stimulatory or suppressive roles in viral infections. Vice versa, the integrity of the commensal microbiota can be altered by invading viruses, causing bacterial dysbiosis in the host.

The interplay between commensal and pathogenic bacteria is now better elucidated, with studying the effects of intestinal microbiota on viral pathogenesis [59]. It has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination.

Competitive or symbiotic relations of intestinal bacteria and viruses and studies on their pathogenic mechanisms tend to focus on one pathogen alone. Bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly [60]. The bacterial-viral-gut interactions involve multiple aspects of inflammatory and immune signaling, nutritional immunity, and shaping the gut microbiome. Possible regulatory mechanisms of bacterial/viral co-infections at the host intestinal mucosal surfaces may create a specialized immune interface.

Conclusion

Current advances in microbiology, especially, DNA sequencing of multiple bacterial species have revealed hundreds of microbial species living in human intestines. Normal gut microbiome is mostly presented by anaerobic bacteria which provide stable metabolism of nutrients in symbiosis with the host organism. They exist in a well-coordinated network which largely depends on the type of diet consumed.

The normal balance of gut microbiota may be, however, disturbed by several factors, e.g., changes in diet, microbial or viral infections, immune-related damage to intestinal mucosa, or effects of medicinal drugs. All these pathogenic factors are acrtual in blood cancer patients subjected to cytostatic therapy and, finally, to bone marrow transplantation which provide a chance for radical cure of the disease.

Intestinal microbiota at different terms of HSCT is modified by several disease- and therapy-related factors: 1) acute toxicity to enterocytes and suppression of gut microbiota by preventive antibacterial treatment; 2) pronounced lympho- and neutropenia caused by conditioning treatment and immunosuppressive drugs; 3) immune damage to intestinal epithelium during early engraftment of donor cells; 4) significant depletion changes and restriction in the diet, according to requirements of a low-microbial nutritional regimen; 5) Deficiency of macro- and micronutrients essential for enterocyte metabolism and cellular regeneration. All these pathogenic factors cause imbalance of intestinal microbiota and promote selection of antibiotic-resistant bacterial strains. Due to damage of intestinal crypts and suppressed local immunity, the intestinal pathogens migrate to blood, lymph nodes causing septicemia and infection in secondary sites. Hence, the management of the post-transplant patients with intestinal complications requires distinct approaches to repair of intestinal epithelium and microbiota, dependent on the stage of underlying pathogenetic events at early and *late phases of posttransplant period.

In order to increase protective potential of intestinal microbiota, the attempts were made to systematize the nutritional support therapy in HSCT patients. In particular, the EBMT working group proposed updated nutrition principles, in which a greater emphasis is placed on compliance with the rules of personal hygiene, rules for food storage and cooking, the so-called food safety-based diet, rather than on rigid dietary restrictions [61].

As seen from the data discussed, different pathogenic factors prevail at distinct periods of host and microbiota impairment after HSCT. In clinical terms, however, it manifests as an intestinal dysfunction proceeding with diarrhea, dehydration, intoxication and high risk of septicemia.

To manage these intestinal complications, one should try some clinical measures aimed for prevention and reduction of these conditions, as follows:
1. Less intensive conditioning regimens associated with reduced epithelial damage;
2. Rational preventive antibiotic therapy with broad-spectrum antibacterial drugs in order to spare normal intestinal microbiota;
3. Effective prevention and treatment of aGvHD, and optimization of immunosuppressive therapy, aiming for alleviation of immune-mediated enterocyte damage.
4. Correction of impaired intestinal microbiota by means of common and novel probiotics, autologous probiotics, or fecal microbiota transplantation.
5. Timely detection of the evolving bacterial strains resistant to antibiotics using bacteriological and DNA-based diagnostics.
6. Rational approach to dietary restrictions, timely nutritional support and usage of prebiotics to increase the functional microbiota activity.

Acknowledgement

This study was supported by a research grant from Russian Science Foundation No. №22-15-00149 of 18.05.2022.

Conflict of interest

None reported.

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Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности – фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило – в виде диареи различной этиологии, в т.ч. в форме антибиотик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-зависимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эндотелиального барьера и тяжелым инфекционным осложнениям, в частности – септицемии, вызванной бактериями кишечного происхождения, особенно – антибиотикорезистентными бактериями. Cущественные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период цитопении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесвирусы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий; (4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ; (5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных пробиотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат 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Голощапов<sup>1</sup>, Максим А. Кучер<sup>1</sup>, Юрий А. Эйсмонт<sup>2</sup>, Алексей Б. Чухловин<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(182) "

Олег В. Голощапов1, Максим А. Кучер1, Юрий А. Эйсмонт2, Алексей Б. Чухловин1

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Детский научно-клинический центр инфекционных болезней ФМБА РФ, Санкт-Петербург, Россия

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Данный обзор касается вопросов патогенеза и диагностики желудочно-кишечных осложнений у больных онкогематологического профиля после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности – фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило – в виде диареи различной этиологии, в т.ч. в форме антибиотик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-зависимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эндотелиального барьера и тяжелым инфекционным осложнениям, в частности – септицемии, вызванной бактериями кишечного происхождения, особенно – антибиотикорезистентными бактериями. Cущественные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период цитопении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесвирусы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий; (4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ; (5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных пробиотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат против хозяина», кишечная микробиота.

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Oleg V. Goloshchapov1, Maxim A. Kucher1, Yury A. Eismont2, Alexei B. Chukhovin1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Kucher MA, Eismont YA, Chukhovin AB. Origin and consequences of intestinal dysfunction following cytostatic chemotherapy and hematopoietic stem cell transplantation. Cell Ther Transplant 2023; 12(2): 4-14.

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The review article deals with pathogenesis and diagnostics of common gastrointestinal (GI) complications in patients with oncohematological diseases subjected to intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). The associated GI disorders may present with hyporexia, nausea, vomiting, diarrhea, dehydration and intoxication thus causing protein-energy malnutrition and reducing efficiency of cancer therapeutics. The symptoms of intestinal dysfunction may develop early before HSCT due to cytostatic and antibacterial therapy. As a rule, it manifests with diarrhea caused by different reasons, e.g., antibiotic-associated bacterial dysbiosis, or enteropathogenic infections, impaired intestinal motility, or due to immune-mediated graft-versus-host disease (GvHD).

The initial dose-dependent mucosal damage following cytostatic therapy may impair intestinal and endothelial interfaces, then being complicated by severe superposing infections with intestinal bacteria, especially, antibiotic-resistant strains. Sufficient changes in gut microbiota are revealed early upon chemotherapy of leukemia patients. Typical pathological findings in cytopenic period and subsequent aGvHD after allo-HSCT, include: (1) cytotoxic damage to intestinal mucosal cells, (2) additional immune-mediated enterocyte lesions induced by donor T cells. The intestinal bacterial dysbiosis caused by antimicrobial therapy leads to suppression of metabolically active microbiota, thus causing the exhaustion of essential nutrients. Therefore, intestinal colonization with antibiotic-resistant bacterial strains may be observed. In particular, a complex interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. A number of endogenous viruses (adeno- and herpes viruses) are commonly activated post-transplant, thus potentially modifying the disease pattern.

To manage the GI complications after HSCT, some clinical measures should be taken to alleviate these conditions, e.g., (1) Reduced-intensity conditioning regimens; (2) Rational preventive antibacterial therapy in order to spare normal intestinal microbiota; (3) Timely detection of antibiotic-resistant bacterial strains; (4) Immunosuppressive therapy optimization to prevent severe intestinal GvHD; (5) Correction of impaired intestinal microbiota using conventional and autologous probiotic bacterial strains, fecal microbiota transplantation; (6) Rational approach to dietary restrictions, timely nutritional support and the use of prebiotics to increase the functional microbiota activity.

Keywords

Hematopoietic stem cell transplantation, gastrointestinal toxicity, mucositis, intestinal dysfunction, graft-versus-host disease, intestinal microbiota.

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Goloshchapov<sup>1</sup>, Maxim A. Kucher<sup>1</sup>, Yury A. Eismont<sup>2</sup>, Alexei B. Chukhovin<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(130) "

Oleg V. Goloshchapov1, Maxim A. Kucher1, Yury A. Eismont2, Alexei B. Chukhovin1

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Oleg V. Goloshchapov1, Maxim A. Kucher1, Yury A. Eismont2, Alexei B. Chukhovin1

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The review article deals with pathogenesis and diagnostics of common gastrointestinal (GI) complications in patients with oncohematological diseases subjected to intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). The associated GI disorders may present with hyporexia, nausea, vomiting, diarrhea, dehydration and intoxication thus causing protein-energy malnutrition and reducing efficiency of cancer therapeutics. The symptoms of intestinal dysfunction may develop early before HSCT due to cytostatic and antibacterial therapy. As a rule, it manifests with diarrhea caused by different reasons, e.g., antibiotic-associated bacterial dysbiosis, or enteropathogenic infections, impaired intestinal motility, or due to immune-mediated graft-versus-host disease (GvHD).

The initial dose-dependent mucosal damage following cytostatic therapy may impair intestinal and endothelial interfaces, then being complicated by severe superposing infections with intestinal bacteria, especially, antibiotic-resistant strains. Sufficient changes in gut microbiota are revealed early upon chemotherapy of leukemia patients. Typical pathological findings in cytopenic period and subsequent aGvHD after allo-HSCT, include: (1) cytotoxic damage to intestinal mucosal cells, (2) additional immune-mediated enterocyte lesions induced by donor T cells. The intestinal bacterial dysbiosis caused by antimicrobial therapy leads to suppression of metabolically active microbiota, thus causing the exhaustion of essential nutrients. Therefore, intestinal colonization with antibiotic-resistant bacterial strains may be observed. In particular, a complex interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. A number of endogenous viruses (adeno- and herpes viruses) are commonly activated post-transplant, thus potentially modifying the disease pattern.

To manage the GI complications after HSCT, some clinical measures should be taken to alleviate these conditions, e.g., (1) Reduced-intensity conditioning regimens; (2) Rational preventive antibacterial therapy in order to spare normal intestinal microbiota; (3) Timely detection of antibiotic-resistant bacterial strains; (4) Immunosuppressive therapy optimization to prevent severe intestinal GvHD; (5) Correction of impaired intestinal microbiota using conventional and autologous probiotic bacterial strains, fecal microbiota transplantation; (6) Rational approach to dietary restrictions, timely nutritional support and the use of prebiotics to increase the functional microbiota activity.

Keywords

Hematopoietic stem cell transplantation, gastrointestinal toxicity, mucositis, intestinal dysfunction, graft-versus-host disease, intestinal microbiota.

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The review article deals with pathogenesis and diagnostics of common gastrointestinal (GI) complications in patients with oncohematological diseases subjected to intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). The associated GI disorders may present with hyporexia, nausea, vomiting, diarrhea, dehydration and intoxication thus causing protein-energy malnutrition and reducing efficiency of cancer therapeutics. The symptoms of intestinal dysfunction may develop early before HSCT due to cytostatic and antibacterial therapy. As a rule, it manifests with diarrhea caused by different reasons, e.g., antibiotic-associated bacterial dysbiosis, or enteropathogenic infections, impaired intestinal motility, or due to immune-mediated graft-versus-host disease (GvHD).

The initial dose-dependent mucosal damage following cytostatic therapy may impair intestinal and endothelial interfaces, then being complicated by severe superposing infections with intestinal bacteria, especially, antibiotic-resistant strains. Sufficient changes in gut microbiota are revealed early upon chemotherapy of leukemia patients. Typical pathological findings in cytopenic period and subsequent aGvHD after allo-HSCT, include: (1) cytotoxic damage to intestinal mucosal cells, (2) additional immune-mediated enterocyte lesions induced by donor T cells. The intestinal bacterial dysbiosis caused by antimicrobial therapy leads to suppression of metabolically active microbiota, thus causing the exhaustion of essential nutrients. Therefore, intestinal colonization with antibiotic-resistant bacterial strains may be observed. In particular, a complex interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. A number of endogenous viruses (adeno- and herpes viruses) are commonly activated post-transplant, thus potentially modifying the disease pattern.

To manage the GI complications after HSCT, some clinical measures should be taken to alleviate these conditions, e.g., (1) Reduced-intensity conditioning regimens; (2) Rational preventive antibacterial therapy in order to spare normal intestinal microbiota; (3) Timely detection of antibiotic-resistant bacterial strains; (4) Immunosuppressive therapy optimization to prevent severe intestinal GvHD; (5) Correction of impaired intestinal microbiota using conventional and autologous probiotic bacterial strains, fecal microbiota transplantation; (6) Rational approach to dietary restrictions, timely nutritional support and the use of prebiotics to increase the functional microbiota activity.

Keywords

Hematopoietic stem cell transplantation, gastrointestinal toxicity, mucositis, intestinal dysfunction, graft-versus-host disease, intestinal microbiota.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Kucher MA, Eismont YA, Chukhovin AB. Origin and consequences of intestinal dysfunction following cytostatic chemotherapy and hematopoietic stem cell transplantation. Cell Ther Transplant 2023; 12(2): 4-14.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Kucher MA, Eismont YA, Chukhovin AB. Origin and consequences of intestinal dysfunction following cytostatic chemotherapy and hematopoietic stem cell transplantation. Cell Ther Transplant 2023; 12(2): 4-14.

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Олег В. Голощапов1, Максим А. Кучер1, Юрий А. Эйсмонт2, Алексей Б. Чухловин1

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Олег В. Голощапов1, Максим А. Кучер1, Юрий А. Эйсмонт2, Алексей Б. Чухловин1

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Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности – фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило – в виде диареи различной этиологии, в т.ч. в форме антибиотик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-зависимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эндотелиального барьера и тяжелым инфекционным осложнениям, в частности – септицемии, вызванной бактериями кишечного происхождения, особенно – антибиотикорезистентными бактериями. Cущественные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период цитопении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесвирусы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий; (4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ; (5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных пробиотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат против хозяина», кишечная микробиота.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6105) "

Данный обзор касается вопросов патогенеза и диагностики желудочно-кишечных осложнений у больных онкогематологического профиля после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности – фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило – в виде диареи различной этиологии, в т.ч. в форме антибиотик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-зависимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эндотелиального барьера и тяжелым инфекционным осложнениям, в частности – септицемии, вызванной бактериями кишечного происхождения, особенно – антибиотикорезистентными бактериями. Cущественные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период цитопении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесвирусы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий; (4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ; (5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных пробиотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат против хозяина», кишечная микробиота.

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Данный обзор касается вопросов патогенеза и диагностики желудочно-кишечных осложнений у больных онкогематологического профиля после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности – фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило – в виде диареи различной этиологии, в т.ч. в форме антибиотик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-зависимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эндотелиального барьера и тяжелым инфекционным осложнениям, в частности – септицемии, вызванной бактериями кишечного происхождения, особенно – антибиотикорезистентными бактериями. Cущественные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период цитопении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесвирусы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий; (4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ; (5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных пробиотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат против хозяина», кишечная микробиота.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Детский научно-клинический центр инфекционных болезней ФМБА РФ, Санкт-Петербург, Россия

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Детский научно-клинический центр инфекционных болезней ФМБА РФ, Санкт-Петербург, Россия

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Introduction

There is no strict consensus on ability of self-renewal and regeneration of myocardial cells in mammals. For a long time, high mortality rates in heart disorders due to low regenerative potential of myocardial cells were explained by inability of mature cardiomyocytes (CMs) to divide. Meanwhile, further studies in the field revealed cardiac stem cells (CSCs) of three distinct types (c-kit+, Sca-1+- and Isl-1+) [1-4], showing a myogenic potential of resident CSCs, thus suggesting their participation in self-renewal and, moreover, regeneration of myocardium [5, 6]. However, absence of distinct evidence for CSC contribution to cardiomyogenesis in adult mammals, and the results of Porrello et al. [7] on ability оf myocardial reconstitution after 20%-dissection of left ventricle in newborn mice led to the hypothesis about regeneration of damaged mammalian myocardium via division of mature CMs rather than by proliferation of CSCs which, however, oose this ability within first week of life. Moreover, some workers presume that the CSCs, in particular, c-kit+-cell population, are absent in adult mammalian myocardium [8]. At the same time, other authors suggest that mature CMs are able to enter the cell cycle after undergoing a de-differentiation step, and to produce new progeny [9, 10].

However, the data obtained by Koudstaal et al. (2013) and Malliaras (2019) confirm participation of c-kit+ CSCs in cardiomyogenesis and consider different approaches to their stimulation aiming for regeneration of damaged myocardium [11, 12].

Participation of CSCs in heart metabolism and cardiomyogenesis in steady state and following myocardial ichemia was also confirmed in Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences (IEPhB RAS), Almazov National Medical Research Centre and Pavlov University. Animal studies have shown that the renewal of resident CMs in mammals may proceed from CSCs throughout life in three ways: (1) by means of CSC proliferation within colonies with the formation of transitory amplifying cells (TACs) followed by their differentiation to CMs [13, 14]; (2) by means of intracellular development of CSCs with the formation of encapsulated "cell-in-cell structures" (CICSs) [15, 16], and (3) by intracellular proliferation inside mature CMs with formation of the capsule-free CICSs [17].

Of note, the presence of some cells within other cells resulting into CICSs was revealed as early as 100 years ago for immune cells (cytophagocytosis and emperipolesis) and, later, for malignant cell populations (entosis) and at the sites of inflammation [18]. So far, however, such intracellular patterns were not described in myocardium in terms of CSC development. Unlike Overholtzer and Brugge [19] who suggested entosis to be a form of cancer cell death, the studies by Belostotskaya et al. [17] provide first evidence for intrinsic role of intracellular CSC division in renewal and regeneration of myocardium.

Despite some proofs of CSC-mediated cardiomyogenesis obtained in animals of different ages, and in adult female 45 y.o. [16] there are no available data on CSCs proliferation in the older and elderly patients with heart disorders.

The present study was aimed for search and identification of proliferating myocardial cells from heart biopsies of the patients of different age groups who underwent cardiosurgery at the Pavlov University. Experimental results supporting our cardiomyogenesis concept were obtained in IEPhB RAS.

Materials and methods

We have studied cardiac biopsies taken in 24 patients of different age groups (47 to 80 years old) operated over the period of 30 June 2021 to 6 December 2021 with following diagnoses: ischemic heart disease (IHD), 15; aneurism of a.ascendens, 3; acquired heart defects, 5; hypertrophic cardiomyopathy, 1. Under artificial blood flow, the IHD patients underwent coronary bypass; in the patients with aortic aneurism the resection of aneurism replaced by a vascular prosthesis with a valve conduit (Bentall operation) and coronary implants. In acquired heart defects, replacement of heart valves, or plastics of mitral valve were performed, and Morrow septal myoectomy was made in hypertrophic cardiomyopathy. When connecting the heart-lung machine, a purse-string suture was placed at the atrial appendage toper- form venous cannulation. The biopsy of a fragment from atrial appendage was made in the center of purse-string suture immediately before the venous cannula was installed. The biopsies of right atrial appendage were performed from the center of purse-string suture immediately before introduction of venous cannula. A portion of biopsy sample was sent to the Laboratory of Morphology (Pavlov University), a the rest of a sample was subject to electron microscopy at the IEPhB of RAS.

The remaining sterile bioptate (a portion of right atrial appendage) was dissected into the fragments 1 to 1.5 mm in size. After its transfer to a tube with sterile saline, the tissues were brought to the IEFB, in order to perform enzymatic disintegration of myocardial fragment in sterile box by a standard protocol according to Lam et al. [18]. The pieces of myocardium were rinsed in Ringer solution (NaCl, 146 mM; KCl, 5 mM; CaCl2, 2 mM; MgCl2, 1 mM; dextrose, 11 mM; HEPES, 10 mM HEPES, pH 7.4), minced and incubated in the same solution supplied with collagenase type IA (Sigma, 1 mg/mL), and trypsin (Biolot, Russia, 0.12%) for 20-30 min. at 37ºС. The suspension was then centrifuged at 1500 rpm for 10 min. Subsequent cultivation was performed by transfer of tissue to the warmed DMEM nutrient medium with 10% embryo calf serum (Biolot, Russia) supplied with 50 ME/mL penicillin and streptomycin (50 mcg/mL, Biolot, Russia). The cells were cultured in 35-mm glass Petri dishes (BioVitrum LLC). Incbation was performed in the СО2 incubator (Binder, Germany) at 5% СО2, humidity 95%, and 37ºС. The medium was changed twice a week without reseeding of cells.

The cultures were observed by means of inverted light microscope (PIM-III, WPI, USA) using a digital camera (Leica DFC300 FX, Germany) with objectives of x4, х10, х25.

To perform confocal microscopy, freshly isolated cells in suspension or cultured cellular monolayer were fixed by means of 2.5-4% paraformadehyde, permeabilized for 10 min. in phosphate buffer with 0,25% Triton X-100. The c-kit+ CSCs were detected by means of FITC-conjugated commercial reagents (Abcam) diluted to 1:100. Cardiac origin of the cells was confirmed with monoclonal antibodies to α-actinin (Sigma-Aldrich) conjugated with Alexa 532, according to Zenon technology (Invitrogen). The cellular nuclei were stained with Hoechst dye 33342 (Molecular Probes, USA, 10 mcg/mL) diluted to 1:1000. The cells were stained at room temperature. Confocal microscopy was performed at the Resource Center of St. Petersburg University using a Leica TCS SP5 microscope with objectives of х10, х25 and х40 (oil), and with a confocal microscope Leica TCS SP5 (х10 and х25 objectives) in IEPhB. According to our concept, we carried out observations of CSCs, their progeny (colonies of TACs), non-encapsulated CICSs, presenting as vacuoles containing TACs within cardiac cells, or as free TACs – containing vacuoles (Fig. 1).

Nemkov-fig01.jpg

Figure 1. Confocal microscopy of the cells from atrial appendage of a men (74 y.o.) after enzymatic treatment. A, at λ=532 nm (red fluorescence); B, in light transmitted light; C, at λ=496 nm (green fluorescence; D, at λ=405 nm (nuclei, blue light), and E, composite

Nemkov-fig02.jpg

Figure 2. Histological pattern of a sample from right atrial appendage (H&E staining), patient K. (78 y.o.)

Nemkov-fig03.jpg

Figure 3. Patient S (75 y.o.). A cardiomyocyte from the right atrial appendage exhibits hypertrophy of the muscle fibres with urregular thickening of Z-membrane and accumulation of small rounded mitochondria with electron-dense matrix. From the outside, the cell is coated with multilayer basal membrane which separates it from the connective tissue with rich collagen bundles and fibroblasts. TEM picture, 11500x.

Results

Light microscopy of the heart biopsies stained by H&E has revealed characteristic histological patterns typical to the patients subjected to cardiosurgery. One may see cardiomyocytes with transverse striation, focal sclerosis regions, and fat tissue associated with connective tissue sprawls; intermuscular sclerosis and scarce diffuse lymphocytic infiltration, as well as extended vessel lumens with some full-blooded vessels. The cardiomyocytes are partially hypertrophic, with thickened fibres and enlarged nuclei, looking edematous (Fig. 2).

Transmision electron microscopy (TEM) of the samples from right atrial appendages made at the IEPhB has shown multiple polymorphic changes in the atrial myocardiocytes. The ultrastructural tissue pattern included multiple polymorphic alterations of contractile structures in the atrial cardiomyocytes, reactive/destructive alterations of cellular organelles, pronounced fibrosis of intercellular connective tissue. Ultrastructural pathology of microcirculatory blood vessels is, generally, characterized by dystrophic changes of endothelium and inhomogeneity of basal membrane (from thinning to notable slerosis). A fragment of contractile myocardiocyte and features of its sarcoplasmic organelles are presented at the Fig. 3.

Fig. 4. demonstrates an increased number of non-encapsulated CICSs derived from the atrial appendage after enzyme treatment and primary culture for different time periods.

When studying cell suspensions isolated from the atrial appendage and left ventricle (24 clinical cases, the samples of 70-150 mg), we have found spheroid structures in all the preparations. They were described as free vacuoles which have been previously shown to emerge within mature CMs after intracellular development of CSCs [17]. These structures evolve into the non-encapsulated CICSs released as TACs-containing vacuoles from the CMs (Fig. 5, A,B) . Daily light microscopy of the primarily cultured cells derived from the biopsies allowed us to observe the heterogenous vacuoles released from the CICS (Fig. 5, C).

Nemkov-fig04.jpg

Figure 4. Increased numbers of non-encapsulated vacuoles, released during cultivation of the bioptate from atrial appendage of a female (47 y.o.) at different terms after enzymatic treatment.

А, immediately after 30-min. enzyme treatment; B and C, following 3 days in culture; D, after 30 days in culture.

Nemkov-fig05.jpg

Figure 5. The non-encapsulated cell-in-cell structures (CICS) and freely-moving TAC-vacuoles in freshly isolated cell suspension from the left ventricle myocardium and atrial appendage cells. Patient Z (80 y.o.)

А, two vacuoles within cardiomyocyte (arrow); B, a vacuole within an atrial cardiomyocyte; C, free vacuole with transitional cell (TK) inside (arrow).

Nemkov-fig06.jpg

Figure 6. A colony of TACs presumed to be the progeny of c-kit+ CSCs (green) showing a marker of in vitro differentiation to myocardial lineage (α-actinin, stained red). Patient K., male, 74 y.o.

These vacuoles, when released from the atrial appendages by enzyme treatment, may increase in their size due to division of small cells (5-12 µm in diameter) inside them. They are stainable by the stemness marker (c-kit) and cardiomyocyte-specific marker (α-actinin), thus being assigned to the CSC progeny differentiated to cardiac lineage (Fig. 1). Moreover, detection of c-kit+ colonies (Fig. 6) confirms the proliferation of CSCs in myocardium of the patients at 70-80 years old.

The variants of vacuoles from non-encapsulated CICSs are shown in Fig. 7 (A-О). The vacuoles are present in males and females of 47 to 78 years old. Meanwhile, the differences are evident in size and number of vacuoles in the samples presented. Variable size of the cell-derived vacuoles from the patients of different age may result from CSC proliferation within these structures, thus correlating with multiple small cells revealed within large vacuoles (Fig. 7, E, J) in atrial appendages from males (47 and 78 y.o., respectively). Moreover, the data allow us to note that the size of CSC vacuoles is increased upon culturing the biopsy material, either from males (Fig. 7, E, J) or females (Fig. 7, M,O) as well as opening of the CSC vacuoles followed by release of TACs (Fig. 7, D).

Nemkov-fig07.jpg

Figure 7. Non-encapsulated cell-in-cell structures (CICS) from the left atrial appendages of operated patients at different age and gender (m, males; f, females) observed in primary cultures at different terms (DIV, days in vitro). Light microscopy.

Confocal microscopy of the fragmented atrial appendages from 2 elderly patients detects c-kit-positive CSCs inside vacuoles (Fig. 8).

Meanwhile, a release of TACs was also shown (Fig. 9), both upon long-term cultivation of atrial appendage cells from a young patient (A, B), and in fresh myocardial suspension of an elderly patient (C), thus suggesting the existence of some regenerative potential in human myocardium over the entire lifespan.

Nemkov-fig08.jpg

Figure 8. Confocal microsopy of the presumed CSC-containing vacuoles from the atrial appendages: patient K (male), 74 (А, B); patient Z (fem), 80 (C). Scales 20 µm.

Nemkov-fig09.jpg

Figure 9. Opening of vacuoles from the non-encapsulated CICSs in the primary myocardial culture of patient Sh., male, 48 (А, DIV 22; B DIV 26); in cell suspension of atrial appendage from patient K., male, 74 (C, D), with triple-stain labeling.

A, B – Light microscopy. C, D – Confocal microscopy.

However, some sufficient differences are observed when comparing the abundance of CSC-related vacuoles. E.g., a lot of vacuoles was observed in samples C, F, H, L, O, in contrast to their scarcity in the samples А, B, I, K (Fig. 7). Moreover, large amounts of small CSC-related vacuoles in younger patients, males or females (pictures B, F, G, N, Fig. 7) may be caused by low proliferative activity of TACs within the vacuoles thus suggesting independence of these events on age or gender of the patients. However, such effects may be caused by the distinct disorders in the patient, being independent on age or gender factors. Anyway, these issues may be cleared by further experiments with different methods of enzymatic treatment for the atrial appendages taken from surgical patients with different heart disorders.

Discussion

Long-term studies of age-dependent regenerative ability of mammalian myocardium were performed in Wistar rats in IEPhB RAS and Almazov National Medical Research Centre [13, 14, 15]. Similar studies were carried out in both healthy animals and rats following experimental myocardial infarction and ischemia [17]. The present cooperative study was performed at the Pavlov University and IEPhB RAS using myocardial fragments of the patients with different cardiac disorders. For the first time it was concerned to assessment of regenerative potential in the persons of different gender and age (47 to 80 years old). Extent of cardiomyogenesis in surgical patients was evaluated by detection of stem cells and clusters of TACs, i.e., their progeny in myocardium which may be related to the 1st variant of cell multiplication and differentiation inside CSC colonies, according to our concept (see Introduction). Encapsulated CICS, i.e., 2nd variant of CSC-mediated cardiomyogenesis, were not revealed in the samples from middle-aged and old patients. However, when observing the in vitro cultures of cells isolated from atrial appendages, we have revealed intracellular CSC development within atrial cardiomyocytes, resulting into non-encapsulated CICS (3rd variant of CSC multiplication).

However, long-term culturing of atrial cells has shown that development of CSCs within mature atrial CMs with CICS formation represents the main way of TAC reproduction. One may suggest that the encapsulated CICSs may emerge in the cardiosurgical samples from newborns and infants, like as the encapsulated CICSs with intracellular CSCs within immature cells [17]. Prevalence of the non-encapsulated CICSs over TACs production inside the observed colonies may be dependent on poor conditions for CSC proliferation in the patients with severe heart disorders, e.g., ischemic heart disease, acquired heart defects, aortal aneurism, thus making the CSCs to migrate to the mature CMs and multiply within intracellular vacuoles which, upon maturation, could contain a big number of TACs. We guess that the CSC proliferation in mature CMs with development of non-encapsulated CICSs may supply numerous TACs of sufficient maturity for regeneration of myocardium.

Therefore, our data may be interpreted in view of sufficient cardiomyogenesis in the individual patients. In practical aspect, we may suggest injection of the own (autologous) in vitro expanded TACs from atrial appendages into the patient’s myocardium. Such therapeutic option is confirmed by our results showing increased size of TACs-containing CICSs from young patient of 48 years old (Fig. 7, E) and old patient of 74 years old (Fig. 7, J). Due to individual ability for such proliferation mode, the cell cultures of intrasurgical biopsies would provide selection of those patients eligible for this type of therapy.

Previously, we have already considered potential clinical usage of autologous encapsulated CICSs [21]. However, after detection of non-encapsulated CICSs and their in vitro cultivation [17], we suggest that application of CSC-containing vacuoles from non-encapsulated CICSs would provide a more effective cardiomyogenesis, due to larger amounts of more differentiated TACs inside the vacuoles.

The idea of using the autologous myocardial cells for heart regeneration following infarction and ischemia occurred soon after CSC detection [1, 22]. As early as in 2004, Messina et al. [23] proposed to perform intramyocardial injections of in vitro produced clusters (cardiospheres) from non-differentiated cells of atrial or ventricular biopsies of murine of human origin. In this respect, special attention was drawn to three clinical trials (SCIPIO, CADUCEUS, Allstar), which studied the opportunity of cardiac cells usage in order to boost myocardial regeneration after heart infarction or ischemia. In the CADUCEUS program (autologous transplants) and Allstar trial (with allogeneic cells), injections of cells obtained from cardiospheres were associated with myocardial regeneration, decreased size of myocardial scars, and expansion of functional tissues [24]. However, the results of Allstar-trial published 6 months later did not show reduction of scars in left ventricle by the cardiosphere treatment [25]. Meanwhile, other studies in CADUCEUS trial have shown a positive effect of cardiosphere therapy (smaller scare size and improved myocardial function) at 6 and 12 months after the infarction [26, 27]. Moreover, the SCIPIO Trial has shown that application of freshly isolated autologous c-kit+-CSCs in ischemic cardiomyopathy was associated with significant improvement of global and regional left ventricular function, reduced infarction size, and increased area of viable tissue thus suggesting a regenerative effect [28].

Stimulation of TACs proliferation under the in vivo conditions may be considered an alternative regeneration mode. Meanwhile, the possibility of using growth factors and cytokines for this purpose was earlier suggested [21], followed by assessing the effects of apoptotic bodies from CMs (AbBc) in collaborative studies with A.I. Tyukavin. It was shown that the AbBc stimulates the development of TACs inside the cell colonies in primary cultures [29]. Hence, a hypothesis is proposed that the AbBc contain a RNA complex that stimulates the proliferation of CSCs and the subsequent their differentiation into mature CMs [30].

Conclusion

The present study was performed by the staff of Pavlov University, IEPhB RAS and St. Petersburg State University using the biopsies from cardiosurgical patients with different heart disorders. For the first time, it concerned assessment of potential for myocardial regeneration in the patients of different gender and age groups (47 to 80 y.o.). Cardiac stem cells (CSCs) and their progeny transitory amplifying cells (TACs) were considered as primary substrate for cellular regeneration. These populations have been shown to multiply and differentiate towards cardiomyocytes, either as colony-forming cells, or within "cell-in-cell structures" (CICSs). We have found CSCs with c-kit+ marker in each biopsy of atrial appendages from young and aged patients (up to 80 y.o.). We did not show any distinct dependence between the numbers of revealed structures, stem cells, and patients’age or gender. We were not able to reveal any encapsulated CICSs typical for the 2nd mode of CSC proliferation, probably, due to the age factor. The next tasks include following technical items: to perform exact counting of CSCs, TACs and CICS, to provide their soft isolation from the suspension and in vitro expansion. Optimal ways should be found for clinical application of this promising autologous biomaterial in order to enhance myocardial regeneration in the most urgent clinical cases.

Acknowledgements

The authors thank the heads of three institutions who participated in joint work: the Rector of St.Petersburg State Pavlov Medical University, the Full Member of RAS S.F. Bagnenko, the Director of IEPhB RAS, Corresponding Member of RAS M.L. Firsov and the Rector of St. Petersburg State University, Corresponding Member of RAS, Doctor of Law N.M Kropachev.

Conflict of interest

None declared.

References

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  2. Beltrami AP, Barlucchi L, Torella D, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003; 114: 763-776. doi: 10.1016/S0092-8674(03)00687-1
  3. Cai Ch, Liang X, Shi Y, Chu P, Pfaff S, Ju Chen, Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003; 5(6): 877-889. doi: 10.1016/s1534-5807(03)00363-0
  4. Parmacek MS, Epstein JA. Pursuing cardiac progenitors: regeneration redux. Cell. 2005; 120: 295-298. doi: 10.1016/j.cell.2005.01.025
  5. Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: A paradigm shift in cardiac biology. Circulation. 2006; 113: 1451-1463. doi: 10.1161/CIRCULATIONAHA.105.595181
  6. Choi YH, Saric T, Nasseri B, Huhn S, Linthout SV, Hetzer R, Tschope C, Stamm C. Cardiac cell therapies: the next generation. Cardiovasc Ther. 2011; 29(1):2-16. doi: 10.1111/j.1755-5922.2010.00191.x
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  12. Malliaras K. Endogenous regeneration of the mammalian heart, in: D. Cokkinos, Ed. Myocardial Preservation. Springer, Cham; 2019: 339-354. ISBN 9783319981857 Editorial SPRINGER.
  13. Golovanova TA, Belostotskaya GB. Ability of rat myocardium to self-renewal in the in vitro experiment: colonies of contractile neonatal cardiomyocytes. Geny i Kletki. 2012; 7(1): 67-72 (In Russian).
  14. Belostotskaya GB, Golovanova TA. Characterization of contracting cardiomyocyte colonies in the primary culture of neonatal rat myocardial cells: A model of in vitro cardiomyogenesis. Cell Cycle. 2014; 13 (6): 910-918. doi: 10.4161/cc.27768
  15. Belostotskaya G, Nevorotin A, Galagudza M. Identification of cardiac stem cells within mature cardiac myocytes. Cell Cycle. 2015; 14(19):3155- 3162. doi: 10.1080/15384101.2015.1078037
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  26. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012; 379(9819): 895-904.
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  29. Tyukavin AI, Belostotskaya GB, Golovanova TA, Galagudza MM, Zakharov EA, Burkova NV, et al. Stimulation of proliferation and differentiation of resident cells of rat myocardium by apoptotic bodies of cardiomyocytes. // Kletochnye Tekhnologii v Biologii I Medicine. 2015; 1:25-28. (In Russian). doi: 10.47056/1814-3490-2020-3-151-157
  30. Tyukavin AI, Belostotskaya GB, Zakharov EA, Ivkin DYu, Rad’ko SV, Knyazev NA, et al. Apoptotic bodies of cardiomyocytes and fibroblasts are regulators of directed differentiation of heart stem cells. Kletochnye Tekhnologii v Biologii I Medicine. 2020; 3:151-157. (In Russian). doi: 10.47056/1814-3490-2020-3-151-157

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Introduction

There is no strict consensus on ability of self-renewal and regeneration of myocardial cells in mammals. For a long time, high mortality rates in heart disorders due to low regenerative potential of myocardial cells were explained by inability of mature cardiomyocytes (CMs) to divide. Meanwhile, further studies in the field revealed cardiac stem cells (CSCs) of three distinct types (c-kit+, Sca-1+- and Isl-1+) [1-4], showing a myogenic potential of resident CSCs, thus suggesting their participation in self-renewal and, moreover, regeneration of myocardium [5, 6]. However, absence of distinct evidence for CSC contribution to cardiomyogenesis in adult mammals, and the results of Porrello et al. [7] on ability оf myocardial reconstitution after 20%-dissection of left ventricle in newborn mice led to the hypothesis about regeneration of damaged mammalian myocardium via division of mature CMs rather than by proliferation of CSCs which, however, oose this ability within first week of life. Moreover, some workers presume that the CSCs, in particular, c-kit+-cell population, are absent in adult mammalian myocardium [8]. At the same time, other authors suggest that mature CMs are able to enter the cell cycle after undergoing a de-differentiation step, and to produce new progeny [9, 10].

However, the data obtained by Koudstaal et al. (2013) and Malliaras (2019) confirm participation of c-kit+ CSCs in cardiomyogenesis and consider different approaches to their stimulation aiming for regeneration of damaged myocardium [11, 12].

Participation of CSCs in heart metabolism and cardiomyogenesis in steady state and following myocardial ichemia was also confirmed in Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences (IEPhB RAS), Almazov National Medical Research Centre and Pavlov University. Animal studies have shown that the renewal of resident CMs in mammals may proceed from CSCs throughout life in three ways: (1) by means of CSC proliferation within colonies with the formation of transitory amplifying cells (TACs) followed by their differentiation to CMs [13, 14]; (2) by means of intracellular development of CSCs with the formation of encapsulated "cell-in-cell structures" (CICSs) [15, 16], and (3) by intracellular proliferation inside mature CMs with formation of the capsule-free CICSs [17].

Of note, the presence of some cells within other cells resulting into CICSs was revealed as early as 100 years ago for immune cells (cytophagocytosis and emperipolesis) and, later, for malignant cell populations (entosis) and at the sites of inflammation [18]. So far, however, such intracellular patterns were not described in myocardium in terms of CSC development. Unlike Overholtzer and Brugge [19] who suggested entosis to be a form of cancer cell death, the studies by Belostotskaya et al. [17] provide first evidence for intrinsic role of intracellular CSC division in renewal and regeneration of myocardium.

Despite some proofs of CSC-mediated cardiomyogenesis obtained in animals of different ages, and in adult female 45 y.o. [16] there are no available data on CSCs proliferation in the older and elderly patients with heart disorders.

The present study was aimed for search and identification of proliferating myocardial cells from heart biopsies of the patients of different age groups who underwent cardiosurgery at the Pavlov University. Experimental results supporting our cardiomyogenesis concept were obtained in IEPhB RAS.

Materials and methods

We have studied cardiac biopsies taken in 24 patients of different age groups (47 to 80 years old) operated over the period of 30 June 2021 to 6 December 2021 with following diagnoses: ischemic heart disease (IHD), 15; aneurism of a.ascendens, 3; acquired heart defects, 5; hypertrophic cardiomyopathy, 1. Under artificial blood flow, the IHD patients underwent coronary bypass; in the patients with aortic aneurism the resection of aneurism replaced by a vascular prosthesis with a valve conduit (Bentall operation) and coronary implants. In acquired heart defects, replacement of heart valves, or plastics of mitral valve were performed, and Morrow septal myoectomy was made in hypertrophic cardiomyopathy. When connecting the heart-lung machine, a purse-string suture was placed at the atrial appendage toper- form venous cannulation. The biopsy of a fragment from atrial appendage was made in the center of purse-string suture immediately before the venous cannula was installed. The biopsies of right atrial appendage were performed from the center of purse-string suture immediately before introduction of venous cannula. A portion of biopsy sample was sent to the Laboratory of Morphology (Pavlov University), a the rest of a sample was subject to electron microscopy at the IEPhB of RAS.

The remaining sterile bioptate (a portion of right atrial appendage) was dissected into the fragments 1 to 1.5 mm in size. After its transfer to a tube with sterile saline, the tissues were brought to the IEFB, in order to perform enzymatic disintegration of myocardial fragment in sterile box by a standard protocol according to Lam et al. [18]. The pieces of myocardium were rinsed in Ringer solution (NaCl, 146 mM; KCl, 5 mM; CaCl2, 2 mM; MgCl2, 1 mM; dextrose, 11 mM; HEPES, 10 mM HEPES, pH 7.4), minced and incubated in the same solution supplied with collagenase type IA (Sigma, 1 mg/mL), and trypsin (Biolot, Russia, 0.12%) for 20-30 min. at 37ºС. The suspension was then centrifuged at 1500 rpm for 10 min. Subsequent cultivation was performed by transfer of tissue to the warmed DMEM nutrient medium with 10% embryo calf serum (Biolot, Russia) supplied with 50 ME/mL penicillin and streptomycin (50 mcg/mL, Biolot, Russia). The cells were cultured in 35-mm glass Petri dishes (BioVitrum LLC). Incbation was performed in the СО2 incubator (Binder, Germany) at 5% СО2, humidity 95%, and 37ºС. The medium was changed twice a week without reseeding of cells.

The cultures were observed by means of inverted light microscope (PIM-III, WPI, USA) using a digital camera (Leica DFC300 FX, Germany) with objectives of x4, х10, х25.

To perform confocal microscopy, freshly isolated cells in suspension or cultured cellular monolayer were fixed by means of 2.5-4% paraformadehyde, permeabilized for 10 min. in phosphate buffer with 0,25% Triton X-100. The c-kit+ CSCs were detected by means of FITC-conjugated commercial reagents (Abcam) diluted to 1:100. Cardiac origin of the cells was confirmed with monoclonal antibodies to α-actinin (Sigma-Aldrich) conjugated with Alexa 532, according to Zenon technology (Invitrogen). The cellular nuclei were stained with Hoechst dye 33342 (Molecular Probes, USA, 10 mcg/mL) diluted to 1:1000. The cells were stained at room temperature. Confocal microscopy was performed at the Resource Center of St. Petersburg University using a Leica TCS SP5 microscope with objectives of х10, х25 and х40 (oil), and with a confocal microscope Leica TCS SP5 (х10 and х25 objectives) in IEPhB. According to our concept, we carried out observations of CSCs, their progeny (colonies of TACs), non-encapsulated CICSs, presenting as vacuoles containing TACs within cardiac cells, or as free TACs – containing vacuoles (Fig. 1).

Nemkov-fig01.jpg

Figure 1. Confocal microscopy of the cells from atrial appendage of a men (74 y.o.) after enzymatic treatment. A, at λ=532 nm (red fluorescence); B, in light transmitted light; C, at λ=496 nm (green fluorescence; D, at λ=405 nm (nuclei, blue light), and E, composite

Nemkov-fig02.jpg

Figure 2. Histological pattern of a sample from right atrial appendage (H&E staining), patient K. (78 y.o.)

Nemkov-fig03.jpg

Figure 3. Patient S (75 y.o.). A cardiomyocyte from the right atrial appendage exhibits hypertrophy of the muscle fibres with urregular thickening of Z-membrane and accumulation of small rounded mitochondria with electron-dense matrix. From the outside, the cell is coated with multilayer basal membrane which separates it from the connective tissue with rich collagen bundles and fibroblasts. TEM picture, 11500x.

Results

Light microscopy of the heart biopsies stained by H&E has revealed characteristic histological patterns typical to the patients subjected to cardiosurgery. One may see cardiomyocytes with transverse striation, focal sclerosis regions, and fat tissue associated with connective tissue sprawls; intermuscular sclerosis and scarce diffuse lymphocytic infiltration, as well as extended vessel lumens with some full-blooded vessels. The cardiomyocytes are partially hypertrophic, with thickened fibres and enlarged nuclei, looking edematous (Fig. 2).

Transmision electron microscopy (TEM) of the samples from right atrial appendages made at the IEPhB has shown multiple polymorphic changes in the atrial myocardiocytes. The ultrastructural tissue pattern included multiple polymorphic alterations of contractile structures in the atrial cardiomyocytes, reactive/destructive alterations of cellular organelles, pronounced fibrosis of intercellular connective tissue. Ultrastructural pathology of microcirculatory blood vessels is, generally, characterized by dystrophic changes of endothelium and inhomogeneity of basal membrane (from thinning to notable slerosis). A fragment of contractile myocardiocyte and features of its sarcoplasmic organelles are presented at the Fig. 3.

Fig. 4. demonstrates an increased number of non-encapsulated CICSs derived from the atrial appendage after enzyme treatment and primary culture for different time periods.

When studying cell suspensions isolated from the atrial appendage and left ventricle (24 clinical cases, the samples of 70-150 mg), we have found spheroid structures in all the preparations. They were described as free vacuoles which have been previously shown to emerge within mature CMs after intracellular development of CSCs [17]. These structures evolve into the non-encapsulated CICSs released as TACs-containing vacuoles from the CMs (Fig. 5, A,B) . Daily light microscopy of the primarily cultured cells derived from the biopsies allowed us to observe the heterogenous vacuoles released from the CICS (Fig. 5, C).

Nemkov-fig04.jpg

Figure 4. Increased numbers of non-encapsulated vacuoles, released during cultivation of the bioptate from atrial appendage of a female (47 y.o.) at different terms after enzymatic treatment.

А, immediately after 30-min. enzyme treatment; B and C, following 3 days in culture; D, after 30 days in culture.

Nemkov-fig05.jpg

Figure 5. The non-encapsulated cell-in-cell structures (CICS) and freely-moving TAC-vacuoles in freshly isolated cell suspension from the left ventricle myocardium and atrial appendage cells. Patient Z (80 y.o.)

А, two vacuoles within cardiomyocyte (arrow); B, a vacuole within an atrial cardiomyocyte; C, free vacuole with transitional cell (TK) inside (arrow).

Nemkov-fig06.jpg

Figure 6. A colony of TACs presumed to be the progeny of c-kit+ CSCs (green) showing a marker of in vitro differentiation to myocardial lineage (α-actinin, stained red). Patient K., male, 74 y.o.

These vacuoles, when released from the atrial appendages by enzyme treatment, may increase in their size due to division of small cells (5-12 µm in diameter) inside them. They are stainable by the stemness marker (c-kit) and cardiomyocyte-specific marker (α-actinin), thus being assigned to the CSC progeny differentiated to cardiac lineage (Fig. 1). Moreover, detection of c-kit+ colonies (Fig. 6) confirms the proliferation of CSCs in myocardium of the patients at 70-80 years old.

The variants of vacuoles from non-encapsulated CICSs are shown in Fig. 7 (A-О). The vacuoles are present in males and females of 47 to 78 years old. Meanwhile, the differences are evident in size and number of vacuoles in the samples presented. Variable size of the cell-derived vacuoles from the patients of different age may result from CSC proliferation within these structures, thus correlating with multiple small cells revealed within large vacuoles (Fig. 7, E, J) in atrial appendages from males (47 and 78 y.o., respectively). Moreover, the data allow us to note that the size of CSC vacuoles is increased upon culturing the biopsy material, either from males (Fig. 7, E, J) or females (Fig. 7, M,O) as well as opening of the CSC vacuoles followed by release of TACs (Fig. 7, D).

Nemkov-fig07.jpg

Figure 7. Non-encapsulated cell-in-cell structures (CICS) from the left atrial appendages of operated patients at different age and gender (m, males; f, females) observed in primary cultures at different terms (DIV, days in vitro). Light microscopy.

Confocal microscopy of the fragmented atrial appendages from 2 elderly patients detects c-kit-positive CSCs inside vacuoles (Fig. 8).

Meanwhile, a release of TACs was also shown (Fig. 9), both upon long-term cultivation of atrial appendage cells from a young patient (A, B), and in fresh myocardial suspension of an elderly patient (C), thus suggesting the existence of some regenerative potential in human myocardium over the entire lifespan.

Nemkov-fig08.jpg

Figure 8. Confocal microsopy of the presumed CSC-containing vacuoles from the atrial appendages: patient K (male), 74 (А, B); patient Z (fem), 80 (C). Scales 20 µm.

Nemkov-fig09.jpg

Figure 9. Opening of vacuoles from the non-encapsulated CICSs in the primary myocardial culture of patient Sh., male, 48 (А, DIV 22; B DIV 26); in cell suspension of atrial appendage from patient K., male, 74 (C, D), with triple-stain labeling.

A, B – Light microscopy. C, D – Confocal microscopy.

However, some sufficient differences are observed when comparing the abundance of CSC-related vacuoles. E.g., a lot of vacuoles was observed in samples C, F, H, L, O, in contrast to their scarcity in the samples А, B, I, K (Fig. 7). Moreover, large amounts of small CSC-related vacuoles in younger patients, males or females (pictures B, F, G, N, Fig. 7) may be caused by low proliferative activity of TACs within the vacuoles thus suggesting independence of these events on age or gender of the patients. However, such effects may be caused by the distinct disorders in the patient, being independent on age or gender factors. Anyway, these issues may be cleared by further experiments with different methods of enzymatic treatment for the atrial appendages taken from surgical patients with different heart disorders.

Discussion

Long-term studies of age-dependent regenerative ability of mammalian myocardium were performed in Wistar rats in IEPhB RAS and Almazov National Medical Research Centre [13, 14, 15]. Similar studies were carried out in both healthy animals and rats following experimental myocardial infarction and ischemia [17]. The present cooperative study was performed at the Pavlov University and IEPhB RAS using myocardial fragments of the patients with different cardiac disorders. For the first time it was concerned to assessment of regenerative potential in the persons of different gender and age (47 to 80 years old). Extent of cardiomyogenesis in surgical patients was evaluated by detection of stem cells and clusters of TACs, i.e., their progeny in myocardium which may be related to the 1st variant of cell multiplication and differentiation inside CSC colonies, according to our concept (see Introduction). Encapsulated CICS, i.e., 2nd variant of CSC-mediated cardiomyogenesis, were not revealed in the samples from middle-aged and old patients. However, when observing the in vitro cultures of cells isolated from atrial appendages, we have revealed intracellular CSC development within atrial cardiomyocytes, resulting into non-encapsulated CICS (3rd variant of CSC multiplication).

However, long-term culturing of atrial cells has shown that development of CSCs within mature atrial CMs with CICS formation represents the main way of TAC reproduction. One may suggest that the encapsulated CICSs may emerge in the cardiosurgical samples from newborns and infants, like as the encapsulated CICSs with intracellular CSCs within immature cells [17]. Prevalence of the non-encapsulated CICSs over TACs production inside the observed colonies may be dependent on poor conditions for CSC proliferation in the patients with severe heart disorders, e.g., ischemic heart disease, acquired heart defects, aortal aneurism, thus making the CSCs to migrate to the mature CMs and multiply within intracellular vacuoles which, upon maturation, could contain a big number of TACs. We guess that the CSC proliferation in mature CMs with development of non-encapsulated CICSs may supply numerous TACs of sufficient maturity for regeneration of myocardium.

Therefore, our data may be interpreted in view of sufficient cardiomyogenesis in the individual patients. In practical aspect, we may suggest injection of the own (autologous) in vitro expanded TACs from atrial appendages into the patient’s myocardium. Such therapeutic option is confirmed by our results showing increased size of TACs-containing CICSs from young patient of 48 years old (Fig. 7, E) and old patient of 74 years old (Fig. 7, J). Due to individual ability for such proliferation mode, the cell cultures of intrasurgical biopsies would provide selection of those patients eligible for this type of therapy.

Previously, we have already considered potential clinical usage of autologous encapsulated CICSs [21]. However, after detection of non-encapsulated CICSs and their in vitro cultivation [17], we suggest that application of CSC-containing vacuoles from non-encapsulated CICSs would provide a more effective cardiomyogenesis, due to larger amounts of more differentiated TACs inside the vacuoles.

The idea of using the autologous myocardial cells for heart regeneration following infarction and ischemia occurred soon after CSC detection [1, 22]. As early as in 2004, Messina et al. [23] proposed to perform intramyocardial injections of in vitro produced clusters (cardiospheres) from non-differentiated cells of atrial or ventricular biopsies of murine of human origin. In this respect, special attention was drawn to three clinical trials (SCIPIO, CADUCEUS, Allstar), which studied the opportunity of cardiac cells usage in order to boost myocardial regeneration after heart infarction or ischemia. In the CADUCEUS program (autologous transplants) and Allstar trial (with allogeneic cells), injections of cells obtained from cardiospheres were associated with myocardial regeneration, decreased size of myocardial scars, and expansion of functional tissues [24]. However, the results of Allstar-trial published 6 months later did not show reduction of scars in left ventricle by the cardiosphere treatment [25]. Meanwhile, other studies in CADUCEUS trial have shown a positive effect of cardiosphere therapy (smaller scare size and improved myocardial function) at 6 and 12 months after the infarction [26, 27]. Moreover, the SCIPIO Trial has shown that application of freshly isolated autologous c-kit+-CSCs in ischemic cardiomyopathy was associated with significant improvement of global and regional left ventricular function, reduced infarction size, and increased area of viable tissue thus suggesting a regenerative effect [28].

Stimulation of TACs proliferation under the in vivo conditions may be considered an alternative regeneration mode. Meanwhile, the possibility of using growth factors and cytokines for this purpose was earlier suggested [21], followed by assessing the effects of apoptotic bodies from CMs (AbBc) in collaborative studies with A.I. Tyukavin. It was shown that the AbBc stimulates the development of TACs inside the cell colonies in primary cultures [29]. Hence, a hypothesis is proposed that the AbBc contain a RNA complex that stimulates the proliferation of CSCs and the subsequent their differentiation into mature CMs [30].

Conclusion

The present study was performed by the staff of Pavlov University, IEPhB RAS and St. Petersburg State University using the biopsies from cardiosurgical patients with different heart disorders. For the first time, it concerned assessment of potential for myocardial regeneration in the patients of different gender and age groups (47 to 80 y.o.). Cardiac stem cells (CSCs) and their progeny transitory amplifying cells (TACs) were considered as primary substrate for cellular regeneration. These populations have been shown to multiply and differentiate towards cardiomyocytes, either as colony-forming cells, or within "cell-in-cell structures" (CICSs). We have found CSCs with c-kit+ marker in each biopsy of atrial appendages from young and aged patients (up to 80 y.o.). We did not show any distinct dependence between the numbers of revealed structures, stem cells, and patients’age or gender. We were not able to reveal any encapsulated CICSs typical for the 2nd mode of CSC proliferation, probably, due to the age factor. The next tasks include following technical items: to perform exact counting of CSCs, TACs and CICS, to provide their soft isolation from the suspension and in vitro expansion. Optimal ways should be found for clinical application of this promising autologous biomaterial in order to enhance myocardial regeneration in the most urgent clinical cases.

Acknowledgements

The authors thank the heads of three institutions who participated in joint work: the Rector of St.Petersburg State Pavlov Medical University, the Full Member of RAS S.F. Bagnenko, the Director of IEPhB RAS, Corresponding Member of RAS M.L. Firsov and the Rector of St. Petersburg State University, Corresponding Member of RAS, Doctor of Law N.M Kropachev.

Conflict of interest

None declared.

References

  1. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Letters. 2002; 530: 239-243. doi: 10.1016/s0014-5793(02)03477-4
  2. Beltrami AP, Barlucchi L, Torella D, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003; 114: 763-776. doi: 10.1016/S0092-8674(03)00687-1
  3. Cai Ch, Liang X, Shi Y, Chu P, Pfaff S, Ju Chen, Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003; 5(6): 877-889. doi: 10.1016/s1534-5807(03)00363-0
  4. Parmacek MS, Epstein JA. Pursuing cardiac progenitors: regeneration redux. Cell. 2005; 120: 295-298. doi: 10.1016/j.cell.2005.01.025
  5. Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: A paradigm shift in cardiac biology. Circulation. 2006; 113: 1451-1463. doi: 10.1161/CIRCULATIONAHA.105.595181
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Немков<sup>1</sup>, Галина Б. Белостоцкая<sup>2</sup>, Александр В. Кривенцов<sup>1</sup>, Владимир В. Комок<sup>1</sup>, Николай С. Буненков<sup>1</sup>, Сергей П. Марченко<sup>1</sup>, Гельфия М. Нутфуллина<sup>1</sup>, Наталья М. Парамонова<sup>2</sup>, Николай А. Костин<sup>3</sup>, Дмитрий А. Сибаров<sup>2</sup>, Геннадий Г. Хубулава<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(554) "

Александр С. Немков1, Галина Б. Белостоцкая2, Александр В. Кривенцов1, Владимир В. Комок1, Николай С. Буненков1, Сергей П. Марченко1, Гельфия М. Нутфуллина1, Наталья М. Парамонова2, Николай А. Костин3, Дмитрий А. Сибаров2, Геннадий Г. Хубулава1

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 НИИ эволюционной физиологии и биохимии им. И. М. Сеченова, Санкт-Петербург, Россия
3 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия

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Высокая смертность от сердечнососудистых заболеваний, обусловленная низким регенеративным потенциалом миокарда, требует поиска новых терапевтических подходов для лечения кардиологических больных. Цель работы: изучить наличие регенеративного потенциала сердца у кардиохирургических пациентов среднего и старшего возраста.

Материалы и методы

Биопсийные образцы миокарда ушек предсердий разрушали с помощью ферментов. Конфокальную микроскопию проводили на культивируемых в первичной культуре клетках и на суспензии фиксированных клеток. Кроме того были выполнены гистологические и электронно-микроскопические исследования биоптатов миокарда.

Результаты

Клеточный компонент регенерации в виде кардиальных стволовых клеток (КСК), их потомков – транзиторных клеток (ТК) в составе колоний, а также в виде «структур клетка-внутри-клетки» (СКВК) обнаружены в каждом биопсийном образце. В данном исследовании в экспериментах in vitro продемонстрировано высвобождение ТК высокого уровня зрелости из вакуолей бескапсульных СКВК ушек сердца кардиохирургических пациентов.

Заключение

Полученные данные не только позволяют ориентировочно оценивать уровень кардиомиогенеза каждого конкретного больного, но и открывают перспективы возможного использования in vitro размноженных аутологичных ТК в качестве клеточного продукта для терапии сердечнососудистых заболеваний.

Ключевые слова

Кардиохирургия, биопсии миокарда, кардиальные стволовые клетки, транзиторные клетки, кардиомиоциты, структура «клетка-внутри-клетки».

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Aleksandr S. Nemkov1, Galina B. Belostotskaya2, Alexandr V. Kriventsov1, Vladimir V. Komok1, Nikolay S. Bunenkov1, Sergey P. Marchenko1, Gelfia M. Nutfullina1, Natalia M. Paramonova2, Nikolay A. Kostin3, Dmitri A. Sibarov2, Gennady G. Khubulava1

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1 Pavlov University, St. Petersburg, Russia
2 Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Aleksandr S. Nemkov, Pavlov University, L. Tolstoy St 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 795-00-47
E-mail: nemk_as@mail.ru


Citation: Nemkov AS, Belostotskaya GB, Kriventsov AV et al. Evaluation of myocardial regenerative potential in cardiosurgery of middle-aged and elderly patients. Cell Ther Transplant 2023; 12(2): 23-31.

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High mortality from cardiovascular diseases, due to the low regenerative potential of the myocardium, requires the search for new therapeutic approaches for the treatment of cardiac patients. Aim of the present work was to assess the regenerative potential of myocardial cells in cardiac surgery patients of middle and older age.

Materials and methods

The biopsy samples of the myocardial auricles were destroyed by enzyme technique. Confocal microscopy was performed on cells cultivated in the primary culture and on a suspension of fixed cells. In addition, histological and electron microscopic studies of myocardial biopsies were performed.

Results

Regenerative ability of cardiac cells was estimated by the presence of cardiac stem cells (CSCs), their progeny, transitory amplifying cells (TACs) inside the colonies, as well as by the presence of "cell-in-cell structures" (CICSs), which were found in each biopsy sample. In this study, in vitro experiments demonstrated the release of TACs from the vacuoles of non-encapsulated CICSs of the heart auricles of cardiac patients.

Conclusion

The data obtained enable us to evaluate the level of cardiomyogenesis in each individual patient. Moreover, they open up prospects for the possible use of in vitro expanded autologous TACs as a cell product for the treatment of cardiovascular diseases.

Keywords

Cardiosurgery, myocardial biopsies, cardiac stem cells, transitory amplifying cells, cardiоmyocytes, "cell-in-cell structures".

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Nemkov<sup>1</sup>, Galina B. Belostotskaya<sup>2</sup>, Alexandr V. Kriventsov<sup>1</sup>, Vladimir V. Komok<sup>1</sup>, Nikolay S. Bunenkov<sup>1</sup>, Sergey P. Marchenko<sup>1</sup>, Gelfia M. Nutfullina<sup>1</sup>, Natalia M. Paramonova<sup>2</sup>, Nikolay A. Kostin<sup>3</sup>, Dmitri A. Sibarov<sup>2</sup>, Gennady G. Khubulava<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(374) "

Aleksandr S. Nemkov1, Galina B. Belostotskaya2, Alexandr V. Kriventsov1, Vladimir V. Komok1, Nikolay S. Bunenkov1, Sergey P. Marchenko1, Gelfia M. Nutfullina1, Natalia M. Paramonova2, Nikolay A. Kostin3, Dmitri A. Sibarov2, Gennady G. Khubulava1

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Aleksandr S. Nemkov1, Galina B. Belostotskaya2, Alexandr V. Kriventsov1, Vladimir V. Komok1, Nikolay S. Bunenkov1, Sergey P. Marchenko1, Gelfia M. Nutfullina1, Natalia M. Paramonova2, Nikolay A. Kostin3, Dmitri A. Sibarov2, Gennady G. Khubulava1

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High mortality from cardiovascular diseases, due to the low regenerative potential of the myocardium, requires the search for new therapeutic approaches for the treatment of cardiac patients. Aim of the present work was to assess the regenerative potential of myocardial cells in cardiac surgery patients of middle and older age.

Materials and methods

The biopsy samples of the myocardial auricles were destroyed by enzyme technique. Confocal microscopy was performed on cells cultivated in the primary culture and on a suspension of fixed cells. In addition, histological and electron microscopic studies of myocardial biopsies were performed.

Results

Regenerative ability of cardiac cells was estimated by the presence of cardiac stem cells (CSCs), their progeny, transitory amplifying cells (TACs) inside the colonies, as well as by the presence of "cell-in-cell structures" (CICSs), which were found in each biopsy sample. In this study, in vitro experiments demonstrated the release of TACs from the vacuoles of non-encapsulated CICSs of the heart auricles of cardiac patients.

Conclusion

The data obtained enable us to evaluate the level of cardiomyogenesis in each individual patient. Moreover, they open up prospects for the possible use of in vitro expanded autologous TACs as a cell product for the treatment of cardiovascular diseases.

Keywords

Cardiosurgery, myocardial biopsies, cardiac stem cells, transitory amplifying cells, cardiоmyocytes, "cell-in-cell structures".

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High mortality from cardiovascular diseases, due to the low regenerative potential of the myocardium, requires the search for new therapeutic approaches for the treatment of cardiac patients. Aim of the present work was to assess the regenerative potential of myocardial cells in cardiac surgery patients of middle and older age.

Materials and methods

The biopsy samples of the myocardial auricles were destroyed by enzyme technique. Confocal microscopy was performed on cells cultivated in the primary culture and on a suspension of fixed cells. In addition, histological and electron microscopic studies of myocardial biopsies were performed.

Results

Regenerative ability of cardiac cells was estimated by the presence of cardiac stem cells (CSCs), their progeny, transitory amplifying cells (TACs) inside the colonies, as well as by the presence of "cell-in-cell structures" (CICSs), which were found in each biopsy sample. In this study, in vitro experiments demonstrated the release of TACs from the vacuoles of non-encapsulated CICSs of the heart auricles of cardiac patients.

Conclusion

The data obtained enable us to evaluate the level of cardiomyogenesis in each individual patient. Moreover, they open up prospects for the possible use of in vitro expanded autologous TACs as a cell product for the treatment of cardiovascular diseases.

Keywords

Cardiosurgery, myocardial biopsies, cardiac stem cells, transitory amplifying cells, cardiоmyocytes, "cell-in-cell structures".

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1 Pavlov University, St. Petersburg, Russia
2 Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Aleksandr S. Nemkov, Pavlov University, L. Tolstoy St 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 795-00-47
E-mail: nemk_as@mail.ru


Citation: Nemkov AS, Belostotskaya GB, Kriventsov AV et al. Evaluation of myocardial regenerative potential in cardiosurgery of middle-aged and elderly patients. Cell Ther Transplant 2023; 12(2): 23-31.

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1 Pavlov University, St. Petersburg, Russia
2 Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Aleksandr S. Nemkov, Pavlov University, L. Tolstoy St 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 795-00-47
E-mail: nemk_as@mail.ru


Citation: Nemkov AS, Belostotskaya GB, Kriventsov AV et al. Evaluation of myocardial regenerative potential in cardiosurgery of middle-aged and elderly patients. Cell Ther Transplant 2023; 12(2): 23-31.

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Александр С. Немков1, Галина Б. Белостоцкая2, Александр В. Кривенцов1, Владимир В. Комок1, Николай С. Буненков1, Сергей П. Марченко1, Гельфия М. Нутфуллина1, Наталья М. Парамонова2, Николай А. Костин3, Дмитрий А. Сибаров2, Геннадий Г. Хубулава1

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Александр С. Немков1, Галина Б. Белостоцкая2, Александр В. Кривенцов1, Владимир В. Комок1, Николай С. Буненков1, Сергей П. Марченко1, Гельфия М. Нутфуллина1, Наталья М. Парамонова2, Николай А. Костин3, Дмитрий А. Сибаров2, Геннадий Г. Хубулава1

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Цель работы: изучить наличие регенеративного потенциала сердца у кардиохирургических пациентов среднего и старшего возраста. </p> <h3>Материалы и методы</h3> <p style="text-align: justify;">Биопсийные образцы миокарда ушек предсердий разрушали с помощью ферментов. Конфокальную микроскопию проводили на культивируемых в первичной культуре клетках и на суспензии фиксированных клеток. Кроме того были выполнены гистологические и электронно-микроскопические исследования биоптатов миокарда.</p> <h3>Результаты</h3> <p style="text-align: justify;">Клеточный компонент регенерации в виде кардиальных стволовых клеток (КСК), их потомков – транзиторных клеток (ТК) в составе колоний, а также в виде «структур клетка-внутри-клетки» (СКВК) обнаружены в каждом биопсийном образце. В данном исследовании в экспериментах <i>in vitro</i> продемонстрировано высвобождение ТК высокого уровня зрелости из вакуолей бескапсульных СКВК ушек сердца кардиохирургических пациентов.</p> <h3>Заключение</h3> <p style="text-align: justify;">Полученные данные не только позволяют ориентировочно оценивать уровень кардиомиогенеза каждого конкретного больного, но и открывают перспективы возможного использования <i>in vitro</i> размноженных аутологичных ТК в качестве клеточного продукта для терапии сердечнососудистых заболеваний. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Кардиохирургия, биопсии миокарда, кардиальные стволовые клетки, транзиторные клетки, кардиомиоциты, структура «клетка-внутри-клетки». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3032) "

Высокая смертность от сердечнососудистых заболеваний, обусловленная низким регенеративным потенциалом миокарда, требует поиска новых терапевтических подходов для лечения кардиологических больных. Цель работы: изучить наличие регенеративного потенциала сердца у кардиохирургических пациентов среднего и старшего возраста.

Материалы и методы

Биопсийные образцы миокарда ушек предсердий разрушали с помощью ферментов. Конфокальную микроскопию проводили на культивируемых в первичной культуре клетках и на суспензии фиксированных клеток. Кроме того были выполнены гистологические и электронно-микроскопические исследования биоптатов миокарда.

Результаты

Клеточный компонент регенерации в виде кардиальных стволовых клеток (КСК), их потомков – транзиторных клеток (ТК) в составе колоний, а также в виде «структур клетка-внутри-клетки» (СКВК) обнаружены в каждом биопсийном образце. В данном исследовании в экспериментах in vitro продемонстрировано высвобождение ТК высокого уровня зрелости из вакуолей бескапсульных СКВК ушек сердца кардиохирургических пациентов.

Заключение

Полученные данные не только позволяют ориентировочно оценивать уровень кардиомиогенеза каждого конкретного больного, но и открывают перспективы возможного использования in vitro размноженных аутологичных ТК в качестве клеточного продукта для терапии сердечнососудистых заболеваний.

Ключевые слова

Кардиохирургия, биопсии миокарда, кардиальные стволовые клетки, транзиторные клетки, кардиомиоциты, структура «клетка-внутри-клетки».

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Высокая смертность от сердечнососудистых заболеваний, обусловленная низким регенеративным потенциалом миокарда, требует поиска новых терапевтических подходов для лечения кардиологических больных. Цель работы: изучить наличие регенеративного потенциала сердца у кардиохирургических пациентов среднего и старшего возраста.

Материалы и методы

Биопсийные образцы миокарда ушек предсердий разрушали с помощью ферментов. Конфокальную микроскопию проводили на культивируемых в первичной культуре клетках и на суспензии фиксированных клеток. Кроме того были выполнены гистологические и электронно-микроскопические исследования биоптатов миокарда.

Результаты

Клеточный компонент регенерации в виде кардиальных стволовых клеток (КСК), их потомков – транзиторных клеток (ТК) в составе колоний, а также в виде «структур клетка-внутри-клетки» (СКВК) обнаружены в каждом биопсийном образце. В данном исследовании в экспериментах in vitro продемонстрировано высвобождение ТК высокого уровня зрелости из вакуолей бескапсульных СКВК ушек сердца кардиохирургических пациентов.

Заключение

Полученные данные не только позволяют ориентировочно оценивать уровень кардиомиогенеза каждого конкретного больного, но и открывают перспективы возможного использования in vitro размноженных аутологичных ТК в качестве клеточного продукта для терапии сердечнососудистых заболеваний.

Ключевые слова

Кардиохирургия, биопсии миокарда, кардиальные стволовые клетки, транзиторные клетки, кардиомиоциты, структура «клетка-внутри-клетки».

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 НИИ эволюционной физиологии и биохимии им. И. М. Сеченова, Санкт-Петербург, Россия
3 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 НИИ эволюционной физиологии и биохимии им. И. М. Сеченова, Санкт-Петербург, Россия
3 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия

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Introduction

Despite advances in the field of allo-HSCT, primary and secondary graft failure (resp., PGF and SGF) remain a challenging problem with respect to life-threatening pancytopenia, prolonged hospitalization, adverse outcomes and the absence of established treatment guidelines. The incidence of this complication is reported to be from 3% to 30%, depending on numerous factors including the diagnosis, status of the disease, stem cell dose, type of HSCT, cellular and humoral rejection factors, viral infections [1]. The risk of PGF is reported to vary from 5% with myeloablative conditioning (MAC) to 10% with RIC or non-myeloablative preparative regimens (RIC) [2, 3, 4]. Al-Shaibani et al. report 100-day overall survival of 22% and 64% in primary and secondary graft failure, respectively [5].

PGF is characterized by the lack of neutrophil recovery (absolute neutrophil count <0.5 x 10*9/L), combined with the lack of donor chimerism in bone and/or peripheral blood cells (<5%) and should be distinguished from poor graft function, or cytopenia with full donor chimerism [6, 7, 8]. SGF is mono- or pancytopenia requiring transfusion of blood products, or growth factor support after achievement of sustained engraftment [6].

When PGF or SGF occurs, the treatment options available are limited and often associated with poor outcomes [9]. For patients who experience graft failure after allo-HSCT, a second transplantation may be necessary to salvage the treatment outcome. However, the efficacy and safety of second transplantations in this setting are not well established, and there are only limited data available on this topic.

The aim of the present study was to report the outcomes in a series of 49 second allo-HSCTs performed for primary or secondary graft failure, and to assess the efficacy of the procedure.

Materials and methods

Clinical features of the patients with GF

A retrospective study was conducted to evaluate the series of HSCT2 performed in 2015-2023 for primary and secondary graft failure (respectively, PGF and SGF) after allo-HSCT in 49 patients with malignant (n=43) and non-malignant diseases (n=6). PGF was defined as absolute neutrophil count (ACN) less 0.5×109/L by day +28 after HSCT, with donor chimerism <5%. SGF was defined as cytopenia with loss of donor chimerism to less 10% with no signs of relapse in case of malignant disease.

The median age of the patients was 31 years (range 18-60). Table 1 outlines the clinical characteristics of 49 recipients of HSCT2. There was a predominance of patients with acute myeloid leukemia (n=21; 44%) and other myeloproliferative neoplasms (n=15; 31%). Almost one-third of patients with malignant disorders had active underlying disease prior to HSCT (n=13; 27%).

Table 1. Demographic and clinical characteristics of the patients subjected to second HSCT

Rudakova-tab01.jpg

Conditioning regimens

The first transplant was performed with fludarabine (180 mg/m2) combined with oral busulfan (n=45), or fludarabine and other agents (n=4). Busulfan dosage was 12-14 mg/kg in 15 patients; in older patients or patients with comorbidities, or in severe aplastic anemia, the dose of busulfan was reduced to 10 mg/kg in 16 cases and 8 mg/kg in 14 cases.

Conditioning regimens for the 2nd HSCT included fludarabine (120 mg/m2) and cyclophosphamide (200 mg/m2) in 41 patients; fludarabine and melphalan (100 mg/m2) in 4 patients; fludarabine and tiotepa (n=3) and fludarabine with treosulfan (n=1).

GvHD prophylaxis

GvHD prophylaxis in the 1st HSCT was cyclophosphamide 50 mg/kg on days +3 and +4 (PtCy) alone, or in combination with other agents (n=43; 88%), anti-thymocyte globulin (n=4; 8%), TCR alfa/beta T cell depletion (n=2; 4%). In the 2nd HSCT, the patients received PtCy with or without other immunosuppressive drugs (n=37), bendamustine (n=8) or calcineurin inhibitors (n= 4).

Second transplantation

The second transplants were performed at a median interval of 43 days (range 30-137) from the first transplants, with median follow up time of 118 days (range: 36-2573). Donors for the second HSCT were haploidentical family members (n=41, 84%), mismatched unrelated donors (MMUD, n=2; 4%), matched unrelated donors (MUD, n=4, 8%), matched related donors (MRD, n=2; 4%). Secondary donor was the same in 26 patients; in 20 and 3 cases another family member or another MUD was chosen respectively.

PGF was the indication for 2nd HSCT (33 cases; 67%), and SGF patients were transplanted in 16 cases (33%). The majority of donors were haploidentical for both the first and the second HSCT. PBSC grafts were prevalent over bone marrow as the stem cell source in both 1st and 2nd transplants. A detailed description of HSCT1 and HSCT2 patients is presented in Table 2.

Table 2. Transplant details at the 1st and 2nd HSCTs in the patients with post-transplant graft failure

Rudakova-tab02.jpg

Note: NC, nucleated cells

Statistical analysis

Patient and transplant characteristics were evaluated by means of descriptive statistics. The Wilcoxon rank-sum test was used for continuous and Chi-square test for categorical factors. All patients were followed longitudinally until death, or last follow-up. Cumulative incidence rates and their 95% confidence intervals were estimated for engraftment (death before Day +30 and relapse before Day+30 were regarded as the competing risks), and for aGvHD with death and relapse as competing risks. Kaplan-Meier analysis was used to estimate overall survival (OS), and event-free survival, with relapse, acute GvHD grade III-IV, or the 3rd HSCT as an event. All statistical procedures were performed with R free software package v.4.3.0.

Rudakova-fig01.jpg

Figure 1. Overall survival rate of HSCT2 recipients at 5-year following the 1st allo-HSCT

Results

Blood recovery and early complications

Neutrophil engraftment was documented in 21 pts with cumulative incidence (CI) of 59% (95%CI, 37-77) and median time of 29 days (range, 1-55). Blood platelet counts of 20×109/L were achieved in 11 patients on day 27 (range 12-190), and the levels of 50×109/L were observed on day 31 (range 22-579) in 9 patients.

A total of 34 pts died during the follow-up period. In 31 cases, the lethal outcome was caused by infectious complications, and 3 patients died with relapse of primary disease. Early death (before D+30) occurred in 11 (22%) cases, with infectious cause of death in 10 patients (including one case of SARS-CoV2 infection), and one case of veno-occlusive disease. The overall survival (OS) was 34% (95% CI; 22-50) at one year after the 1st HSCT, and 28% (95%CI; 18-45) at 5 years after the 1st HSCT (Fig. 1).

Non-relapse mortality rate (NRM) was 65% (95% CI, 51-79) at one year after the 2nd HSCT. Event-free survival rate was 19.5% (95% CI; 10-35) at one year post-transplant (with relapse, acute GvHD III-IV or the 3rd HSCT considered an event. Infectious episodes were documented in 42 cases, while 38 patients had active infection at the time of the 2HSCT (Fig. 2). Fourteen patients underwent the 3rd HSCT, due to primary graft failure in 11 cases, and secondary graft failure in three patients.

Early post-transplant toxicity manifested as mucositis 1-3 grade (n=22; 34%), cystitis (n=6; 23%), cytokine release syndrome (n=6; 9%), venoocclusive disease (n=6; 9%), thrombotic microangiopathy (n=2; 1%), hemorrhagic complications (n=16; 25%). Cumulative incidence of acute GvHD was 25% (95% CI, 13-37). Acute GvHD grade III-IV occurred in 9 patients (18%) with involvement of the skin (n=7) and gastrointestinal tract (n=2).

Rudakova-fig02.jpg

Figure 2. Incidence of infectious complications among the patients subjected to HSCT2 (A, Infectious episodes during the first post-transplant period; B, infections by the date of HSCT2)

Infectious landscape

Majority of patients (47 of 49) had, at least, one infectious condition after HSCT1. Five patients had separate or combined bacterial, fungal and viral episodes of infections after HSCT1; 12 patients had bacterial and viral episodes. In 8 cases, bacterial and fungal episodes were documented. A total of 33 patients exhibited active bacterial infection at the time of HSCT2, while 5 patients had active bacterial and viral infection, and one patient had active combined bacterial, fungal and viral infection at the time of HSCT2 (Fig. 2). Ten patients were free of clinical infection prior to HSCT2, and engraftment rate after HSCT2 in the patients with active infection was 42% (95%CI; 24-59) versus 65% (95%CI; 17-90), p=0.57, while overall survival was 27% (95%CI; 16-47) for the group with active infection vs. 30% (95%CI; 15-47) for the group with no infection at the time of HSCT2 (p=0.8).

A total of 45 patients experienced, at least, one infectious episode after HSCT2. Of them, a single bacterial pathogen was revealed in 6 cases, 4 patients had only viral infections, isolated fungal infection was found in one case. 15 patients had both bacterial and viral infections; bacterial and fungal episodes were documented in 9 cases, combined bacterial, fungal and viral infections were registered in 10 cases. A total of 27 patients had mixed infection, of them 10 cases were caused by bacterial and fungal pathogens; 11, by bacterial and viral agents; 4, by bacterial, fungal and viral pathogens, and, 2 by viral and fungal agents. Reactivation of cytomegalovirus (CMV) was observed most frequently, occurring in 19 patients (39%), with reactivation before D+30 in 10 cases. Meanwhile, HHV6 was detected in 11 cases (22%), with early reactivation in five patients. Eight patients had other significant infections, e.g., BK virus (n=6), JC virus (n=1), SARS-CoV-2 (n=1).

Since prolonged aplasia may be associated with viral infection, we evaluated the influence of early viral reactivation occurring upon the engraftment period after HSCT2. There was no difference for engraftment rates in the subgroups with vs. without early CMV or HSV6 reactivation, 53 % (95%CI; 13-82) vs. 42% (95%CI; 26-59), p=0.84.

Donor-specific antibodies (DSA)

In 20 patients, blood serum samples were tested prior to transplant for DSA using solid-phase immunoassays. Seven patients proved to be DSA-positive (35%) and 13 patients were DSA-negative (65%). Of the 7 DSA-positive patients, three achieved engraftment at HSCT2.

Macrophages

BM aspirates were obtained from all 49 patients at a similar time period, i.e., between 2-3 weeks, both after first and second HSCT. All specimens showed reduced cellularity. As seen from Fig. 3, the median macrophage count before the second HSCT was 7.7% (range: 0.6-100) in non-engrafted patients vs. 16.5% (0.6 to 60) in engrafted ones (p=0.45). Median macrophage count after the second HSCT was 45.5% (range: 10-100) in non-engrafted patients vs. 3.75% (range: 0.04-26) in engrafted ones (p-value=0.29).

Upon univariate analysis, PBSC as a graft source compared to BM proved to be the only factor associated with better engraftment, OS and NRM rates, i.e., 50% (95%CI; 15-65) versus 26% (95%CI; 21-66, p=0.04); 41% versus 9%, p=0.04; 26% (95%CI, 12-42) vs. 57% (95%CI; 20-82, p=0.06), respectively.

Rudakova-fig03.jpg

Figure 3. Macrophage counts before (A) and after HSCT2 (B) with or without engraftment (abscissa). Ordinate, macrophage counts in bone marrow (%)

Discussion

Second HCT is frequently used to treat GF occurring after allo-HSCT. We report similar, or slightly better outcomes of HSCT2 as salvage therapy for primary and secondary GF than it was published elsewhere by Schriber et al., and Lund et al. [10, 11] who analyzed cohorts with mixed diagnoses, whereas the recent, less heterogeneous cohort studies show higher rate of engraftment (73-98%), lower rate of acute GvHD III-IV grade (8-17%) [12-14]. Nevertheless, rates of overall survival and NRM in our study were concordant with those in a study performed on behalf of the Acute Leukemia Working Party of the EBMT [12].

Infections are reported to be the main cause of death in the setting of salvage second allo-HSCT [11, 12, 14]. Our study confirms this statement by 63% (n=31) of lethal infectious complications after HSCT2. Bacterial infections were prevalent in our study. Although there is evidence of an effect of viral reactivation on the bone marrow function, our study found no association between viral reactivation and engraftment [15-17]. Post-transplant toxicity profile was acceptable with rate of VOD and TMA being not higher than in general transplant population [18, 19].

Recently, the donor-specific antibodies (DSA) have been found to be predictive of primary GF in the setting of HLA haploidentical mismatched family transplants, especially in multiply transfused patients [20]. In our study, the proportion of haploidentical allo-HSCT was relatively high. However, due to retrospective nature of the analysis, not all haploidentical cases were tested for DSA, which present a clear limitation of our study, along with small group size.

A number of studies propose "seed, soil and climate" model to describe factors influencing engraftment and functioning of the hematopoietic stem cell graft [21, 22]. The available data suggest a hypothesis about complex mechanisms which may be activated during GF involving both soluble molecules and cellular components [23, 24]. Since macrophages are known to be effector cells of IFNγ-mediated inflammatory pathway, we suggested macrophage count to be an indirect marker of primary graft failure [25, 26]. No statistically significant association between macrophage counts and engraftment was demonstrated in our study, but there was a tendency to higher macrophage numbers in non-engrafted patients after HSCT2. That finding also might result from concomitant triggers of allo-immunity, such as viral reactivation or severe bacterial infections [27].

There are several obvious limitations in this study. First, this is a retrospective study conducted at a single referral center. Second, we studied a small patient group with high heterogeneity in primary diagnoses of allo-HSCT recipients, different factors of prognosis and outcomes after allo-HSCT. Due to these limitations, only univariate analysis was performed. Usage of PBSC as a graft source proved to be the only factor, supported with a number of previous reports which showed statistically significant association with better engraftment and overall survival [28, 29].

Conclusion

Thus, being a salvage treatment of life-threatening GF, HSCT2 with RIC is a feasible treatment option which can rescue about a third of patients with primary and secondary GF after HSCT1. However, NRM remains high, mainly due to infectious complications. Further studies aiming at improved engraftment, reduction of infection rates and transplant-related toxicity are warranted, attempting for better outcomes in the patients with post-transplantation graft failure.

Conflict of interests

The authors have declared no competing interests.

Compliance with ethical standards

All human clinical studies have been approved by the appropriate institutional Ethics Committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All medical procedures performed were in accordance with the Ethical Standards of the responsible committee on human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.

References

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  2. Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015; 29(8):1754-1762. doi: 10.1038/leu.2015.75
  3. Slot S, Smits K, van de Donk NW, Witte BI, Raymakers R, Janssen JJ, et al. Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis. Bone Marrow Transplant. 2015; 50(11):1424-1431. doi: 10.1038/bmt.2015.172
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  10. Schriber J, Agovi MA, Ho V, Ballen KK, Bacigalupo A, Lazarus HM, et al. Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant. 2010;16:1099-1106. doi: 10.1016/j.bbmt.2010.02.013
  11. Lund TC, Liegel J, Bejanyan N, Orchard PJ, Cao Q, Tolar J, et al. Second allogeneic hematopoietic cell transplantation for graft failure: poor outcomes for neutropenic graft failure. Am J Hematol. 2015; 90(10):892-896. doi: 10.1002/ajh.24111
  12. Nagler A, Labopin M, Swoboda R, Kulagin A, Velardi A, Sanz J, et al. Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2023. doi: 10.1038/s41409-023-02012-5
  13. Laberko A, Sultanova E, Idarmacheva A, Skvortsova Y, Shelikhova L, Nechesnyuk A, et al. Second allogeneic hematopoietic stem cell transplantation in patients with inborn errors of immunity. Bone Marrow Transplant; 58(3), 273-281 (2023). doi: 10.1038/s41409-022-01883-4
  14. Giammarco S, Raiola AM, Di Grazia C, Bregante S, Gualandi F, Varaldo R, et al. Second haploidentical stem cell transplantation for primary graft failure. Bone Marrow Transplant. 2021; 56(6):1291-1296. doi: 10.1038/s41409-020-01183-9
  15. Dulery R, Salleron J, Dewilde A, Rossignol J, Boyle EM, Gay J, et al. Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study. Biol Blood Marrow Transplant. 2012; 18(7):1080-1089. doi: 10.1016/j.bbmt.2011.12.579
  16. Randolph-Habecker J, Iwata M, Torok-Storb B. Cytomegalovirus Mediated Myelosuppression. J Clin Virol. 2002; 25:51-56.
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  18. Mohty M, Malard F, Alaskar AS, Aljurf M, Arat M, Bader P, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2023. doi: 10.1038/s41409-023-01992-8. Epub ahead of print.
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  20. Ciurea SO, Cao K, Fernandez-Vina M, Kongtim P, Malki MA, Fuchs E, et al. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the detection and treatment of donor-specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplant. 2018; 53(5):521-534. doi: 10.1038/s41409-017-0062-8
  21. Prabahran AA, Koldej R, Chee L, Ritchie DS. Clinical features, pathophysiology and therapy of poor graft function post allogeneic stem cell transplantation. Blood Adv. 2021; 6:1947-1959. doi: 10.1182/bloodadvances.2021004537
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  24. Merli P, Caruana I, De Vito R, Strocchio L, Weber G, Bufalo FD, et al. Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation. Haematologica. 2019; 104(11):2314-2323. doi: 10.3324/haematol.2019.216101
  25. Rottman M, Soudais C, Vogt G, Renia L, Emile JF, Decaluwe H, et al. IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts. PLoS Med. 2008; 5(1):e26. doi: 10.1371/journal.pmed.0050026
  26. Liu Y, Kloc M, Li XC. Macrophages as effectors of acute and chronic allograft injury. Curr Transplant Rep. 2016; 3(4):303-312.
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  27. Lin F, Han T, Zhang Y, Cheng Y, Xu Z, Mo X, et al. The incidence, outcomes, and risk factors of secondary poor graft function in haploidentical hematopoietic stem cell transplantation for acquired aplastic anemia. Front Immunol. 2022; 13:896034.
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  28. Fuji S, Nakamura F, Hatanaka K, Taniguchi S, Sato M, Mori S, et al. Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: a retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2012;18(9):1407-1414.
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  29. Chen J, Pang A, Zhao Y, Liu L, Ma R, Wei J, et al. Primary graft failure following allogeneic hematopoietic stem cell transplantation: risk factors, treatment and outcomes. Hematology. 2022;27(1):293-299. doi: 10.1080/16078454.2022.2042064

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Introduction

Despite advances in the field of allo-HSCT, primary and secondary graft failure (resp., PGF and SGF) remain a challenging problem with respect to life-threatening pancytopenia, prolonged hospitalization, adverse outcomes and the absence of established treatment guidelines. The incidence of this complication is reported to be from 3% to 30%, depending on numerous factors including the diagnosis, status of the disease, stem cell dose, type of HSCT, cellular and humoral rejection factors, viral infections [1]. The risk of PGF is reported to vary from 5% with myeloablative conditioning (MAC) to 10% with RIC or non-myeloablative preparative regimens (RIC) [2, 3, 4]. Al-Shaibani et al. report 100-day overall survival of 22% and 64% in primary and secondary graft failure, respectively [5].

PGF is characterized by the lack of neutrophil recovery (absolute neutrophil count <0.5 x 10*9/L), combined with the lack of donor chimerism in bone and/or peripheral blood cells (<5%) and should be distinguished from poor graft function, or cytopenia with full donor chimerism [6, 7, 8]. SGF is mono- or pancytopenia requiring transfusion of blood products, or growth factor support after achievement of sustained engraftment [6].

When PGF or SGF occurs, the treatment options available are limited and often associated with poor outcomes [9]. For patients who experience graft failure after allo-HSCT, a second transplantation may be necessary to salvage the treatment outcome. However, the efficacy and safety of second transplantations in this setting are not well established, and there are only limited data available on this topic.

The aim of the present study was to report the outcomes in a series of 49 second allo-HSCTs performed for primary or secondary graft failure, and to assess the efficacy of the procedure.

Materials and methods

Clinical features of the patients with GF

A retrospective study was conducted to evaluate the series of HSCT2 performed in 2015-2023 for primary and secondary graft failure (respectively, PGF and SGF) after allo-HSCT in 49 patients with malignant (n=43) and non-malignant diseases (n=6). PGF was defined as absolute neutrophil count (ACN) less 0.5×109/L by day +28 after HSCT, with donor chimerism <5%. SGF was defined as cytopenia with loss of donor chimerism to less 10% with no signs of relapse in case of malignant disease.

The median age of the patients was 31 years (range 18-60). Table 1 outlines the clinical characteristics of 49 recipients of HSCT2. There was a predominance of patients with acute myeloid leukemia (n=21; 44%) and other myeloproliferative neoplasms (n=15; 31%). Almost one-third of patients with malignant disorders had active underlying disease prior to HSCT (n=13; 27%).

Table 1. Demographic and clinical characteristics of the patients subjected to second HSCT

Rudakova-tab01.jpg

Conditioning regimens

The first transplant was performed with fludarabine (180 mg/m2) combined with oral busulfan (n=45), or fludarabine and other agents (n=4). Busulfan dosage was 12-14 mg/kg in 15 patients; in older patients or patients with comorbidities, or in severe aplastic anemia, the dose of busulfan was reduced to 10 mg/kg in 16 cases and 8 mg/kg in 14 cases.

Conditioning regimens for the 2nd HSCT included fludarabine (120 mg/m2) and cyclophosphamide (200 mg/m2) in 41 patients; fludarabine and melphalan (100 mg/m2) in 4 patients; fludarabine and tiotepa (n=3) and fludarabine with treosulfan (n=1).

GvHD prophylaxis

GvHD prophylaxis in the 1st HSCT was cyclophosphamide 50 mg/kg on days +3 and +4 (PtCy) alone, or in combination with other agents (n=43; 88%), anti-thymocyte globulin (n=4; 8%), TCR alfa/beta T cell depletion (n=2; 4%). In the 2nd HSCT, the patients received PtCy with or without other immunosuppressive drugs (n=37), bendamustine (n=8) or calcineurin inhibitors (n= 4).

Second transplantation

The second transplants were performed at a median interval of 43 days (range 30-137) from the first transplants, with median follow up time of 118 days (range: 36-2573). Donors for the second HSCT were haploidentical family members (n=41, 84%), mismatched unrelated donors (MMUD, n=2; 4%), matched unrelated donors (MUD, n=4, 8%), matched related donors (MRD, n=2; 4%). Secondary donor was the same in 26 patients; in 20 and 3 cases another family member or another MUD was chosen respectively.

PGF was the indication for 2nd HSCT (33 cases; 67%), and SGF patients were transplanted in 16 cases (33%). The majority of donors were haploidentical for both the first and the second HSCT. PBSC grafts were prevalent over bone marrow as the stem cell source in both 1st and 2nd transplants. A detailed description of HSCT1 and HSCT2 patients is presented in Table 2.

Table 2. Transplant details at the 1st and 2nd HSCTs in the patients with post-transplant graft failure

Rudakova-tab02.jpg

Note: NC, nucleated cells

Statistical analysis

Patient and transplant characteristics were evaluated by means of descriptive statistics. The Wilcoxon rank-sum test was used for continuous and Chi-square test for categorical factors. All patients were followed longitudinally until death, or last follow-up. Cumulative incidence rates and their 95% confidence intervals were estimated for engraftment (death before Day +30 and relapse before Day+30 were regarded as the competing risks), and for aGvHD with death and relapse as competing risks. Kaplan-Meier analysis was used to estimate overall survival (OS), and event-free survival, with relapse, acute GvHD grade III-IV, or the 3rd HSCT as an event. All statistical procedures were performed with R free software package v.4.3.0.

Rudakova-fig01.jpg

Figure 1. Overall survival rate of HSCT2 recipients at 5-year following the 1st allo-HSCT

Results

Blood recovery and early complications

Neutrophil engraftment was documented in 21 pts with cumulative incidence (CI) of 59% (95%CI, 37-77) and median time of 29 days (range, 1-55). Blood platelet counts of 20×109/L were achieved in 11 patients on day 27 (range 12-190), and the levels of 50×109/L were observed on day 31 (range 22-579) in 9 patients.

A total of 34 pts died during the follow-up period. In 31 cases, the lethal outcome was caused by infectious complications, and 3 patients died with relapse of primary disease. Early death (before D+30) occurred in 11 (22%) cases, with infectious cause of death in 10 patients (including one case of SARS-CoV2 infection), and one case of veno-occlusive disease. The overall survival (OS) was 34% (95% CI; 22-50) at one year after the 1st HSCT, and 28% (95%CI; 18-45) at 5 years after the 1st HSCT (Fig. 1).

Non-relapse mortality rate (NRM) was 65% (95% CI, 51-79) at one year after the 2nd HSCT. Event-free survival rate was 19.5% (95% CI; 10-35) at one year post-transplant (with relapse, acute GvHD III-IV or the 3rd HSCT considered an event. Infectious episodes were documented in 42 cases, while 38 patients had active infection at the time of the 2HSCT (Fig. 2). Fourteen patients underwent the 3rd HSCT, due to primary graft failure in 11 cases, and secondary graft failure in three patients.

Early post-transplant toxicity manifested as mucositis 1-3 grade (n=22; 34%), cystitis (n=6; 23%), cytokine release syndrome (n=6; 9%), venoocclusive disease (n=6; 9%), thrombotic microangiopathy (n=2; 1%), hemorrhagic complications (n=16; 25%). Cumulative incidence of acute GvHD was 25% (95% CI, 13-37). Acute GvHD grade III-IV occurred in 9 patients (18%) with involvement of the skin (n=7) and gastrointestinal tract (n=2).

Rudakova-fig02.jpg

Figure 2. Incidence of infectious complications among the patients subjected to HSCT2 (A, Infectious episodes during the first post-transplant period; B, infections by the date of HSCT2)

Infectious landscape

Majority of patients (47 of 49) had, at least, one infectious condition after HSCT1. Five patients had separate or combined bacterial, fungal and viral episodes of infections after HSCT1; 12 patients had bacterial and viral episodes. In 8 cases, bacterial and fungal episodes were documented. A total of 33 patients exhibited active bacterial infection at the time of HSCT2, while 5 patients had active bacterial and viral infection, and one patient had active combined bacterial, fungal and viral infection at the time of HSCT2 (Fig. 2). Ten patients were free of clinical infection prior to HSCT2, and engraftment rate after HSCT2 in the patients with active infection was 42% (95%CI; 24-59) versus 65% (95%CI; 17-90), p=0.57, while overall survival was 27% (95%CI; 16-47) for the group with active infection vs. 30% (95%CI; 15-47) for the group with no infection at the time of HSCT2 (p=0.8).

A total of 45 patients experienced, at least, one infectious episode after HSCT2. Of them, a single bacterial pathogen was revealed in 6 cases, 4 patients had only viral infections, isolated fungal infection was found in one case. 15 patients had both bacterial and viral infections; bacterial and fungal episodes were documented in 9 cases, combined bacterial, fungal and viral infections were registered in 10 cases. A total of 27 patients had mixed infection, of them 10 cases were caused by bacterial and fungal pathogens; 11, by bacterial and viral agents; 4, by bacterial, fungal and viral pathogens, and, 2 by viral and fungal agents. Reactivation of cytomegalovirus (CMV) was observed most frequently, occurring in 19 patients (39%), with reactivation before D+30 in 10 cases. Meanwhile, HHV6 was detected in 11 cases (22%), with early reactivation in five patients. Eight patients had other significant infections, e.g., BK virus (n=6), JC virus (n=1), SARS-CoV-2 (n=1).

Since prolonged aplasia may be associated with viral infection, we evaluated the influence of early viral reactivation occurring upon the engraftment period after HSCT2. There was no difference for engraftment rates in the subgroups with vs. without early CMV or HSV6 reactivation, 53 % (95%CI; 13-82) vs. 42% (95%CI; 26-59), p=0.84.

Donor-specific antibodies (DSA)

In 20 patients, blood serum samples were tested prior to transplant for DSA using solid-phase immunoassays. Seven patients proved to be DSA-positive (35%) and 13 patients were DSA-negative (65%). Of the 7 DSA-positive patients, three achieved engraftment at HSCT2.

Macrophages

BM aspirates were obtained from all 49 patients at a similar time period, i.e., between 2-3 weeks, both after first and second HSCT. All specimens showed reduced cellularity. As seen from Fig. 3, the median macrophage count before the second HSCT was 7.7% (range: 0.6-100) in non-engrafted patients vs. 16.5% (0.6 to 60) in engrafted ones (p=0.45). Median macrophage count after the second HSCT was 45.5% (range: 10-100) in non-engrafted patients vs. 3.75% (range: 0.04-26) in engrafted ones (p-value=0.29).

Upon univariate analysis, PBSC as a graft source compared to BM proved to be the only factor associated with better engraftment, OS and NRM rates, i.e., 50% (95%CI; 15-65) versus 26% (95%CI; 21-66, p=0.04); 41% versus 9%, p=0.04; 26% (95%CI, 12-42) vs. 57% (95%CI; 20-82, p=0.06), respectively.

Rudakova-fig03.jpg

Figure 3. Macrophage counts before (A) and after HSCT2 (B) with or without engraftment (abscissa). Ordinate, macrophage counts in bone marrow (%)

Discussion

Second HCT is frequently used to treat GF occurring after allo-HSCT. We report similar, or slightly better outcomes of HSCT2 as salvage therapy for primary and secondary GF than it was published elsewhere by Schriber et al., and Lund et al. [10, 11] who analyzed cohorts with mixed diagnoses, whereas the recent, less heterogeneous cohort studies show higher rate of engraftment (73-98%), lower rate of acute GvHD III-IV grade (8-17%) [12-14]. Nevertheless, rates of overall survival and NRM in our study were concordant with those in a study performed on behalf of the Acute Leukemia Working Party of the EBMT [12].

Infections are reported to be the main cause of death in the setting of salvage second allo-HSCT [11, 12, 14]. Our study confirms this statement by 63% (n=31) of lethal infectious complications after HSCT2. Bacterial infections were prevalent in our study. Although there is evidence of an effect of viral reactivation on the bone marrow function, our study found no association between viral reactivation and engraftment [15-17]. Post-transplant toxicity profile was acceptable with rate of VOD and TMA being not higher than in general transplant population [18, 19].

Recently, the donor-specific antibodies (DSA) have been found to be predictive of primary GF in the setting of HLA haploidentical mismatched family transplants, especially in multiply transfused patients [20]. In our study, the proportion of haploidentical allo-HSCT was relatively high. However, due to retrospective nature of the analysis, not all haploidentical cases were tested for DSA, which present a clear limitation of our study, along with small group size.

A number of studies propose "seed, soil and climate" model to describe factors influencing engraftment and functioning of the hematopoietic stem cell graft [21, 22]. The available data suggest a hypothesis about complex mechanisms which may be activated during GF involving both soluble molecules and cellular components [23, 24]. Since macrophages are known to be effector cells of IFNγ-mediated inflammatory pathway, we suggested macrophage count to be an indirect marker of primary graft failure [25, 26]. No statistically significant association between macrophage counts and engraftment was demonstrated in our study, but there was a tendency to higher macrophage numbers in non-engrafted patients after HSCT2. That finding also might result from concomitant triggers of allo-immunity, such as viral reactivation or severe bacterial infections [27].

There are several obvious limitations in this study. First, this is a retrospective study conducted at a single referral center. Second, we studied a small patient group with high heterogeneity in primary diagnoses of allo-HSCT recipients, different factors of prognosis and outcomes after allo-HSCT. Due to these limitations, only univariate analysis was performed. Usage of PBSC as a graft source proved to be the only factor, supported with a number of previous reports which showed statistically significant association with better engraftment and overall survival [28, 29].

Conclusion

Thus, being a salvage treatment of life-threatening GF, HSCT2 with RIC is a feasible treatment option which can rescue about a third of patients with primary and secondary GF after HSCT1. However, NRM remains high, mainly due to infectious complications. Further studies aiming at improved engraftment, reduction of infection rates and transplant-related toxicity are warranted, attempting for better outcomes in the patients with post-transplantation graft failure.

Conflict of interests

The authors have declared no competing interests.

Compliance with ethical standards

All human clinical studies have been approved by the appropriate institutional Ethics Committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All medical procedures performed were in accordance with the Ethical Standards of the responsible committee on human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.

References

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["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29756" ["VALUE"]=> array(2) { ["TEXT"]=> string(552) "<p>Татьяна А. Рудакова, Екатерина С. Якименко, Никита П. Волков, Анастасия В. Бейнарович, Дмитрий К. Жоголев, Юлия А. Рогачева, Мария В. Барабанщикова, Юлия Ю. Власова, Александр Л. Алянский, Мария Д. Владовская, Олег В. Голощапов, Марина О. Попова, Елена В. Морозова, Иван С. Моисеев, Александр Д. Кулагин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(540) "

Татьяна А. Рудакова, Екатерина С. Якименко, Никита П. Волков, Анастасия В. Бейнарович, Дмитрий К. Жоголев, Юлия А. Рогачева, Мария В. Барабанщикова, Юлия Ю. Власова, Александр Л. Алянский, Мария Д. Владовская, Олег В. Голощапов, Марина О. Попова, Елена В. Морозова, Иван С. Моисеев, Александр Д. Кулагин

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29757" ["VALUE"]=> array(2) { ["TEXT"]=> string(373) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(361) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29758" ["VALUE"]=> array(2) { ["TEXT"]=> string(3833) "<p style="text-align: justify;"> Мы оценивали клинические исходы у 49 пациентов, перенесших аллогенную трансплантацию неманипулированных гемопоэтических стволовых клеток (алло-ТГСК) в качестве лечения спасения при первичной (ПНТ) и вторичной недостаточности трансплантата (ВНТ). Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (n=43, 88%) и незлокачественные заболевания (n=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (n=42, 86%), HLA-совместимых родственных (n=2, 4%) и неродственных (n=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5×10<sup>9</sup>/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (CI), равной 33% (95% CI: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50×10<sup>9</sup>/л было отмечено у 11 пациентов (22%). 3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях – рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% CI 51–79), годичная безрецидивная выживаемость) – 20% (95% CI 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% CI 22-50), 5-летняя ОВ – 28% (95% CI 18-45). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, CI: 31-66) по сравнению с костным мозгом (26%; 95%, CI 2-65, р=0,049).</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3753) "

Мы оценивали клинические исходы у 49 пациентов, перенесших аллогенную трансплантацию неманипулированных гемопоэтических стволовых клеток (алло-ТГСК) в качестве лечения спасения при первичной (ПНТ) и вторичной недостаточности трансплантата (ВНТ). Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (n=43, 88%) и незлокачественные заболевания (n=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (n=42, 86%), HLA-совместимых родственных (n=2, 4%) и неродственных (n=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5×109/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (CI), равной 33% (95% CI: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50×109/л было отмечено у 11 пациентов (22%). 3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях – рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% CI 51–79), годичная безрецидивная выживаемость) – 20% (95% CI 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% CI 22-50), 5-летняя ОВ – 28% (95% CI 18-45). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, CI: 31-66) по сравнению с костным мозгом (26%; 95%, CI 2-65, р=0,049).

Ключевые слова

Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы.

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Tatiana A. Rudakova, Ekaterina S. Yakimenko, Nikita P. Volkov, Anastasia V. Beinarovich, Dmitriy K. Zhogolev, Yulia A. Rogacheva, Maria V. Barabanshikova, Yulia Yu. Vlasova, Alexander L. Alyanskiy, Maria D. Vladovskaya, Oleg V. Goloshchapov, Marina O. Popova, Elena V. Morozova, Ivan S. Moiseev, Alexander D. Kulagin

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana A. Rudakova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, 197922, Russia
E-mail: t_a_rudakova@mail.ru


Citation: Rudakova TA, Yakimenko ES, Volkov NP et al. Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients. Cell Ther Transplant 2023; 12(2): 15-22.

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We have evaluated clinical outcomes in 49 patients who received unmanipulated allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a salvage treatment for primary (PGF) and secondary graft failure (SGF). The median age of patients was 31 years. Indications for the first allo-HSCT were malignant (n=43, 88%) and nonmalignant diseases (n=6, 12%). Thirteen patients with malignant diseases (27%) were in the active phase of disease. Patients with PGF received a second graft, at a median interval of 43 days (34-82) after allo-HSCT. The second allo-HSCT (HSCT2) were performed from haploidentical (n=42, 86%), HLA-matched related (n=2, 4%) and unrelated (n=5, 10%) donors. Donor-specific antibodies (DSA) before the 1st allo-HSCT (HSCT1) were examined in 21 cases, and detected in 7 patients. Donor change in 2nd HSCT was performed in 23 cases. Following HSCT2, the neutrophil counts exceeding 0.5×109/L were achieved in 21(43%) patients with a cumulative incidence (CI) of 33% (95% CI, 19-48) and median engraftment time of 29 (1-41) days; blood platelet counts over 50×109/L were achieved in 11(22%) patients. The 3rd allo-HSCT was required in 14 patients. A total of 34 patients died, the cause of death in 31 cases was infection, in three cases – relapse of the underlying disease. The one-year relapse-free survival rate after HSCT2 was 65% (95% CI 51-79), the one-year event-free survival rate) was 20% (95%CI, 11-37) with relapce, acute graft-versus-host disease (aGvHD) grade 3-4 considered as event. One-year overall survival (OS) was 33% (95% CI, 22-50), 5 year OS was 28% (95% CI, 18-45). Source of the graft was the only factor which showed an association with OS: usage of peripheral blood stem cells (50%; 95%, CI 31-66) versus bone marrow (26%; 95% CI 2-65, p=0.049).

Keywords

Graft failure, hematopoietic stem cell transplantation, allogeneic, secondary, efficiency, outcomes.

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Tatiana A. Rudakova, Ekaterina S. Yakimenko, Nikita P. Volkov, Anastasia V. Beinarovich, Dmitriy K. Zhogolev, Yulia A. Rogacheva, Maria V. Barabanshikova, Yulia Yu. Vlasova, Alexander L. Alyanskiy, Maria D. Vladovskaya, Oleg V. Goloshchapov, Marina O. Popova, Elena V. Morozova, Ivan S. Moiseev, Alexander D. Kulagin

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29762" ["VALUE"]=> array(2) { ["TEXT"]=> string(2190) "<p style="text-align: justify;"> We have evaluated clinical outcomes in 49 patients who received unmanipulated allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a salvage treatment for primary (PGF) and secondary graft failure (SGF). The median age of patients was 31 years. Indications for the first allo-HSCT were malignant (n=43, 88%) and nonmalignant diseases (n=6, 12%). Thirteen patients with malignant diseases (27%) were in the active phase of disease. Patients with PGF received a second graft, at a median interval of 43 days (34-82) after allo-HSCT. The second allo-HSCT (HSCT2) were performed from haploidentical (n=42, 86%), HLA-matched related (n=2, 4%) and unrelated (n=5, 10%) donors. Donor-specific antibodies (DSA) before the 1<sup>st</sup> allo-HSCT (HSCT1) were examined in 21 cases, and detected in 7 patients. Donor change in 2<sup>nd</sup> HSCT was performed in 23 cases. Following HSCT2, the neutrophil counts exceeding 0.5×10<sup>9</sup>/L were achieved in 21(43%) patients with a cumulative incidence (CI) of 33% (95% CI, 19-48) and median engraftment time of 29 (1-41) days; blood platelet counts over 50×10<sup>9</sup>/L were achieved in 11(22%) patients. The 3<sup>rd</sup> allo-HSCT was required in 14 patients. A total of 34 patients died, the cause of death in 31 cases was infection, in three cases – relapse of the underlying disease. The one-year relapse-free survival rate after HSCT2 was 65% (95% CI 51-79), the one-year event-free survival rate) was 20% (95%CI, 11-37) with relapce, acute graft-versus-host disease (aGvHD) grade 3-4 considered as event. One-year overall survival (OS) was 33% (95% CI, 22-50), 5 year OS was 28% (95% CI, 18-45). Source of the graft was the only factor which showed an association with OS: usage of peripheral blood stem cells (50%; 95%, CI 31-66) <i>versus </i>bone marrow (26%; 95% CI 2-65, p=0.049). </p> <h2>Keywords</h2> <p style="text-align: justify;"> Graft failure, hematopoietic stem cell transplantation, allogeneic, secondary, efficiency, outcomes. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2062) "

We have evaluated clinical outcomes in 49 patients who received unmanipulated allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a salvage treatment for primary (PGF) and secondary graft failure (SGF). The median age of patients was 31 years. Indications for the first allo-HSCT were malignant (n=43, 88%) and nonmalignant diseases (n=6, 12%). Thirteen patients with malignant diseases (27%) were in the active phase of disease. Patients with PGF received a second graft, at a median interval of 43 days (34-82) after allo-HSCT. The second allo-HSCT (HSCT2) were performed from haploidentical (n=42, 86%), HLA-matched related (n=2, 4%) and unrelated (n=5, 10%) donors. Donor-specific antibodies (DSA) before the 1st allo-HSCT (HSCT1) were examined in 21 cases, and detected in 7 patients. Donor change in 2nd HSCT was performed in 23 cases. Following HSCT2, the neutrophil counts exceeding 0.5×109/L were achieved in 21(43%) patients with a cumulative incidence (CI) of 33% (95% CI, 19-48) and median engraftment time of 29 (1-41) days; blood platelet counts over 50×109/L were achieved in 11(22%) patients. The 3rd allo-HSCT was required in 14 patients. A total of 34 patients died, the cause of death in 31 cases was infection, in three cases – relapse of the underlying disease. The one-year relapse-free survival rate after HSCT2 was 65% (95% CI 51-79), the one-year event-free survival rate) was 20% (95%CI, 11-37) with relapce, acute graft-versus-host disease (aGvHD) grade 3-4 considered as event. One-year overall survival (OS) was 33% (95% CI, 22-50), 5 year OS was 28% (95% CI, 18-45). Source of the graft was the only factor which showed an association with OS: usage of peripheral blood stem cells (50%; 95%, CI 31-66) versus bone marrow (26%; 95% CI 2-65, p=0.049).

Keywords

Graft failure, hematopoietic stem cell transplantation, allogeneic, secondary, efficiency, outcomes.

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We have evaluated clinical outcomes in 49 patients who received unmanipulated allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a salvage treatment for primary (PGF) and secondary graft failure (SGF). The median age of patients was 31 years. Indications for the first allo-HSCT were malignant (n=43, 88%) and nonmalignant diseases (n=6, 12%). Thirteen patients with malignant diseases (27%) were in the active phase of disease. Patients with PGF received a second graft, at a median interval of 43 days (34-82) after allo-HSCT. The second allo-HSCT (HSCT2) were performed from haploidentical (n=42, 86%), HLA-matched related (n=2, 4%) and unrelated (n=5, 10%) donors. Donor-specific antibodies (DSA) before the 1st allo-HSCT (HSCT1) were examined in 21 cases, and detected in 7 patients. Donor change in 2nd HSCT was performed in 23 cases. Following HSCT2, the neutrophil counts exceeding 0.5×109/L were achieved in 21(43%) patients with a cumulative incidence (CI) of 33% (95% CI, 19-48) and median engraftment time of 29 (1-41) days; blood platelet counts over 50×109/L were achieved in 11(22%) patients. The 3rd allo-HSCT was required in 14 patients. A total of 34 patients died, the cause of death in 31 cases was infection, in three cases – relapse of the underlying disease. The one-year relapse-free survival rate after HSCT2 was 65% (95% CI 51-79), the one-year event-free survival rate) was 20% (95%CI, 11-37) with relapce, acute graft-versus-host disease (aGvHD) grade 3-4 considered as event. One-year overall survival (OS) was 33% (95% CI, 22-50), 5 year OS was 28% (95% CI, 18-45). Source of the graft was the only factor which showed an association with OS: usage of peripheral blood stem cells (50%; 95%, CI 31-66) versus bone marrow (26%; 95% CI 2-65, p=0.049).

Keywords

Graft failure, hematopoietic stem cell transplantation, allogeneic, secondary, efficiency, outcomes.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana A. Rudakova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, 197922, Russia
E-mail: t_a_rudakova@mail.ru


Citation: Rudakova TA, Yakimenko ES, Volkov NP et al. Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients. Cell Ther Transplant 2023; 12(2): 15-22.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana A. Rudakova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, 197922, Russia
E-mail: t_a_rudakova@mail.ru


Citation: Rudakova TA, Yakimenko ES, Volkov NP et al. Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients. Cell Ther Transplant 2023; 12(2): 15-22.

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Татьяна А. Рудакова, Екатерина С. Якименко, Никита П. Волков, Анастасия В. Бейнарович, Дмитрий К. Жоголев, Юлия А. Рогачева, Мария В. Барабанщикова, Юлия Ю. Власова, Александр Л. Алянский, Мария Д. Владовская, Олег В. Голощапов, Марина О. Попова, Елена В. Морозова, Иван С. Моисеев, Александр Д. Кулагин

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Татьяна А. Рудакова, Екатерина С. Якименко, Никита П. Волков, Анастасия В. Бейнарович, Дмитрий К. Жоголев, Юлия А. Рогачева, Мария В. Барабанщикова, Юлия Ю. Власова, Александр Л. Алянский, Мария Д. Владовская, Олег В. Голощапов, Марина О. Попова, Елена В. Морозова, Иван С. Моисеев, Александр Д. Кулагин

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Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (n=43, 88%) и незлокачественные заболевания (n=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (n=42, 86%), HLA-совместимых родственных (n=2, 4%) и неродственных (n=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5×10<sup>9</sup>/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (CI), равной 33% (95% CI: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50×10<sup>9</sup>/л было отмечено у 11 пациентов (22%). 3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях – рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% CI 51–79), годичная безрецидивная выживаемость) – 20% (95% CI 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% CI 22-50), 5-летняя ОВ – 28% (95% CI 18-45). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, CI: 31-66) по сравнению с костным мозгом (26%; 95%, CI 2-65, р=0,049).</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3753) "

Мы оценивали клинические исходы у 49 пациентов, перенесших аллогенную трансплантацию неманипулированных гемопоэтических стволовых клеток (алло-ТГСК) в качестве лечения спасения при первичной (ПНТ) и вторичной недостаточности трансплантата (ВНТ). Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (n=43, 88%) и незлокачественные заболевания (n=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (n=42, 86%), HLA-совместимых родственных (n=2, 4%) и неродственных (n=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5×109/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (CI), равной 33% (95% CI: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50×109/л было отмечено у 11 пациентов (22%). 3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях – рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% CI 51–79), годичная безрецидивная выживаемость) – 20% (95% CI 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% CI 22-50), 5-летняя ОВ – 28% (95% CI 18-45). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, CI: 31-66) по сравнению с костным мозгом (26%; 95%, CI 2-65, р=0,049).

Ключевые слова

Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы.

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Мы оценивали клинические исходы у 49 пациентов, перенесших аллогенную трансплантацию неманипулированных гемопоэтических стволовых клеток (алло-ТГСК) в качестве лечения спасения при первичной (ПНТ) и вторичной недостаточности трансплантата (ВНТ). Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (n=43, 88%) и незлокачественные заболевания (n=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (n=42, 86%), HLA-совместимых родственных (n=2, 4%) и неродственных (n=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5×109/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (CI), равной 33% (95% CI: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50×109/л было отмечено у 11 пациентов (22%). 3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях – рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% CI 51–79), годичная безрецидивная выживаемость) – 20% (95% CI 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% CI 22-50), 5-летняя ОВ – 28% (95% CI 18-45). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, CI: 31-66) по сравнению с костным мозгом (26%; 95%, CI 2-65, р=0,049).

Ключевые слова

Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease based on reciprocal translocation producing a chimeric BCR-ABL gene encoding a mutant tyrosine kinase, which leads to intensive proliferation of granulocytic cells and their impaired maturation. CML is a rare disease in children and adolescents, which occurs, respectively, in 2% and 9% of all pediatric leukemias. The annual incidence of CML in this group increases with age (from 1 per million cases under 15 years to 2.5/Mio at the age of 15 to 19 years old). Pediatric CML occurs at the mean age of 10-12 years [1-3, 6]. According to the diagnostic criteria and classification principles adopted by European LeukemiaNet (ELN), 3 phases are distinguished (Table 1): chronic phase (CP), acceleration phase (AP), blast transformation phase or blast crisis (BC) [4]

Table 1. CML classification by clinical phases (ELN 2020)

Sheveleva-tab01.jpg

Clinical course of CML in children and adolescents is more aggressive than in adults manifesting by a higher degree of anemia, hyperleukocytosis in combination with thrombocytosis and splenomegaly. In patients under 18 years of age, the advanced stage (AP, BC) accounts for up to 7.5% of newly diagnosed cases of CML, compared with 5.7% in adult patients [5-10]. The aggressive onset of CML disease in the pediatric group may be associated with molecular biological features, i.e., bimodal distribution of breakpoints in the BCR gene in prepubertal children, different profile of CD34+ cell gene expression and cytogenetic landscape, dysregulation of the Rho signaling pathway, prevalence of ASXL1 gene mutations in chronic phase of CML (29% of cases <18 years old; 7 to 13% in older groups). However, the prognostic significance of molecular biological features in CML children and adolescents is still controversial [1, 11-14, 18].

Over the past 20 years, tyrosine kinase inhibitors (TKIs) have been the standard first-line therapy for CML, which have shown high efficacy [4, 15]. For children and adolescents with newly diagnosed chronic phase CML, only three TKIs have been approved by the Food and Drug Administration (FDA) (Imatinib since 2003, Dasatinib since 2017, Nilotinib since 2018). So far, some issues of TKI therapy remain unresolved, especially in pediatric cohort, such as hematological and non-hematological toxicity, long-term side effects, primary and secondary resistance [16-22]. The experience of CML therapy in children and adolescents is limited in Russian Federation. Therefore, the existing Federal Clinical Guidelines are based on the experience of therapy in adult patients [23-27].

Among potential biological factors of the drug resistance, mutations in the kinase domain of BCR-ABL are the most studied [28]. A number of studies show that, in adult patients with CML, BCR-ABL-dependent resistance to imatinib occurs in 12% to 63% of TKI-treated cases, resistance to nilotinib or dasatinib is observed from 14 to 33% [29]. In pediatric group with CML progression to blast crisis, mutations in the BCR-ABL kinase domain are detected in 60% of cases [30, 31].

A common prognostically unfavorable mutation causes resistance to the first-generation TKIs (TKI 1, imatinib), and second-generation drugs (TKI 2, nilotinib, dasatinib and bosutinib). It represents threonine-to-isoleucine substitution at position 315 (T315I). The frequency of the T315I mutation in the adult cohort of patients with CML in most studies ranges from 3 to 15%, depending on the sensitivity of the analytical methods [32, 33]. However, in one of the studies, the detection rate of the T315I mutation was as high as 43.4% [34]. In the world literature, there are no data on the occurrence of the T315I mutation in children and adolescents with CML, only 7 cases have been published (one case with CP CML; one patients with AP CML, and 5 children with BC CML) [35-38].

At the present time, two 3rd-generation TKIs are adopted by FDA for treatment of adult CML patients with T315I mutation, i.e., ponatinib (since 2012), and asciminib (since 2021), which showed appropriate efficiency. Ponatinib therapy is associated with higher response rates but less satisfactory safety profile (high incidence of cardiovascular adverse effects) when compared with asciminib [39-40]. In pediatric CML patients, clinical trials are performed, with respect to efficiency and safety of ponatinib in chronic and advanced phase (NCT03934372), and asciminib treatment only in first chronic phase without T315I mutation (NCT04925479). So far, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only curative therapeutic option for pediatric and adolescent patients with CML harboring T315I mutation.

Due to rarity of this condition in children and adolescents, absence of appropriate therapeutic standards and limited number of randomized clinical studies in this cohort, we would like to present three clinical cases.

Clinical case 1

A female patient was born in 2013. The disease manifested since 5 years old with persistent fewer, pronounced hepato- and splenomegaly. The liver protrusion was 2 cm; spleen emerged by 18 cm under the costal arch. Blood counts were as follows: Hb, 86 g/L; platelets, 599×109/L; leukocytes, 35×109/L; blast cells, 14%; promyelocytes, 2%; myelocytes, 8%; young myelocytes, 2%; monocytes, 4%; basophyls, 11%; eosinophiles, 2%; lymphocytes, 17%. Blood biochemistry revealed a 6-fold increase of lactate dehydrogenase from upper reference values.

A trephine biopsy was carried out in order to specify fibrotic changes in bone marrow. Histological examination of the biopsy revealed massive deposits of megakaryocytes. The cells are enlarged, contain one or two nuclei/nuclear lobes, nearly filling the lacunar lumens (Fig. 1 A, B and C); focal clusters of granulocytic cells are also observed, mostly, at intermediate differentiation steps. Some small groups or single erythroid cells are seen. There are scarce cells with blast morphology, as well as single plasmatic cells. Interstitially located lymphoid cells are observed in small amounts.

Sheveleva-fig01.jpg

Figure 1. Patient 1, trephine biopsy histology. A, multiple large megakaryocytes with 1-2 nuclei/lobes are seen in the lacunar lumen (magnification 200x); B, the megakaryocytes are filling the lacunar lumen (Azur-Eosin staining, magnification 200x); C, megakaryocytes are labeled with CD42b-specific antibodies (immunoperoxidase staining, 100x magnification)

Sheveleva-fig02.jpg

Figure 2. Patient 1, fibrotic changes in bone marrow (staining by Gomori method, 200 x magnification)

Upon silver impregnation, a dense network of partially crossed reticulin fibers with focal and crude collagen bundles was revealed, thus corresponding to MF2 (70%) and MF3 (30%) by the European Consensus on grading of bone marrow fibrosis (Fig. 2).

Standard cytogenetic examination of bone marrow samples revealed an abnormal clone with reciprocal t(9;22) translocation in 100% of metaphases. Molecular biology studies using real-time PCR detected overexpression of WT1 gene, as well as t(9;22) BCR-ABL1 p190 и p210 transcripts, with relative expression levels of chimeric BCR/ABL of 0.1893 and 55.7452 (50% expression as BCR-ABL1 on the International Scale, IS).On the basis of clinical and laboratory data, the diagnosis of chronic myeloid leukemia (acceleration phase) was assessed by the accepted ELN 2020 criteria.

The first-line therapy included imatinib, the 1st generation TKI, starting with daily dose of 340 mg/m2. The dynamics of response to imatinib determined by the ELN criteria, was as follows: at 1 month, clinical improvement was observed (decreased hepatosplenomegaly, absence of leukocytosis, myelocytic shift, blast cells and basophil/eosinophilic association in peripheral blood); at 3 months, absence of complete hematological response (platelet counts increased to 1929×109/L) and cytogenetic response (Ph+ cells, 100) was documented; at 6 months, thrombocytosis still persisted (900×109/L) with minimal cytogenetic response (Ph+ cells, 90%), the levels of chimeric BCR-ABL1 transcript showed a decrease with time (Table 2).

Table 2. Time dynamics (months) of BCR-ABL1 gene expression upon treatment with TKI drugs of the patient No.1

Sheveleva-tab02.jpg

Hence, the patient lacked clinical response to the TKI 1 treatment thus requiring escalated daily dosage of imatinib (520 mg/m2/day) followed by switching to TKI 2 (nilotinib) at a dose 230 mg/m2/twice-daily. However, regular therapy with nilotinib at the recommended dose was not feasible due to grade 4 neutropenia. The nilotinib treatment resulted into a complete hematological and cytogenetic response within 3 months. The in-depth study of mutational status at 3, 6 and 12 months of targeted therapy did not reveal any mutations of chimeric BCR-ABL, and ASXL, JAK2 genes (exones 12 and 14).

16 months after commencing the target therapy, we have registered loss of complete cytogenetic response, along with decreased BCR-ABL1 expression (Table 2). Meanwhile, the T315I (944C>T) mutation of BCR-ABL was revealed by means of direct Sanger sequencing.

According to the toxicity criteria (NCI CTCAE), the targeted therapy was accompanied by hematological and non-hematological toxicities (Table 3).

Table 3. Toxicity profile in the TKI-treated patient No.1 (NCI CTCAE)

Sheveleva-tab03.jpg

Secondary resistance to TKI drugs associated with T315I mutation of BCR-ABL gene kinase domain was a pre-requisite for allo-HSCT. A fully HLA-compatible donor was found in an international registry. At the age of 7 years, i.e., 1 year 10 months after CML diagnosis, allogeneic HSCT was performed. General somatic status (Karnofsky scale, Lansky modification) before allo-HSCT was 100%. The patient was underwent a reduced-intensity conditioning regimen (fludarabine, 150 mg/m2, busulfan, 10 mg/kg). Peripheral blood stem cells (PBSCs) have been collected in a male donor. Total number of transplated CD34+ cells, was 10.2×106/kg of recipient weight. To prevent GvHD, we performed a multi-component immunosuppressive therapy, i.e., cyclophosphamide (PTCy) on the day +3 and +4 post-transplant, mycophenolate mofetil (MMF) and tacrolimus since day 5. Engraftment was achieved on day +19. Restaging of disease (day+21) revealed mixed donor chimerism (90-97%), complete hematologic, сomplete cytogenetic and molecular response. Early post-transplant period was complicated on day +12 by febrile neutropenia and Grade 1 oral mucositis.

Upon complete canceling of immunosuppressive therapy (MMF, by day+45; tacrolimus, by day+90), full donor chimerism was achieved by the day+180. Targeted therapy with TKIs was not performed during the post-transplant period. The follow-up after HSCT lasting for 1 year 10 months showed a satisfactory graft functioning, full donor chimerism, absence of GvHD, and complete response (hematologic, cytogenetic, molecular) in CML.

Clinical case 2

Male patient, born in 1990. CML (chronic phase) was diagnosed at the age of 15. The onset of disease manifested by pronounced hepato- and splenomegaly, with liver protrusion of 5 cm, and the spleen emerged by 25 cm under the costal arch. We observed hyperleukocytosis up to 500×109/L, increase of platelet counts to 794×109/L, blast cells in peripheral blood (up to 6%).

The therapy was carried out at the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology from 2005 to 2009. Cytoreductive treatment was performed with hydroxyurea. At the 1st line of therapy, the TKI 1 (imatinib) was used at a daily dose of 400 mg. The dynamics of response, according to ELN 2020 criteria was as follows: at 1 month, complete hematological response; at 12 months, minimal cytogenetic response. Imatinib dose was escalated to 600 mg daily, with subsequent switch to dasatinib (TKI 2) at a daily dose of 100 mg. During treatment with TKI 2, a progression of CML to acceleration phase was observed, along with emergence of accessory chromosomal aberration (+der22), and T315I mutation of the BCR-ABL kinase domain.

A secondary TKI drug resistance associated with T315I mutation of BCR-ABL chimeric gene was an indication for allogeneic HSCT. Prior to HSCT, chemotherapy was performed using the 5+2 protocol (cytarabine and daunorubicin) and hydroxyurea treatment. There was no available HLA-matched donor. Therefore, allo-HSCT from haploidentical donor was carried out at the age of 17 years, i.e., 2 years 8 months after CML diagnosis. Karnofsky performance status was 80% before allo-HSCT.

Due to non-engraftment of the transplant, the 2nd HSCT was performed from the same donor, with achieving engraftment of stem cells by the day+13. Due to rejection of the second graft, a 3rd transplantation from another donor was carried out on the day +44 after the 2nd HSCT. This time, the engraftment proceeded on day+12 after 3rd HSCT. Table 4 presents general parameters of transplants, the drugs used for conditioning and GvHD prevention.

The posttransplant period was complicated by the grade 4 gastrointestinal mucositis, septicemia documented on day+5, generalized non-controlled infection (catheter-associated bloodstream infection with P.aeruginosa and S. epidermidis on day+5), left-sided purulent parotitis on day+18, cytomegalovirus disease with lung affection on day+31. Despite combination antimicrobial therapy, the lethal outcome was registered on day+51.

Table 4. Characteristics of HSCT in clinical case 2

Sheveleva-tab04.jpg

Clinical case 3

A boy, born in 1995. At the age of 12 years, CML (acceleration phase) was diagnosed. The onset of disease was characterized by hyperleukocytosis (up to 99×109/L), blast cells in peripheral blood (12%) and in bone marrow (27%). Over the period of 2007 to 2010, the treatment was performed at the place of residence. A complete hematological response was obtained during chemotherapy which included the ADE (cytarabine, daunorubicin, and etoposide) protocol and imatinib (400 mg daily). Due to absence of complete cytogenetic and molecular response, the second-line treatment was performed with 2nd-generation TKI (dasatinib) at a dose of 100 mg/day. The molecular biology studies showed a T315I mutation of BCR-ABL.

In 2011, the patient was consulted at the R. Gorbacheva Memorial Research Institute where allogeneic HSCT was recommended due to secondary TKI resistance associated with T315I mutation. An unrelated, fully HLA-compatible male donor was found in an international registry. The patient underwent allo-HSCT at the age of 16, i.e., 3 years 8 months after primary diagnosis. The Karnofsky performance status was 80% prior to HSCT.

Myeloablative conditioning treatment included cyclophosphamide (120 mg/kg) and busulfan (16 mg/kg). Bone marrow was the source of hematopoietic cells. The number of transfused CD34+ cells was 7.8×106/kg weight of the recipient. MMF and tacrolimus were used for the GvHD prophylaxis. Antithymocyte immunoglobulin was applied as serotherapy.

Engraftment following HSCT was achieved on day +13. The restaging on day+21 has revealed full donor chimerism and complete response (hematologic, cytogenetic, molecular) in CML.

The posttransplant period was complicated by the febrile neutropenia, stage 2 gastrointestinal mucositis, acute GvHD (grade 4) on day+17 with grade 3 skin affection and gastrointestinal stage 4, hemorrhagic cystitis on day +21. Despite the combined immunosuppressive therapy (glucocorticosteroids, MMF, infliximab, alemtuzumab), the patient’s condition was not stabilized, and a lethal outcome was registered on the day +34 after HSCT.

Conclusion

Despite the advent of TKI therapy, the issue of evolving drug resistance still remains quite difficult. Therefore, molecular studies are required in order to detect the resistance mutations of BCR-ABL kinase domain and beyond it. The T315I mutation of BCR-ABL is characterized by aggressive course of CML. Currently allo-HSCT is the only effective and available therapeutic option for the pediatric and adolescent patients with secondary TKI resistance. Clinical success of allo-HSCT directly depends on the following factors: Karnofsky (Lansky) performance status of the patient; phase of the disease, optimal donor choice, conditioning regimen, and GvHD prophylaxis. Allo-HSCT with reduced-intensity conditioning and GvHD prevention with posttransplant cyclophosphamide may reduce risks of emerging complications associated with high lethality during early posttransplant period, in particular, preventing the development of acute and chronic GvHD.

Conflict of interest

None declared.

References

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Introduction

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease based on reciprocal translocation producing a chimeric BCR-ABL gene encoding a mutant tyrosine kinase, which leads to intensive proliferation of granulocytic cells and their impaired maturation. CML is a rare disease in children and adolescents, which occurs, respectively, in 2% and 9% of all pediatric leukemias. The annual incidence of CML in this group increases with age (from 1 per million cases under 15 years to 2.5/Mio at the age of 15 to 19 years old). Pediatric CML occurs at the mean age of 10-12 years [1-3, 6]. According to the diagnostic criteria and classification principles adopted by European LeukemiaNet (ELN), 3 phases are distinguished (Table 1): chronic phase (CP), acceleration phase (AP), blast transformation phase or blast crisis (BC) [4]

Table 1. CML classification by clinical phases (ELN 2020)

Sheveleva-tab01.jpg

Clinical course of CML in children and adolescents is more aggressive than in adults manifesting by a higher degree of anemia, hyperleukocytosis in combination with thrombocytosis and splenomegaly. In patients under 18 years of age, the advanced stage (AP, BC) accounts for up to 7.5% of newly diagnosed cases of CML, compared with 5.7% in adult patients [5-10]. The aggressive onset of CML disease in the pediatric group may be associated with molecular biological features, i.e., bimodal distribution of breakpoints in the BCR gene in prepubertal children, different profile of CD34+ cell gene expression and cytogenetic landscape, dysregulation of the Rho signaling pathway, prevalence of ASXL1 gene mutations in chronic phase of CML (29% of cases <18 years old; 7 to 13% in older groups). However, the prognostic significance of molecular biological features in CML children and adolescents is still controversial [1, 11-14, 18].

Over the past 20 years, tyrosine kinase inhibitors (TKIs) have been the standard first-line therapy for CML, which have shown high efficacy [4, 15]. For children and adolescents with newly diagnosed chronic phase CML, only three TKIs have been approved by the Food and Drug Administration (FDA) (Imatinib since 2003, Dasatinib since 2017, Nilotinib since 2018). So far, some issues of TKI therapy remain unresolved, especially in pediatric cohort, such as hematological and non-hematological toxicity, long-term side effects, primary and secondary resistance [16-22]. The experience of CML therapy in children and adolescents is limited in Russian Federation. Therefore, the existing Federal Clinical Guidelines are based on the experience of therapy in adult patients [23-27].

Among potential biological factors of the drug resistance, mutations in the kinase domain of BCR-ABL are the most studied [28]. A number of studies show that, in adult patients with CML, BCR-ABL-dependent resistance to imatinib occurs in 12% to 63% of TKI-treated cases, resistance to nilotinib or dasatinib is observed from 14 to 33% [29]. In pediatric group with CML progression to blast crisis, mutations in the BCR-ABL kinase domain are detected in 60% of cases [30, 31].

A common prognostically unfavorable mutation causes resistance to the first-generation TKIs (TKI 1, imatinib), and second-generation drugs (TKI 2, nilotinib, dasatinib and bosutinib). It represents threonine-to-isoleucine substitution at position 315 (T315I). The frequency of the T315I mutation in the adult cohort of patients with CML in most studies ranges from 3 to 15%, depending on the sensitivity of the analytical methods [32, 33]. However, in one of the studies, the detection rate of the T315I mutation was as high as 43.4% [34]. In the world literature, there are no data on the occurrence of the T315I mutation in children and adolescents with CML, only 7 cases have been published (one case with CP CML; one patients with AP CML, and 5 children with BC CML) [35-38].

At the present time, two 3rd-generation TKIs are adopted by FDA for treatment of adult CML patients with T315I mutation, i.e., ponatinib (since 2012), and asciminib (since 2021), which showed appropriate efficiency. Ponatinib therapy is associated with higher response rates but less satisfactory safety profile (high incidence of cardiovascular adverse effects) when compared with asciminib [39-40]. In pediatric CML patients, clinical trials are performed, with respect to efficiency and safety of ponatinib in chronic and advanced phase (NCT03934372), and asciminib treatment only in first chronic phase without T315I mutation (NCT04925479). So far, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only curative therapeutic option for pediatric and adolescent patients with CML harboring T315I mutation.

Due to rarity of this condition in children and adolescents, absence of appropriate therapeutic standards and limited number of randomized clinical studies in this cohort, we would like to present three clinical cases.

Clinical case 1

A female patient was born in 2013. The disease manifested since 5 years old with persistent fewer, pronounced hepato- and splenomegaly. The liver protrusion was 2 cm; spleen emerged by 18 cm under the costal arch. Blood counts were as follows: Hb, 86 g/L; platelets, 599×109/L; leukocytes, 35×109/L; blast cells, 14%; promyelocytes, 2%; myelocytes, 8%; young myelocytes, 2%; monocytes, 4%; basophyls, 11%; eosinophiles, 2%; lymphocytes, 17%. Blood biochemistry revealed a 6-fold increase of lactate dehydrogenase from upper reference values.

A trephine biopsy was carried out in order to specify fibrotic changes in bone marrow. Histological examination of the biopsy revealed massive deposits of megakaryocytes. The cells are enlarged, contain one or two nuclei/nuclear lobes, nearly filling the lacunar lumens (Fig. 1 A, B and C); focal clusters of granulocytic cells are also observed, mostly, at intermediate differentiation steps. Some small groups or single erythroid cells are seen. There are scarce cells with blast morphology, as well as single plasmatic cells. Interstitially located lymphoid cells are observed in small amounts.

Sheveleva-fig01.jpg

Figure 1. Patient 1, trephine biopsy histology. A, multiple large megakaryocytes with 1-2 nuclei/lobes are seen in the lacunar lumen (magnification 200x); B, the megakaryocytes are filling the lacunar lumen (Azur-Eosin staining, magnification 200x); C, megakaryocytes are labeled with CD42b-specific antibodies (immunoperoxidase staining, 100x magnification)

Sheveleva-fig02.jpg

Figure 2. Patient 1, fibrotic changes in bone marrow (staining by Gomori method, 200 x magnification)

Upon silver impregnation, a dense network of partially crossed reticulin fibers with focal and crude collagen bundles was revealed, thus corresponding to MF2 (70%) and MF3 (30%) by the European Consensus on grading of bone marrow fibrosis (Fig. 2).

Standard cytogenetic examination of bone marrow samples revealed an abnormal clone with reciprocal t(9;22) translocation in 100% of metaphases. Molecular biology studies using real-time PCR detected overexpression of WT1 gene, as well as t(9;22) BCR-ABL1 p190 и p210 transcripts, with relative expression levels of chimeric BCR/ABL of 0.1893 and 55.7452 (50% expression as BCR-ABL1 on the International Scale, IS).On the basis of clinical and laboratory data, the diagnosis of chronic myeloid leukemia (acceleration phase) was assessed by the accepted ELN 2020 criteria.

The first-line therapy included imatinib, the 1st generation TKI, starting with daily dose of 340 mg/m2. The dynamics of response to imatinib determined by the ELN criteria, was as follows: at 1 month, clinical improvement was observed (decreased hepatosplenomegaly, absence of leukocytosis, myelocytic shift, blast cells and basophil/eosinophilic association in peripheral blood); at 3 months, absence of complete hematological response (platelet counts increased to 1929×109/L) and cytogenetic response (Ph+ cells, 100) was documented; at 6 months, thrombocytosis still persisted (900×109/L) with minimal cytogenetic response (Ph+ cells, 90%), the levels of chimeric BCR-ABL1 transcript showed a decrease with time (Table 2).

Table 2. Time dynamics (months) of BCR-ABL1 gene expression upon treatment with TKI drugs of the patient No.1

Sheveleva-tab02.jpg

Hence, the patient lacked clinical response to the TKI 1 treatment thus requiring escalated daily dosage of imatinib (520 mg/m2/day) followed by switching to TKI 2 (nilotinib) at a dose 230 mg/m2/twice-daily. However, regular therapy with nilotinib at the recommended dose was not feasible due to grade 4 neutropenia. The nilotinib treatment resulted into a complete hematological and cytogenetic response within 3 months. The in-depth study of mutational status at 3, 6 and 12 months of targeted therapy did not reveal any mutations of chimeric BCR-ABL, and ASXL, JAK2 genes (exones 12 and 14).

16 months after commencing the target therapy, we have registered loss of complete cytogenetic response, along with decreased BCR-ABL1 expression (Table 2). Meanwhile, the T315I (944C>T) mutation of BCR-ABL was revealed by means of direct Sanger sequencing.

According to the toxicity criteria (NCI CTCAE), the targeted therapy was accompanied by hematological and non-hematological toxicities (Table 3).

Table 3. Toxicity profile in the TKI-treated patient No.1 (NCI CTCAE)

Sheveleva-tab03.jpg

Secondary resistance to TKI drugs associated with T315I mutation of BCR-ABL gene kinase domain was a pre-requisite for allo-HSCT. A fully HLA-compatible donor was found in an international registry. At the age of 7 years, i.e., 1 year 10 months after CML diagnosis, allogeneic HSCT was performed. General somatic status (Karnofsky scale, Lansky modification) before allo-HSCT was 100%. The patient was underwent a reduced-intensity conditioning regimen (fludarabine, 150 mg/m2, busulfan, 10 mg/kg). Peripheral blood stem cells (PBSCs) have been collected in a male donor. Total number of transplated CD34+ cells, was 10.2×106/kg of recipient weight. To prevent GvHD, we performed a multi-component immunosuppressive therapy, i.e., cyclophosphamide (PTCy) on the day +3 and +4 post-transplant, mycophenolate mofetil (MMF) and tacrolimus since day 5. Engraftment was achieved on day +19. Restaging of disease (day+21) revealed mixed donor chimerism (90-97%), complete hematologic, сomplete cytogenetic and molecular response. Early post-transplant period was complicated on day +12 by febrile neutropenia and Grade 1 oral mucositis.

Upon complete canceling of immunosuppressive therapy (MMF, by day+45; tacrolimus, by day+90), full donor chimerism was achieved by the day+180. Targeted therapy with TKIs was not performed during the post-transplant period. The follow-up after HSCT lasting for 1 year 10 months showed a satisfactory graft functioning, full donor chimerism, absence of GvHD, and complete response (hematologic, cytogenetic, molecular) in CML.

Clinical case 2

Male patient, born in 1990. CML (chronic phase) was diagnosed at the age of 15. The onset of disease manifested by pronounced hepato- and splenomegaly, with liver protrusion of 5 cm, and the spleen emerged by 25 cm under the costal arch. We observed hyperleukocytosis up to 500×109/L, increase of platelet counts to 794×109/L, blast cells in peripheral blood (up to 6%).

The therapy was carried out at the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantology from 2005 to 2009. Cytoreductive treatment was performed with hydroxyurea. At the 1st line of therapy, the TKI 1 (imatinib) was used at a daily dose of 400 mg. The dynamics of response, according to ELN 2020 criteria was as follows: at 1 month, complete hematological response; at 12 months, minimal cytogenetic response. Imatinib dose was escalated to 600 mg daily, with subsequent switch to dasatinib (TKI 2) at a daily dose of 100 mg. During treatment with TKI 2, a progression of CML to acceleration phase was observed, along with emergence of accessory chromosomal aberration (+der22), and T315I mutation of the BCR-ABL kinase domain.

A secondary TKI drug resistance associated with T315I mutation of BCR-ABL chimeric gene was an indication for allogeneic HSCT. Prior to HSCT, chemotherapy was performed using the 5+2 protocol (cytarabine and daunorubicin) and hydroxyurea treatment. There was no available HLA-matched donor. Therefore, allo-HSCT from haploidentical donor was carried out at the age of 17 years, i.e., 2 years 8 months after CML diagnosis. Karnofsky performance status was 80% before allo-HSCT.

Due to non-engraftment of the transplant, the 2nd HSCT was performed from the same donor, with achieving engraftment of stem cells by the day+13. Due to rejection of the second graft, a 3rd transplantation from another donor was carried out on the day +44 after the 2nd HSCT. This time, the engraftment proceeded on day+12 after 3rd HSCT. Table 4 presents general parameters of transplants, the drugs used for conditioning and GvHD prevention.

The posttransplant period was complicated by the grade 4 gastrointestinal mucositis, septicemia documented on day+5, generalized non-controlled infection (catheter-associated bloodstream infection with P.aeruginosa and S. epidermidis on day+5), left-sided purulent parotitis on day+18, cytomegalovirus disease with lung affection on day+31. Despite combination antimicrobial therapy, the lethal outcome was registered on day+51.

Table 4. Characteristics of HSCT in clinical case 2

Sheveleva-tab04.jpg

Clinical case 3

A boy, born in 1995. At the age of 12 years, CML (acceleration phase) was diagnosed. The onset of disease was characterized by hyperleukocytosis (up to 99×109/L), blast cells in peripheral blood (12%) and in bone marrow (27%). Over the period of 2007 to 2010, the treatment was performed at the place of residence. A complete hematological response was obtained during chemotherapy which included the ADE (cytarabine, daunorubicin, and etoposide) protocol and imatinib (400 mg daily). Due to absence of complete cytogenetic and molecular response, the second-line treatment was performed with 2nd-generation TKI (dasatinib) at a dose of 100 mg/day. The molecular biology studies showed a T315I mutation of BCR-ABL.

In 2011, the patient was consulted at the R. Gorbacheva Memorial Research Institute where allogeneic HSCT was recommended due to secondary TKI resistance associated with T315I mutation. An unrelated, fully HLA-compatible male donor was found in an international registry. The patient underwent allo-HSCT at the age of 16, i.e., 3 years 8 months after primary diagnosis. The Karnofsky performance status was 80% prior to HSCT.

Myeloablative conditioning treatment included cyclophosphamide (120 mg/kg) and busulfan (16 mg/kg). Bone marrow was the source of hematopoietic cells. The number of transfused CD34+ cells was 7.8×106/kg weight of the recipient. MMF and tacrolimus were used for the GvHD prophylaxis. Antithymocyte immunoglobulin was applied as serotherapy.

Engraftment following HSCT was achieved on day +13. The restaging on day+21 has revealed full donor chimerism and complete response (hematologic, cytogenetic, molecular) in CML.

The posttransplant period was complicated by the febrile neutropenia, stage 2 gastrointestinal mucositis, acute GvHD (grade 4) on day+17 with grade 3 skin affection and gastrointestinal stage 4, hemorrhagic cystitis on day +21. Despite the combined immunosuppressive therapy (glucocorticosteroids, MMF, infliximab, alemtuzumab), the patient’s condition was not stabilized, and a lethal outcome was registered on the day +34 after HSCT.

Conclusion

Despite the advent of TKI therapy, the issue of evolving drug resistance still remains quite difficult. Therefore, molecular studies are required in order to detect the resistance mutations of BCR-ABL kinase domain and beyond it. The T315I mutation of BCR-ABL is characterized by aggressive course of CML. Currently allo-HSCT is the only effective and available therapeutic option for the pediatric and adolescent patients with secondary TKI resistance. Clinical success of allo-HSCT directly depends on the following factors: Karnofsky (Lansky) performance status of the patient; phase of the disease, optimal donor choice, conditioning regimen, and GvHD prophylaxis. Allo-HSCT with reduced-intensity conditioning and GvHD prevention with posttransplant cyclophosphamide may reduce risks of emerging complications associated with high lethality during early posttransplant period, in particular, preventing the development of acute and chronic GvHD.

Conflict of interest

None declared.

References

  1. Suttorp M, Millot F, Sembill S, Deutsch H, Metzler M. Definition, epidemiology, pathophysiology, and essential criteria for diagnosis of pediatric chronic myeloid leukemia. Cancers (Basel). 2021;13(4):798. doi: 10.3390/cancers13040798
  2. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2017; National Cancer Institute: Be-thesda, MD, USA, 2020. https://seer.cancer.gov/archive/csr/1975_2017/
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Шевелева, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Ольга А. Слесарчук, Анна В. Ботина, Вадим В. Байков, Татьяна Л. Гиндина, Николай Н. Мамаев, Eкатерина А. Измайлова, Ильдар М. Бархатов, Татьяна А. Быкова, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровска</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(512) "

Полина В. Шевелева, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Ольга А. Слесарчук, Анна В. Ботина, Вадим В. Байков, Татьяна Л. Гиндина, Николай Н. Мамаев, Eкатерина А. Измайлова, Ильдар М. Бархатов, Татьяна А. Быкова, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровска

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Данные о частоте встречаемости и характере мутаций в киназном домене BCR-ABL, эффективности и безопасности терапии у детей и подростков с резистентным течением хронического миелоидного лейкоза (ХМЛ) ограничены. До сих пор единственной терапевтической опцией в педиатрической группе с ХМЛ остается аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК), которая способна полностью излечить заболевание, однако сопряжена с высоким риском развития тяжелых осложнений. В статье проанализированы течение, лечение и исходы хронического миелоидного лейкоза у трех пациентов, у которых на фоне терапии ИТК была обнаружена мутация T315I в киназном домене химерного гена BCR-ABL1.

Ключевые слова

Хронический миелоидный лейкоз, дети, мутация T315I, ингибиторы тирозинкиназ, аллогенная трансплантация гемпоэтических стволовых клеток.

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Polina V. Sheveleva, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Olga A. Slesarchuk, Anna V. Botina, Vadim V. Baykov, Tatyana L. Gindina, Nikolay N. Mamaev, Ekaterina A. Izmailova, Ildar M. Barkhatov, Tatyana A. Bykova, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Polina V. Sheveleva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
E-mail: sheveleva_p@list.ru


Citation: Sheveleva PV, Morozova EV, Osipova AA et al. Clinical course of chronic myeloid leukemia with T315I mutation of BCR-ABL gene in pediatric and adolescent patients. Cell Ther Transplant 2023; 12(2): 32-39.

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There is a limited number of publications on the incidence of different mutations in the BCR-ABL kinase domain, the efficacy and safety of therapy in children and adolescents with resistant forms of chronic myeloid leukemia (СML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only method able to cure the disease completely in pediatric and adolescent patients with CML, however, being associated with life-threatening complications. This article analyzes the course, treatment and outcomes of chronic myeloid leukemia in 3 pediatric patients pre-treated with tyrosine kinase inhibitors (TKI) who exhibited the T315I mutation in BCR-ABL kinase domain.

Keywords

Chronic myeloid leukemia, children, adolescents, T315I mutation, tyrosine kinase inhibitors, allogeneic hematopoietic stem cell transplantation.

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Sheveleva, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Olga A. Slesarchuk, Anna V. Botina, Vadim V. Baykov, Tatyana L. Gindina, Nikolay N. Mamaev, Ekaterina A. Izmailova, Ildar M. Barkhatov, Tatyana A. Bykova, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(301) "

Polina V. Sheveleva, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Olga A. Slesarchuk, Anna V. Botina, Vadim V. Baykov, Tatyana L. Gindina, Nikolay N. Mamaev, Ekaterina A. Izmailova, Ildar M. Barkhatov, Tatyana A. Bykova, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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Polina V. Sheveleva, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Olga A. Slesarchuk, Anna V. Botina, Vadim V. Baykov, Tatyana L. Gindina, Nikolay N. Mamaev, Ekaterina A. Izmailova, Ildar M. Barkhatov, Tatyana A. Bykova, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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There is a limited number of publications on the incidence of different mutations in the BCR-ABL kinase domain, the efficacy and safety of therapy in children and adolescents with resistant forms of chronic myeloid leukemia (СML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only method able to cure the disease completely in pediatric and adolescent patients with CML, however, being associated with life-threatening complications. This article analyzes the course, treatment and outcomes of chronic myeloid leukemia in 3 pediatric patients pre-treated with tyrosine kinase inhibitors (TKI) who exhibited the T315I mutation in BCR-ABL kinase domain.

Keywords

Chronic myeloid leukemia, children, adolescents, T315I mutation, tyrosine kinase inhibitors, allogeneic hematopoietic stem cell transplantation.

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There is a limited number of publications on the incidence of different mutations in the BCR-ABL kinase domain, the efficacy and safety of therapy in children and adolescents with resistant forms of chronic myeloid leukemia (СML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only method able to cure the disease completely in pediatric and adolescent patients with CML, however, being associated with life-threatening complications. This article analyzes the course, treatment and outcomes of chronic myeloid leukemia in 3 pediatric patients pre-treated with tyrosine kinase inhibitors (TKI) who exhibited the T315I mutation in BCR-ABL kinase domain.

Keywords

Chronic myeloid leukemia, children, adolescents, T315I mutation, tyrosine kinase inhibitors, allogeneic hematopoietic stem cell transplantation.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Polina V. Sheveleva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
E-mail: sheveleva_p@list.ru


Citation: Sheveleva PV, Morozova EV, Osipova AA et al. Clinical course of chronic myeloid leukemia with T315I mutation of BCR-ABL gene in pediatric and adolescent patients. Cell Ther Transplant 2023; 12(2): 32-39.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Polina V. Sheveleva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
E-mail: sheveleva_p@list.ru


Citation: Sheveleva PV, Morozova EV, Osipova AA et al. Clinical course of chronic myeloid leukemia with T315I mutation of BCR-ABL gene in pediatric and adolescent patients. Cell Ther Transplant 2023; 12(2): 32-39.

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Полина В. Шевелева, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Ольга А. Слесарчук, Анна В. Ботина, Вадим В. Байков, Татьяна Л. Гиндина, Николай Н. Мамаев, Eкатерина А. Измайлова, Ильдар М. Бархатов, Татьяна А. Быкова, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровска

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Данные о частоте встречаемости и характере мутаций в киназном домене BCR-ABL, эффективности и безопасности терапии у детей и подростков с резистентным течением хронического миелоидного лейкоза (ХМЛ) ограничены. До сих пор единственной терапевтической опцией в педиатрической группе с ХМЛ остается аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК), которая способна полностью излечить заболевание, однако сопряжена с высоким риском развития тяжелых осложнений. В статье проанализированы течение, лечение и исходы хронического миелоидного лейкоза у трех пациентов, у которых на фоне терапии ИТК была обнаружена мутация T315I в киназном домене химерного гена BCR-ABL1.

Ключевые слова

Хронический миелоидный лейкоз, дети, мутация T315I, ингибиторы тирозинкиназ, аллогенная трансплантация гемпоэтических стволовых клеток.

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Данные о частоте встречаемости и характере мутаций в киназном домене BCR-ABL, эффективности и безопасности терапии у детей и подростков с резистентным течением хронического миелоидного лейкоза (ХМЛ) ограничены. До сих пор единственной терапевтической опцией в педиатрической группе с ХМЛ остается аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК), которая способна полностью излечить заболевание, однако сопряжена с высоким риском развития тяжелых осложнений. В статье проанализированы течение, лечение и исходы хронического миелоидного лейкоза у трех пациентов, у которых на фоне терапии ИТК была обнаружена мутация T315I в киназном домене химерного гена BCR-ABL1.

Ключевые слова

Хронический миелоидный лейкоз, дети, мутация T315I, ингибиторы тирозинкиназ, аллогенная трансплантация гемпоэтических стволовых клеток.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

According to the estimates of World Health Organization, high incidence of cardio-vascular diseases and high mortality rates caused by these disorders are still registered worldwide [1]. The common surgical methods aimed for treatment of these diseases include bypass grafting, stenting, and prosthetic repair of arteries affected by atherosclerosis. During bypass surgery, vascular shunting is performed by means of native vessels (autologous veins or arteries), or synthetic polymer prostheses (grafts) in order to get around the occluded or thrombosed vessel. A stenting procedure includes insertion of a metal frame into the damaged vessel, thus extending vascular lumen and providing free blood flow. During prosthetic repair, a portion of the damaged vessel is substituted with a graft made of synthetic polymers, or native materials [2].

When autologous vessels are used for bypass grafting or prosthetic treatment, the implant usually becomes integrated into the living body. Since these implants contain functional endothelial layer and cause only minimal inflammation, they are successfully used for bypassing the low-diameter vessels. However, the amount of autologous material is limited, especially when several arteries require intervention, or in cases of repeated surgery. Autologous arteries are rarely used, because of considerably disturbed local blood supply when taking these vessels for surgery. Therefore, autologous veins are mainly used; their absence is relatively easily compensated by other veins, and, therefore, no pronounced tissue damage occurs.

However, thickness of a vein wall is significantly lower than that in arteries, and degenerative processes are observed in the walls of autologous veins within a prolonged period of time after the operation, with potential development of aneurysms [3, 4]. Moreover, taking autologous material is an additional trauma to the patient, thus complicating the entire surgical procedure.

On the contrary, stenting is a low-traumatic intervention. A metal stent in its collapsed form attached to the outside of a balloon catheter is threaded through the damaged part of an artery. Then the balloon is inflated, causing expansion of the stent followed by deflation of the balloon and its removal from the organism, with a metal stent remaining within the vessel. This surgery has its disadvantages. First, there is a risk of restenosis due to neointimal hyperplasia caused by the contact between stent and vessel wall. Secondly, repeated stenting (if required at the same site) is difficult, since the metallic frame remains in the organism of a patient lifelong. Recently, the novel stents have been developed, consisting of bioresorbable materials (polylactide and magnesium alloys). However, their surgical parameters are still inferior to those of common non-bioresorbable alloy stents. Thus, these innovative stents are yet not widely applied [5, 6]. Moreover, the stenting procedures become difficult in the cases of extensive atherosclerotic damage, at the sites with complex configuration (e.g., arterial bifurcation), or in the cases of complete luminal closure with atherosclerotic plaque. Stenting is also counter-indicated when the plaque is unstable, i.e, the atherosclerotic plaque cap becomes damaged and may be ruptured when inflating the stent. Both thrombosis and embolism may appear at the site of damage, followed by their migration in bloodstream, causing arterial and venous thrombosis. Their risk is especially high during surgical intervention in coronary and cerebral arteries.

Prosthetics and bypass surgery using synthetic polymeric grafts are conventional and conservative procedures. Advantages of synthetic grafts include good mechanical characteristics, wide range of sizes and shaping, like as commercial availability. They can be used for prosthetic repair of prolonged areas of a vessel, or for simultaneous treatment of several vessels; they are also suitable in the case of complete vascular occlusion. Synthetic grafts are also employed when the stenting is not possible, due to high risk of atherosclerotic plaque rupture. However, currently used grafts are made of polytetrafluoroethylene, lavsan, and their combinations, thus being unable for biological resorption in the body. No protective endothelial layer is formed on their surface, and, moreover, intimal hyperplasia is frequently observed in the area of anastomosis being a pre-requisite for thrombosis, especially inside the narrow vessel grafts, where blood flows relatively slowly. The grafts under 5 mm in diameter are not used, due to development of early thromboses [7, 8]. When the synthetic grafts are implanted in children, complex repeated surgery is required, e.g., replacement of small grafts for larger ones [9].

One possible solution for these issues may be provided by the tissue-engineered vascular grafts (TEVG), which involves three main components: bioresorbable scaffold, cell material, mechanical and biological signaling [10]. To date, five main techniques for TEVG preparation have been developed: (1) use of bioresorbable polymeric scaffolds (grafts) [11-16]; (2) bioprinting [17, 18]; (3) layer-by-layer tissue engineering [19, 20]; (4) use of decellularized vessels [21]; and (5) use of granulation tissue [22]. Despite a variety of existing approaches, there is still no solution complying with all requirements for the vascular grafts. In particular, the need for usage cell materials at the in vitro preparation stage has not been proven. Some authors deliberately omit this stage due to technological complexity and low reproducibility [14, 23-25].

Therefore, we have developed the technique for preparation of polymeric bioresorbable TEVG with low diameters by electrospinning of microfibers from poly(L-lactide) (PLLA) solution, followed by their partial crystallization on the collecting electrode [14, 26]. The grafts prepared in such a way are biocompatible, non-toxic, showing high athrombogenicity (TEVG permeability exceeded 90%), and possess ability for complete bioresorption within 16 months, involving gradual replacement of polymeric fibers with native tissues [14]. In addition, these grafts demonstrate high porosity, which facilitates cell growth; the cells fill the whole intermediate volume of the graft in a short time. Since the pores have small diameters, bleeding does not occur during implantation and in the early postoperative period. However, we observed aneurysms of various sizes upon complete bioresorption of the grafts. Occurence of these defects is caused by formation of structures with low mechanical strength (as compared with that of a native vessel), instead of resorbed grafts. Aneurysm is a life-threatening condition, since the dilated vessel may rupture, thus leading to uncontrolled bleeding and death of a patient.

Therefore, the aims of the present work included development of a two-layer polymeric TEVG with low diameter consisting of a layer of bioresorbable PLLA microfibers reinforced with a layer of non-resorbable fluoropolymer microfibers, and the results of in vivo observations of these grafts.

Materials and methods

Preparation of grafts

Poly(L-lactide) (PLLA) Purasorb PL-10 (Corbion Purac, Netherlands) was used in preparation of porous tubular grafts. Electrospinning was performed in the following manner. PLLA was dissolved in trichloromethane (chloroform, Sigma-Aldrich, USA); concentration of the solution was 15%. Using an injection pump, the prepared solution was fed through a metallic tubular electrode into electric field (Е = 1.5∙104–4.0∙105 V/m, the distance between electrodes 15 cm). Microfibers were precipitated on a grounded metallic cylindrical electrode 1.1 mm in diameter; rotation rate was 1500 rpm. The produced grafts fixed on the cylindrical electrode were subjected to thermal treatment at 70°C for 10 min, resulting into partial crystallization of PLLA, thus leading to considerable enhancement of its mechanical and operating parameters. Upon thermal treatment, the thickness of graft wall was equal to 200 µm. The graft preparation procedure developed by our group is described in detail elsewhere [14, 26]. The PLLA grafts (still located on the electrode) were then placed into electrospinning setup again, in order to apply the layer of fluoropolymer (FP) microfibers on their outer surface. We used Fluoropolymer F-32LV (poly(1-chloro-1,2,2-trifluoroethylene-1,1-difluoroethylene), (-CFCl-CF2-)n[-CF2-CH2-]m) produced by AO "GaloPolymer" (Russia). Our preliminary studies demonstrated that this FP could be easily dissolved, possesses good mechanical parameters and very high athrombogenicity. The grafts prepared of this material remain permeable in 98% of cases. FP was dissolved in ethyl acetate (Sigma-Aldrich, USA), and 15% solution was obtained. Electrospinning parameters were similar to those described above for PLLA. A 50-µm thick layer of microfibers was deposited, and the resulting two-layer graft was taken off the collecting electrode.

Electron microscopy studies of the samples were performed using a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) in the secondary electron imaging mode. Before SEM study, a thin platinum layer was sprayed onto the sample surface. The images were taken at 1 hour, 2 days, 1, 2, 4, 12, 24, 48, 56, 64, 72, 80, and 96 weeks after implantation.

Assessment of mechanical properties

Mechanical characteristics of the grafts were determined by means of an Instron 5943 universal testing machine (Instron, UK) in the uniaxial tension mode; the extension rate was 10 mm/min. Young’s modulus, tensile strength and tensile strain were measured for PLLA and PLLA-FP grafts (internal diameter 1.1 mm, wall thickness 250 µm), and native rat aorta. PLLA grafts were also partially crystallized on the collecting electrode. The sample base length was 20 mm in all cases.

Contact angle determination

The experiments were performed using a DSA 30 setup (Kruss, Germany) on the surface of four types of samples: non-porous PLLA, FP films obtained by pouring polymer solution onto glass support followed by drying, porous PLLA, and non-woven FP films prepared by electrospinning. Compositions of solutions and electrospinning parameters are given above (‘Preparation of grafts’).

Studies of barrier properties of grafts

Two types of grafts (PLLA and two-layer PLLA-FP samples) were tested, with following sizes: inner diameter, 1.1 mm; length, 30 mm; wall thickness, 250 µm. A special setup was designed for these measurements: an NE-1000 programmable single syringe pump (a roller pump for blood perfusion) (New Era Pump Systems, Inc., USA) equipped with a 20 mL syringe was connected with a graft via tubular adapter; another end of the graft was connected via adapter with a transparent tube with an inner diameter of 4 mm and a length of 2 m. This tube was placed in vertical position, and a scale was set against the tube in order to measure the height of a liquid column. Two types of liquids were used in the studies: (i) water colored with a green dye to improve visualization and (ii) rat blood supplemented with sodium citrate (3.95% concentration) as anticoagulant. A liquid was fed through the studied graft at a constant rate into the tube; then it rose through the tube. When the first drops of a liquid appeared on the outer surface of a graft, the experiment was stopped, and the height of the liquid column was measured. The volume feed rate was 10 mL/min, thus corresponding to linear rate of liquid in the graft lumen equal to 0.18 m/s. This value is typical of blood flow rate in arteries 1.5-2 mm in diameter that are included in human systemic circulation [27]. Thus, in these experiments, the value of hydrodynamic pressure remained constant, while hydrostatic pressure increased gradually. Each measurement was made in five repeats.

Experiments with animals

The in vivo experiments involved 52 male white Wistar rats (age: 3 months, weight: 200-250 g); 4 animals were used in each series of experiments. The surgical manipulations were performed under general anesthesia [Zoletil 100 dissolved in 20 mL of physiological solution (0.1 mL) and Rometar (20 mg/mL, 0.0125 mL of solution per 0.1 kg of animal weight), intraperitoneally, once]. Y-shaped incision for laparotomy was made; microvascular surgery was used to mobilize infrarenal portion of the abdominal aorta and to insert a prosthetic graft; 8 sutures were put at each anastomosis using atraumatic needles with Prolen 9-0 threads. In all experiments, no significant bleeding through graft wall or along the lines of anastomosis was observed after restoration of blood flow. No anticoagulants or disaggregant drugs were used. Vascular permeability was estimated according to the classical method [28]. Then the front abdominal wall was sutured in layers using atraumatic needles with Prolen 9-0 threads. Upon suturing, the rats were caged individually, had free access to water and were fed a standard diet. Color and temperature of skin of hind extremities of the animals were monitored; their physical activity was estimated.

Compliance with ethical standards

The animal experiments were carried out in accordance with the regulations concerning use of laboratory animals (principles of European Convention (Strasbourg, 1986) and the Declaration of Helsinki developed by the World Medical Association concerning humane treatment of animals (1996)), and State Standard 33216-2014 ("Guide to keeping and care of laboratory animals. Regulations for keeping and care of laboratory rodents and rabbits").

Morphological studies

At 2 days, 1, 2, 4, 12, 24, 48, 56, 64, 72, 80 and 96 weeks, TEVG with fragments of native aorta were excised and fixed in 10% neutral solution of formalin in phosphate buffer (рН=7.4) for, at least, 24 hrs. Then the samples were dehydrated using a series of ethanol solutions at increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin slices (5 μm thick) were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). The connective tissue elements were visualized according to the Mallory and Masson technique (BioVitrum, Russia).

For immunohistochemical detection of macrophages and multinucleated foreign body giant cells (MFBGC), mouse primary monoclonal antibodies [Anti-CD68 antibody (ab 31630), Abcam, UK] was used (dilution 1:1000, 20°C, exposure time: 1 h). To reveal bound primary antibodies, multimeric biotin-free detection system was used (D&A, Reveal-Biotin-Free Polyvalent DAB, Spring Bioscience Corporation, USA). The preparations were additionally stained with Mayer hematoxylin (BioVitrum, Russia). In order to detect actin-containing cells (smooth muscle cells and miofibroblasts) after standard procedure of deparaffinization, the slices were treated with mouse monoclonal smooth muscle α-actin antibodies (clone 1A4, dilution 1:2000) (AbCam, UK) for 10 min at room temperature. A MACH2 Mouse kit (Biocare Medical, USA) was used as secondary reagent. To visualize the product of immunohistochemical reaction, the preparations were treated with 3’,3’-diaminobenzidine (DAB+, Dako, Denmark). Microscopic analysis of the TEVG-containing preparations was performed using a Nikon Eclipse Ni light microscope (Nikon, Japan) with a 10× ocular, and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Ri2 camera (Nikon, Japan). In all series of experiments, thickness of connective tissue interlayer between the two TEVG layers was measured sequentially ten times along the longitudinal histological section, and the average values were deduced. Statistical treatment of the obtained data was performed using the standard software package (Statistica 7.0, Stat.Soft for Windows). The arithmetic mean value and its standard deviation (M±SD) were calculated; significance of differences was estimated using the Wilcoxon criterion and the Mann-Whitney U test. The significance of differences was determined at P < 0.05.

Results

Fig. 1 presents SEM images of a two-layer PLLA-FP graft. The inner PLLA layer consists of microfibers with round cross-sections, 3-5 µm in diameter, at the pore size between fibers varying from 5 to 40 µm. This layer is significantly thicker than the outer layer; it contacts blood directly and undergoes bioresorption. The outer FP layer consists of microfibers with dumbbell-shaped cross-sections 2 to 10 µm wide, 1-3 µm high, with pore sizes ranging from 3 to 30 µm. This layer is significantly thinner, being not susceptible to bioresorption. Its main purpose is to enhance mechanical characteristics of TEVG after complete bioresorption of the inner layer, and, thus, to prevent formation of aneurysms. The amount of non-resorbable polymer retained in the body should be minimal. Therefore, this layer is relatively thin, but it should have a sufficient thickness to perform its mechanical function. Both layers possess high porosity and pore sizes suitable for migration of cells into graft wall. After implantation, the migrating cells fill free volume in the pores between fibers of polymeric graft thus creating a natural vascular graft without a need for preliminary cell repopulation of the grafts.

Popryaduhin-fig01.jpg

Figure 1. Scanning electron microscopy (SEM) images of the PLLA-FP graft. A and B, cross-section; C, internal surface; D, outer surface

In order to prevent formation of aneurysms and their rupture, the initial graft should have good mechanical characteristics. In this work, comparative analysis of mechanical properties of PLLA-FP, PLLA grafts and native rat aorta was performed. It was demonstrated that mechanical strength and Young’s modulus of PLLA-FP and PLLA grafts were considerably higher than those of the native aorta. The grafts also demonstrated higher elasticity (tensile strain) as seen from Table 1. Rupture of PLLA-FP grafts proceeds in two stages. At the first stage, the internal layer of PLLA undergoes destruction, while the FP layer retains integrity and continues to stretch until the elongation value reaches 273±28%. This property of the graft provides additional protection from destruction and bleeding.

Table 1. Mechanical properties of vascular grafts and rat native aorta

Popryaduhin-tab01.jpg

* Note: The parameters were obtained before starting the destruction of PLLA layer

The obtained grafts are highly porous products. Therefore, one of the most important characteristics of a graft is permeability of its wall for various liquids, mainly their blood permeability. Our studies of barrier properties involving water and stabilized rat blood showed that the two-layer PLLA-FP graft possessed considerably better barrier properties than the monolayer PLLA graft (Table 2). This is due to the two-stage impregnation of PLLA-FP graft with a liquid: the inner PLLA layer is impregnated followed by considerable rise in hydrostatic pressure, thus causing saturation of the outer FP layer (Fig. 2). Moreover, both layers consist of highly hydrophobic substances. The non-woven materials prepared by electrospinning have higher hydrophobicity (due to their peculiar surface relief) than non-porous films of the same materials (Table 3). After implantation of PLLA-FP grafts into rat aorta, visual observation revealed that the internal PLLA layer was soaked with blood, whereas the outer FP layer was not impregnated; this observation confirms good barrier properties of the bilayer graft.

Popryaduhin-fig02.jpg

Figure 2. Studies of barrier properties of PLLA-FP grafts. A, original view; B, impregnation of the PLLA layer with colored water; C, impregnation of two layers of the graft with colored water; D, impregnation of two layers of the graft with blood

Table 2. Barrier properties of PLLA-FP and PLLA grafts

Popryaduhin-tab02.jpg

Table 3. Water contact angles of the materials based on PLLA and FP

Popryaduhin-tab03.jpg

One hour after implantation of the graft into rat aorta, no macroscopic thromboses were revealed, and blood pulsation above and distally from the implantation site was clearly seen. Scanning electron microscopy studies showed that the whole internal surface of the graft was coated with a thin fibrin layer 3-5 µm thick. The fibrin film was coated with a 10-15 µm thick layer of erythrocytes. Fibrin covered the major part of graft surface, without predominant localization. Fibrin was also found within the graft wall; it filled the pores and formed bridges between polymeric fibers (Supplementary file, Fig. 3 a, b). The amount of fibrin was higher in the pores located near the inner graft surface. Virtually no fibrin was found near the outer graft surface. The appearance of fibrin plugs in the pores inside the graft after starting blood flow led to enhancement of barrier properties and, as a consequence, decreased risk of bleeding.

Two days after surgery, during explantation of grafts, no visual signs of active inflammatory response were revealed in abdominal cavity and in retroperitoneal space. The grafts were not adherent to the surrounding tissues. Neither their external appearance nor manually determined mechanical characteristics were changed. SEM and histological studies showed that the inner surfaces of grafts were covered with a thin fibrin layer (like as samples from the previous series), but no erythrocyte layer was revealed (Fig. 3 c, d), which indicates the involvement of blood anticoagulation system. Isolated leukocytes and erythrocytes were found between PLLA and FP fibers; the cells migrated into this space due to impregnation of the graft with blood. CD68+ cells (macrophages, MFBGC) and α-actin-containing cells were not observed.

Popryaduhin-fig03.jpg

Figure 3. Scanning electron microscopy (SEM) images of PLLA-FP graft taken at 1 hour (A, B) and 2 days (C, D) after implantation. A and C, internal surface; B and D, graft wall (PLLA layer, longitudinal section)

One week after the surgery, no visual signs of active inflammation were observed; a thin connective tissue capsule was formed on the outer surface of the graft. Histological and SEM studies revealed a homogeneous fibrin layer on the inner graft surface. In the anastomosis area, gradual transition of aortal intima and media to inner graft surface was observed; endothelium and smooth myocytes were grown in this area. The PLLA layer was homogeneously populated with small amount of CD68+ cells. The FP layer was densely populated with CD68+ cells; at the periphery of the outer surface, single phagocytizing MFBGC were detected. In both graft layers, small amounts of α-actin-containing cells were distributed homogeneously. At one week of experimental observation, a thin connective tissue interlayer 2.9±1.1-µm thick appeared between PLLA and FP layers of the graft (Table 4). Moderate amounts of CD 68+ cells were present in the formed connective tissue capsule (neoadventitia).

Table 4. Morphometric analysis of the Time-dependent changes of thickness of connective tissue interlayer between PLLA and FP layers of the graft (n=4)

Popryaduhin-tab04.jpg

Note: * , the parameters significantly differ from those observed after 1 week of experiment, р <0.05 (р = 0.0001207); **, the parameters significantly differ from those after 2 weeks of experiment, р <0.05 (р = 0.0000001)

No visual signs of inflammation were observed at histological section within 2 weeks after implantation. The grafts were surrounded with connective tissue that virtually did not grow into the graft walls. Histological analysis of aortal anastomosis area revealed the presence of endothelium and smooth myocytes; which have grown within intraluminal surface of the scaffold and formed the neointimal structures. In the PLLA layer, moderate amounts of CD68+ cells and α-actin-containing cells were found. On the contrary, the FP layer was populated with a large amount of CD 68+ cells, including numerous MFBGC located at peripheral areas; no α-actin-containing cells were revealed. The connective tissue interlayer between graft walls became significantly thicker (6.0±3.2 µm) than the layer formed at 1st week (Table 4). Neoadventitia consisted of young collagen fibers, fibroblasts and CD 68+ cells.

Four weeks after surgery, the connective tissue capsule around the graft was seen more clearly; no signs of inflammation were observed. The capsule was adhered to the surrounding tissues, but remained movable, being penetrated with blood vessels. Histological analysis showed the presence of completely formed neointima over the whole internal surface of the graft. Neointima consisted of endothelial cells, subendothelial layer and smooth muscle cells. A moderate amount of CD 68+ cells still remained in the PLLA layer, while the amount of α-actin-containing cells decreased. Like as by 2 weeks after operation, the FP layer was populated with numerous CD 68+ cells and MFBGC without α-actin-containing cells. Within both graft walls, collagen fibers appeared between the polymeric microfibers. The fibrils were synthesized by fibroblasts that migrated from the adventitial side into the graft. The connective tissue structures continued to grow between PLLA and FP layers, and their thickness reached 12.2±3.3 µm (Table 4). The neoadventitial structures were similar to those observed at earlier terms (i.e., 2 weeks after surgery).

By 12 weeks (3 months) after implantation, no visual signs of inflammation were found, whereas the connective tissue capsule surrounding the graft became more densely connected with native tissues than in 4 weeks. The capsule had a smooth shiny surface and was penetrated with numerous small blood vessels. Histological pattern observed in this period of time was virtually similar to that revealed in 4 weeks after operation. The thickness of connective tissue interlayer between PLLA and FP layers was 18.6±8.2 µm (Table 4).

In 24 weeks (6 months) after implantation, we, generally, observed a similar tissue pattern (Fig. 4 a, b). However, it should be noted that neointima contained small calcifications. Thickness of the connective tissue interlayer between two graft walls was 20.6±7.9 µm (Table 4). In the neoadventitia, a continuous cluster of MFBGCs was formed which closely fitted to the outer wall of the FP layer.

In 48 weeks (12 months) after implantation, the histological picture did not undergo any significant changes and remained virtually similar to the patterns observed in 12 and 24 weeks after implantation (Fig. 4 c, d). However, clear signs of bioresorption of PLLA microfibers were observed (fragmentation and formation of pores in the fibers, thus resembling a spongy structure). No signs of fluoropolymer (FP) biodegradation were revealed, which was the expected purpose of our work. One should note that bioresorption rate of PLLA microfibers incorporated in the double-layer PLLA-FP graft was significantly lower than that of the monolayer PLLA graft [14]. In the anastomosis area, a smooth transition of intima from aorta to the graft surface was observed. No signs of hyperplasia were revealed (similarly to the previous two series, i.e., 12 and 24 weeks). Thickness of the connective tissue interlayer between PLLA and FP parts was 25.1±8.7 µm. The clusters of MFBGCs still retained close to the outer FP wall.

Popryaduhin-fig4.jpg

Figure 4. SEM images and histological sections of PLLA-FP grafts taken 6 (A, B) and 12 months (C, D) after the in vivo implantation.

A, the graft wall, cross section; B, longitudinal section; C, immunohistochemistry (α-actin stained brown); D, staining by Mallory method (collagen stained blue). Ob. 10×.

Histological analyses performed within the period from 56 weeks (14 months) to 96 weeks (2 years) of the experiment showed that neointima was formed by continuous endothelium layer, smooth muscle cells grown from native aortal segments, and a thin layer of collagen fibers were observed (Fig. 5). It should be noted that calcifications were formed in the anastomosis zones in several animals, however, without signs of neointimal hyperplasia. Bioresorption of polymeric structures continued in the PLLA layer. Meanwhile, the amount of collagen fibers increased, and they filled the space previously occupied by PLLA microfibers. Moderate amounts of CD 68+ cells populated the entire layer. The numbers of α-actin-containing cells decreased, according to visual estimates. They were revealed at negligible amounts, predominantly in the outer part of the PLLA layer. As at earlier terms, there were no signs of bioresorption in the FP layer. This portion of graft was completely occupied with CD 68+ cells and surrounded with the MFBGC deposits; no α-actin-containing cells were revealed. Thickness of the connective tissue streak between the graft layers gradually increased up to 30.2±6.9 µm. Neoadventitia was represented by loose connective tissue, containing fibroblasts and CD68+ cells.

Popryaduhin-fig05.jpg

Figure 5. SEM images and histological section of PLLA-FP grafts taken in 24 months after implantation.

A, C – graft wall, cross section, B, D – longitudinal section. (c) Immunohistochemical detection (α-actin), (d) staining by Masson method (collagen stained green). Ob. 10×.

Discussion

In the current work, we report the results of experimental testing of an original two-layer PLLA-FP low-diameter vascular grafts. Their mechanical and barrier properties were investigated, hydrophobic characteristics were determined, and in vivo experiments were performed during long period of time (from 1 h to 2 years). The mechanical characteristics of the grafts were shown to be superior to those of the native rat aorta. This result is very important for development of vascular grafts (especially bioresorbable and partially bioresorbable products). Biological resorption is followed by renewal of native vascular tissues with low mechanical strength, which may be too thin to endure blood pressure. As a result, vascular aneurysms may appear. Spontaneous ruptures of such aneurysms may cause internal bleeding and threaten the patient’s life. The inner PLLA layer of implanted graft is bioresorbable; it degrades slowly being replaced with native tissues. The outer non-bioresorbable FP layer imparts mechanical strength to the newly formed vessel walls. No aneurysms were found at any time during the whole observation period, thus supporting validity of the chosen approach (Fig. 6). However, the PLLA layer did not disappear completely even 2 years after graft implantation. The polymer fibers were partially disrupted, but were able to reinforce graft walls to a certain degree.

Popryaduhin-fig06.jpg

Figure 6. Macroscopic views of PLLA-FP graft extracted 24 months after implantation. A, after explantation; B, complete clamping with a surgical instrument; C, graft reshaping after declamping

The barrier properties of two-layer PLLA-FP graft were considerably better than those of the monolayer PLLA graft. These characteristics are especially important for highly porous grafts (e.g., prepared by electrospinning). Bleeding through graft wall may lead to significant blood loss and, therefore, presenting a threat to patient’s life. Therefore, usage of two-layer PLLA-FP graft it is preferable to the monolayer PLLA prosthesis.

During the in vivo experiments, we studied thromboresistance properties of the grafts (absence of thrombi and degree of permeability) as well as biocompatibility, rate and mechanism of living tissue ingrowth into graft wall, and bioresorption of PLLA fibers were investigated. Total permeability of grafts was 96%, a very high value for the low-diameter vascular grafts (5 mm and smaller). However, we should consider implantation of the graft into abdominal aorta, where blood flow rate is higher than that in peripheral vessels, and, thus, a risk of thrombosis is lower.

High biocompatibility between the polymer grafts and living tissues was observed during the whole experiment. No pronounced inflammation (macroscopic or microscopic) was revealed in the PLLA layer (only moderate or insignificant amounts of CD68+ cells were present). In the FP layer, the reaction was more pronounced, and the layer was populated with CD68+ cells, and the MFBGC clustering was observed around its wall, being a typical in vivo response to the foreign body invasion.

Immediately after starting blood flow in the graft, its porous walls became impregnated with blood (mainly, its liquid component). Thin fibrin depositions were observed inside the graft pores and its surface, as clearly seen within the first week post-implant. One week after grafting, smooth growth of intima from aorta to the inner side of the graft was observed in the anastomosis areas. During this period, thin connective tissue interlayer was developed between PLLA and FP layers of the graft. Thickness of this layer gradually increased until the end of observation period. This interlayer improves mechanical characteristics of the graft and its barrier properties. However, it prevents cell migration and, thus, potentially inhibits resorption of the PLLA layer.

In four weeks, neointima was completely formed over the whole inner surface of the graft. It consisted of endothelial cells, subendothelial layer, and smooth muscle cells. The presence of neointima at this early stage provided thromboresistance of the graft. Moreover, no signs of neointimal hyperplasia were found throughout the experiment, thus being a very favorable prognostic sign, which also suggests high biocompatibility of the graft.

Ingrowth of native tissues into the graft started since the first week of the experiment. Across the whole width of the PLLA layer, virtually in all series and terms of experiments, we observed moderate amounts of CD68+ and α-actin-containing cells (presumably, myofibroblasts, in absence of smooth myocytes). The amounts of fibroblasts and collagen fibers gradually increased with time, while the fibers filled the space between polymer fibers and the volume that was earlier occupied with bioresorbable PLLA fibers. The FP layer was repopulated with numerous CD 68+ cells, starting from the 2nd week of the experiment.

Conclusion

The original vascular graft based on a double-layer structure (degradable and undegradable polymeric components) has demonstrated high biocompatibility, thromboresistance, mechanical strength, bioresorbability (in PLLA layer) during the 2-year experimental observation, and, thus, may be recommended for further studies and potential clinical use.

Conflict of interests

Authors do not declare any conflicts of interests.

References

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Introduction

According to the estimates of World Health Organization, high incidence of cardio-vascular diseases and high mortality rates caused by these disorders are still registered worldwide [1]. The common surgical methods aimed for treatment of these diseases include bypass grafting, stenting, and prosthetic repair of arteries affected by atherosclerosis. During bypass surgery, vascular shunting is performed by means of native vessels (autologous veins or arteries), or synthetic polymer prostheses (grafts) in order to get around the occluded or thrombosed vessel. A stenting procedure includes insertion of a metal frame into the damaged vessel, thus extending vascular lumen and providing free blood flow. During prosthetic repair, a portion of the damaged vessel is substituted with a graft made of synthetic polymers, or native materials [2].

When autologous vessels are used for bypass grafting or prosthetic treatment, the implant usually becomes integrated into the living body. Since these implants contain functional endothelial layer and cause only minimal inflammation, they are successfully used for bypassing the low-diameter vessels. However, the amount of autologous material is limited, especially when several arteries require intervention, or in cases of repeated surgery. Autologous arteries are rarely used, because of considerably disturbed local blood supply when taking these vessels for surgery. Therefore, autologous veins are mainly used; their absence is relatively easily compensated by other veins, and, therefore, no pronounced tissue damage occurs.

However, thickness of a vein wall is significantly lower than that in arteries, and degenerative processes are observed in the walls of autologous veins within a prolonged period of time after the operation, with potential development of aneurysms [3, 4]. Moreover, taking autologous material is an additional trauma to the patient, thus complicating the entire surgical procedure.

On the contrary, stenting is a low-traumatic intervention. A metal stent in its collapsed form attached to the outside of a balloon catheter is threaded through the damaged part of an artery. Then the balloon is inflated, causing expansion of the stent followed by deflation of the balloon and its removal from the organism, with a metal stent remaining within the vessel. This surgery has its disadvantages. First, there is a risk of restenosis due to neointimal hyperplasia caused by the contact between stent and vessel wall. Secondly, repeated stenting (if required at the same site) is difficult, since the metallic frame remains in the organism of a patient lifelong. Recently, the novel stents have been developed, consisting of bioresorbable materials (polylactide and magnesium alloys). However, their surgical parameters are still inferior to those of common non-bioresorbable alloy stents. Thus, these innovative stents are yet not widely applied [5, 6]. Moreover, the stenting procedures become difficult in the cases of extensive atherosclerotic damage, at the sites with complex configuration (e.g., arterial bifurcation), or in the cases of complete luminal closure with atherosclerotic plaque. Stenting is also counter-indicated when the plaque is unstable, i.e, the atherosclerotic plaque cap becomes damaged and may be ruptured when inflating the stent. Both thrombosis and embolism may appear at the site of damage, followed by their migration in bloodstream, causing arterial and venous thrombosis. Their risk is especially high during surgical intervention in coronary and cerebral arteries.

Prosthetics and bypass surgery using synthetic polymeric grafts are conventional and conservative procedures. Advantages of synthetic grafts include good mechanical characteristics, wide range of sizes and shaping, like as commercial availability. They can be used for prosthetic repair of prolonged areas of a vessel, or for simultaneous treatment of several vessels; they are also suitable in the case of complete vascular occlusion. Synthetic grafts are also employed when the stenting is not possible, due to high risk of atherosclerotic plaque rupture. However, currently used grafts are made of polytetrafluoroethylene, lavsan, and their combinations, thus being unable for biological resorption in the body. No protective endothelial layer is formed on their surface, and, moreover, intimal hyperplasia is frequently observed in the area of anastomosis being a pre-requisite for thrombosis, especially inside the narrow vessel grafts, where blood flows relatively slowly. The grafts under 5 mm in diameter are not used, due to development of early thromboses [7, 8]. When the synthetic grafts are implanted in children, complex repeated surgery is required, e.g., replacement of small grafts for larger ones [9].

One possible solution for these issues may be provided by the tissue-engineered vascular grafts (TEVG), which involves three main components: bioresorbable scaffold, cell material, mechanical and biological signaling [10]. To date, five main techniques for TEVG preparation have been developed: (1) use of bioresorbable polymeric scaffolds (grafts) [11-16]; (2) bioprinting [17, 18]; (3) layer-by-layer tissue engineering [19, 20]; (4) use of decellularized vessels [21]; and (5) use of granulation tissue [22]. Despite a variety of existing approaches, there is still no solution complying with all requirements for the vascular grafts. In particular, the need for usage cell materials at the in vitro preparation stage has not been proven. Some authors deliberately omit this stage due to technological complexity and low reproducibility [14, 23-25].

Therefore, we have developed the technique for preparation of polymeric bioresorbable TEVG with low diameters by electrospinning of microfibers from poly(L-lactide) (PLLA) solution, followed by their partial crystallization on the collecting electrode [14, 26]. The grafts prepared in such a way are biocompatible, non-toxic, showing high athrombogenicity (TEVG permeability exceeded 90%), and possess ability for complete bioresorption within 16 months, involving gradual replacement of polymeric fibers with native tissues [14]. In addition, these grafts demonstrate high porosity, which facilitates cell growth; the cells fill the whole intermediate volume of the graft in a short time. Since the pores have small diameters, bleeding does not occur during implantation and in the early postoperative period. However, we observed aneurysms of various sizes upon complete bioresorption of the grafts. Occurence of these defects is caused by formation of structures with low mechanical strength (as compared with that of a native vessel), instead of resorbed grafts. Aneurysm is a life-threatening condition, since the dilated vessel may rupture, thus leading to uncontrolled bleeding and death of a patient.

Therefore, the aims of the present work included development of a two-layer polymeric TEVG with low diameter consisting of a layer of bioresorbable PLLA microfibers reinforced with a layer of non-resorbable fluoropolymer microfibers, and the results of in vivo observations of these grafts.

Materials and methods

Preparation of grafts

Poly(L-lactide) (PLLA) Purasorb PL-10 (Corbion Purac, Netherlands) was used in preparation of porous tubular grafts. Electrospinning was performed in the following manner. PLLA was dissolved in trichloromethane (chloroform, Sigma-Aldrich, USA); concentration of the solution was 15%. Using an injection pump, the prepared solution was fed through a metallic tubular electrode into electric field (Е = 1.5∙104–4.0∙105 V/m, the distance between electrodes 15 cm). Microfibers were precipitated on a grounded metallic cylindrical electrode 1.1 mm in diameter; rotation rate was 1500 rpm. The produced grafts fixed on the cylindrical electrode were subjected to thermal treatment at 70°C for 10 min, resulting into partial crystallization of PLLA, thus leading to considerable enhancement of its mechanical and operating parameters. Upon thermal treatment, the thickness of graft wall was equal to 200 µm. The graft preparation procedure developed by our group is described in detail elsewhere [14, 26]. The PLLA grafts (still located on the electrode) were then placed into electrospinning setup again, in order to apply the layer of fluoropolymer (FP) microfibers on their outer surface. We used Fluoropolymer F-32LV (poly(1-chloro-1,2,2-trifluoroethylene-1,1-difluoroethylene), (-CFCl-CF2-)n[-CF2-CH2-]m) produced by AO "GaloPolymer" (Russia). Our preliminary studies demonstrated that this FP could be easily dissolved, possesses good mechanical parameters and very high athrombogenicity. The grafts prepared of this material remain permeable in 98% of cases. FP was dissolved in ethyl acetate (Sigma-Aldrich, USA), and 15% solution was obtained. Electrospinning parameters were similar to those described above for PLLA. A 50-µm thick layer of microfibers was deposited, and the resulting two-layer graft was taken off the collecting electrode.

Electron microscopy studies of the samples were performed using a Supra 55VP scanning electron microscope (Carl Zeiss, Germany) in the secondary electron imaging mode. Before SEM study, a thin platinum layer was sprayed onto the sample surface. The images were taken at 1 hour, 2 days, 1, 2, 4, 12, 24, 48, 56, 64, 72, 80, and 96 weeks after implantation.

Assessment of mechanical properties

Mechanical characteristics of the grafts were determined by means of an Instron 5943 universal testing machine (Instron, UK) in the uniaxial tension mode; the extension rate was 10 mm/min. Young’s modulus, tensile strength and tensile strain were measured for PLLA and PLLA-FP grafts (internal diameter 1.1 mm, wall thickness 250 µm), and native rat aorta. PLLA grafts were also partially crystallized on the collecting electrode. The sample base length was 20 mm in all cases.

Contact angle determination

The experiments were performed using a DSA 30 setup (Kruss, Germany) on the surface of four types of samples: non-porous PLLA, FP films obtained by pouring polymer solution onto glass support followed by drying, porous PLLA, and non-woven FP films prepared by electrospinning. Compositions of solutions and electrospinning parameters are given above (‘Preparation of grafts’).

Studies of barrier properties of grafts

Two types of grafts (PLLA and two-layer PLLA-FP samples) were tested, with following sizes: inner diameter, 1.1 mm; length, 30 mm; wall thickness, 250 µm. A special setup was designed for these measurements: an NE-1000 programmable single syringe pump (a roller pump for blood perfusion) (New Era Pump Systems, Inc., USA) equipped with a 20 mL syringe was connected with a graft via tubular adapter; another end of the graft was connected via adapter with a transparent tube with an inner diameter of 4 mm and a length of 2 m. This tube was placed in vertical position, and a scale was set against the tube in order to measure the height of a liquid column. Two types of liquids were used in the studies: (i) water colored with a green dye to improve visualization and (ii) rat blood supplemented with sodium citrate (3.95% concentration) as anticoagulant. A liquid was fed through the studied graft at a constant rate into the tube; then it rose through the tube. When the first drops of a liquid appeared on the outer surface of a graft, the experiment was stopped, and the height of the liquid column was measured. The volume feed rate was 10 mL/min, thus corresponding to linear rate of liquid in the graft lumen equal to 0.18 m/s. This value is typical of blood flow rate in arteries 1.5-2 mm in diameter that are included in human systemic circulation [27]. Thus, in these experiments, the value of hydrodynamic pressure remained constant, while hydrostatic pressure increased gradually. Each measurement was made in five repeats.

Experiments with animals

The in vivo experiments involved 52 male white Wistar rats (age: 3 months, weight: 200-250 g); 4 animals were used in each series of experiments. The surgical manipulations were performed under general anesthesia [Zoletil 100 dissolved in 20 mL of physiological solution (0.1 mL) and Rometar (20 mg/mL, 0.0125 mL of solution per 0.1 kg of animal weight), intraperitoneally, once]. Y-shaped incision for laparotomy was made; microvascular surgery was used to mobilize infrarenal portion of the abdominal aorta and to insert a prosthetic graft; 8 sutures were put at each anastomosis using atraumatic needles with Prolen 9-0 threads. In all experiments, no significant bleeding through graft wall or along the lines of anastomosis was observed after restoration of blood flow. No anticoagulants or disaggregant drugs were used. Vascular permeability was estimated according to the classical method [28]. Then the front abdominal wall was sutured in layers using atraumatic needles with Prolen 9-0 threads. Upon suturing, the rats were caged individually, had free access to water and were fed a standard diet. Color and temperature of skin of hind extremities of the animals were monitored; their physical activity was estimated.

Compliance with ethical standards

The animal experiments were carried out in accordance with the regulations concerning use of laboratory animals (principles of European Convention (Strasbourg, 1986) and the Declaration of Helsinki developed by the World Medical Association concerning humane treatment of animals (1996)), and State Standard 33216-2014 ("Guide to keeping and care of laboratory animals. Regulations for keeping and care of laboratory rodents and rabbits").

Morphological studies

At 2 days, 1, 2, 4, 12, 24, 48, 56, 64, 72, 80 and 96 weeks, TEVG with fragments of native aorta were excised and fixed in 10% neutral solution of formalin in phosphate buffer (рН=7.4) for, at least, 24 hrs. Then the samples were dehydrated using a series of ethanol solutions at increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. The paraffin slices (5 μm thick) were obtained with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). The connective tissue elements were visualized according to the Mallory and Masson technique (BioVitrum, Russia).

For immunohistochemical detection of macrophages and multinucleated foreign body giant cells (MFBGC), mouse primary monoclonal antibodies [Anti-CD68 antibody (ab 31630), Abcam, UK] was used (dilution 1:1000, 20°C, exposure time: 1 h). To reveal bound primary antibodies, multimeric biotin-free detection system was used (D&A, Reveal-Biotin-Free Polyvalent DAB, Spring Bioscience Corporation, USA). The preparations were additionally stained with Mayer hematoxylin (BioVitrum, Russia). In order to detect actin-containing cells (smooth muscle cells and miofibroblasts) after standard procedure of deparaffinization, the slices were treated with mouse monoclonal smooth muscle α-actin antibodies (clone 1A4, dilution 1:2000) (AbCam, UK) for 10 min at room temperature. A MACH2 Mouse kit (Biocare Medical, USA) was used as secondary reagent. To visualize the product of immunohistochemical reaction, the preparations were treated with 3’,3’-diaminobenzidine (DAB+, Dako, Denmark). Microscopic analysis of the TEVG-containing preparations was performed using a Nikon Eclipse Ni light microscope (Nikon, Japan) with a 10× ocular, and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Ri2 camera (Nikon, Japan). In all series of experiments, thickness of connective tissue interlayer between the two TEVG layers was measured sequentially ten times along the longitudinal histological section, and the average values were deduced. Statistical treatment of the obtained data was performed using the standard software package (Statistica 7.0, Stat.Soft for Windows). The arithmetic mean value and its standard deviation (M±SD) were calculated; significance of differences was estimated using the Wilcoxon criterion and the Mann-Whitney U test. The significance of differences was determined at P < 0.05.

Results

Fig. 1 presents SEM images of a two-layer PLLA-FP graft. The inner PLLA layer consists of microfibers with round cross-sections, 3-5 µm in diameter, at the pore size between fibers varying from 5 to 40 µm. This layer is significantly thicker than the outer layer; it contacts blood directly and undergoes bioresorption. The outer FP layer consists of microfibers with dumbbell-shaped cross-sections 2 to 10 µm wide, 1-3 µm high, with pore sizes ranging from 3 to 30 µm. This layer is significantly thinner, being not susceptible to bioresorption. Its main purpose is to enhance mechanical characteristics of TEVG after complete bioresorption of the inner layer, and, thus, to prevent formation of aneurysms. The amount of non-resorbable polymer retained in the body should be minimal. Therefore, this layer is relatively thin, but it should have a sufficient thickness to perform its mechanical function. Both layers possess high porosity and pore sizes suitable for migration of cells into graft wall. After implantation, the migrating cells fill free volume in the pores between fibers of polymeric graft thus creating a natural vascular graft without a need for preliminary cell repopulation of the grafts.

Popryaduhin-fig01.jpg

Figure 1. Scanning electron microscopy (SEM) images of the PLLA-FP graft. A and B, cross-section; C, internal surface; D, outer surface

In order to prevent formation of aneurysms and their rupture, the initial graft should have good mechanical characteristics. In this work, comparative analysis of mechanical properties of PLLA-FP, PLLA grafts and native rat aorta was performed. It was demonstrated that mechanical strength and Young’s modulus of PLLA-FP and PLLA grafts were considerably higher than those of the native aorta. The grafts also demonstrated higher elasticity (tensile strain) as seen from Table 1. Rupture of PLLA-FP grafts proceeds in two stages. At the first stage, the internal layer of PLLA undergoes destruction, while the FP layer retains integrity and continues to stretch until the elongation value reaches 273±28%. This property of the graft provides additional protection from destruction and bleeding.

Table 1. Mechanical properties of vascular grafts and rat native aorta

Popryaduhin-tab01.jpg

* Note: The parameters were obtained before starting the destruction of PLLA layer

The obtained grafts are highly porous products. Therefore, one of the most important characteristics of a graft is permeability of its wall for various liquids, mainly their blood permeability. Our studies of barrier properties involving water and stabilized rat blood showed that the two-layer PLLA-FP graft possessed considerably better barrier properties than the monolayer PLLA graft (Table 2). This is due to the two-stage impregnation of PLLA-FP graft with a liquid: the inner PLLA layer is impregnated followed by considerable rise in hydrostatic pressure, thus causing saturation of the outer FP layer (Fig. 2). Moreover, both layers consist of highly hydrophobic substances. The non-woven materials prepared by electrospinning have higher hydrophobicity (due to their peculiar surface relief) than non-porous films of the same materials (Table 3). After implantation of PLLA-FP grafts into rat aorta, visual observation revealed that the internal PLLA layer was soaked with blood, whereas the outer FP layer was not impregnated; this observation confirms good barrier properties of the bilayer graft.

Popryaduhin-fig02.jpg

Figure 2. Studies of barrier properties of PLLA-FP grafts. A, original view; B, impregnation of the PLLA layer with colored water; C, impregnation of two layers of the graft with colored water; D, impregnation of two layers of the graft with blood

Table 2. Barrier properties of PLLA-FP and PLLA grafts

Popryaduhin-tab02.jpg

Table 3. Water contact angles of the materials based on PLLA and FP

Popryaduhin-tab03.jpg

One hour after implantation of the graft into rat aorta, no macroscopic thromboses were revealed, and blood pulsation above and distally from the implantation site was clearly seen. Scanning electron microscopy studies showed that the whole internal surface of the graft was coated with a thin fibrin layer 3-5 µm thick. The fibrin film was coated with a 10-15 µm thick layer of erythrocytes. Fibrin covered the major part of graft surface, without predominant localization. Fibrin was also found within the graft wall; it filled the pores and formed bridges between polymeric fibers (Supplementary file, Fig. 3 a, b). The amount of fibrin was higher in the pores located near the inner graft surface. Virtually no fibrin was found near the outer graft surface. The appearance of fibrin plugs in the pores inside the graft after starting blood flow led to enhancement of barrier properties and, as a consequence, decreased risk of bleeding.

Two days after surgery, during explantation of grafts, no visual signs of active inflammatory response were revealed in abdominal cavity and in retroperitoneal space. The grafts were not adherent to the surrounding tissues. Neither their external appearance nor manually determined mechanical characteristics were changed. SEM and histological studies showed that the inner surfaces of grafts were covered with a thin fibrin layer (like as samples from the previous series), but no erythrocyte layer was revealed (Fig. 3 c, d), which indicates the involvement of blood anticoagulation system. Isolated leukocytes and erythrocytes were found between PLLA and FP fibers; the cells migrated into this space due to impregnation of the graft with blood. CD68+ cells (macrophages, MFBGC) and α-actin-containing cells were not observed.

Popryaduhin-fig03.jpg

Figure 3. Scanning electron microscopy (SEM) images of PLLA-FP graft taken at 1 hour (A, B) and 2 days (C, D) after implantation. A and C, internal surface; B and D, graft wall (PLLA layer, longitudinal section)

One week after the surgery, no visual signs of active inflammation were observed; a thin connective tissue capsule was formed on the outer surface of the graft. Histological and SEM studies revealed a homogeneous fibrin layer on the inner graft surface. In the anastomosis area, gradual transition of aortal intima and media to inner graft surface was observed; endothelium and smooth myocytes were grown in this area. The PLLA layer was homogeneously populated with small amount of CD68+ cells. The FP layer was densely populated with CD68+ cells; at the periphery of the outer surface, single phagocytizing MFBGC were detected. In both graft layers, small amounts of α-actin-containing cells were distributed homogeneously. At one week of experimental observation, a thin connective tissue interlayer 2.9±1.1-µm thick appeared between PLLA and FP layers of the graft (Table 4). Moderate amounts of CD 68+ cells were present in the formed connective tissue capsule (neoadventitia).

Table 4. Morphometric analysis of the Time-dependent changes of thickness of connective tissue interlayer between PLLA and FP layers of the graft (n=4)

Popryaduhin-tab04.jpg

Note: * , the parameters significantly differ from those observed after 1 week of experiment, р <0.05 (р = 0.0001207); **, the parameters significantly differ from those after 2 weeks of experiment, р <0.05 (р = 0.0000001)

No visual signs of inflammation were observed at histological section within 2 weeks after implantation. The grafts were surrounded with connective tissue that virtually did not grow into the graft walls. Histological analysis of aortal anastomosis area revealed the presence of endothelium and smooth myocytes; which have grown within intraluminal surface of the scaffold and formed the neointimal structures. In the PLLA layer, moderate amounts of CD68+ cells and α-actin-containing cells were found. On the contrary, the FP layer was populated with a large amount of CD 68+ cells, including numerous MFBGC located at peripheral areas; no α-actin-containing cells were revealed. The connective tissue interlayer between graft walls became significantly thicker (6.0±3.2 µm) than the layer formed at 1st week (Table 4). Neoadventitia consisted of young collagen fibers, fibroblasts and CD 68+ cells.

Four weeks after surgery, the connective tissue capsule around the graft was seen more clearly; no signs of inflammation were observed. The capsule was adhered to the surrounding tissues, but remained movable, being penetrated with blood vessels. Histological analysis showed the presence of completely formed neointima over the whole internal surface of the graft. Neointima consisted of endothelial cells, subendothelial layer and smooth muscle cells. A moderate amount of CD 68+ cells still remained in the PLLA layer, while the amount of α-actin-containing cells decreased. Like as by 2 weeks after operation, the FP layer was populated with numerous CD 68+ cells and MFBGC without α-actin-containing cells. Within both graft walls, collagen fibers appeared between the polymeric microfibers. The fibrils were synthesized by fibroblasts that migrated from the adventitial side into the graft. The connective tissue structures continued to grow between PLLA and FP layers, and their thickness reached 12.2±3.3 µm (Table 4). The neoadventitial structures were similar to those observed at earlier terms (i.e., 2 weeks after surgery).

By 12 weeks (3 months) after implantation, no visual signs of inflammation were found, whereas the connective tissue capsule surrounding the graft became more densely connected with native tissues than in 4 weeks. The capsule had a smooth shiny surface and was penetrated with numerous small blood vessels. Histological pattern observed in this period of time was virtually similar to that revealed in 4 weeks after operation. The thickness of connective tissue interlayer between PLLA and FP layers was 18.6±8.2 µm (Table 4).

In 24 weeks (6 months) after implantation, we, generally, observed a similar tissue pattern (Fig. 4 a, b). However, it should be noted that neointima contained small calcifications. Thickness of the connective tissue interlayer between two graft walls was 20.6±7.9 µm (Table 4). In the neoadventitia, a continuous cluster of MFBGCs was formed which closely fitted to the outer wall of the FP layer.

In 48 weeks (12 months) after implantation, the histological picture did not undergo any significant changes and remained virtually similar to the patterns observed in 12 and 24 weeks after implantation (Fig. 4 c, d). However, clear signs of bioresorption of PLLA microfibers were observed (fragmentation and formation of pores in the fibers, thus resembling a spongy structure). No signs of fluoropolymer (FP) biodegradation were revealed, which was the expected purpose of our work. One should note that bioresorption rate of PLLA microfibers incorporated in the double-layer PLLA-FP graft was significantly lower than that of the monolayer PLLA graft [14]. In the anastomosis area, a smooth transition of intima from aorta to the graft surface was observed. No signs of hyperplasia were revealed (similarly to the previous two series, i.e., 12 and 24 weeks). Thickness of the connective tissue interlayer between PLLA and FP parts was 25.1±8.7 µm. The clusters of MFBGCs still retained close to the outer FP wall.

Popryaduhin-fig4.jpg

Figure 4. SEM images and histological sections of PLLA-FP grafts taken 6 (A, B) and 12 months (C, D) after the in vivo implantation.

A, the graft wall, cross section; B, longitudinal section; C, immunohistochemistry (α-actin stained brown); D, staining by Mallory method (collagen stained blue). Ob. 10×.

Histological analyses performed within the period from 56 weeks (14 months) to 96 weeks (2 years) of the experiment showed that neointima was formed by continuous endothelium layer, smooth muscle cells grown from native aortal segments, and a thin layer of collagen fibers were observed (Fig. 5). It should be noted that calcifications were formed in the anastomosis zones in several animals, however, without signs of neointimal hyperplasia. Bioresorption of polymeric structures continued in the PLLA layer. Meanwhile, the amount of collagen fibers increased, and they filled the space previously occupied by PLLA microfibers. Moderate amounts of CD 68+ cells populated the entire layer. The numbers of α-actin-containing cells decreased, according to visual estimates. They were revealed at negligible amounts, predominantly in the outer part of the PLLA layer. As at earlier terms, there were no signs of bioresorption in the FP layer. This portion of graft was completely occupied with CD 68+ cells and surrounded with the MFBGC deposits; no α-actin-containing cells were revealed. Thickness of the connective tissue streak between the graft layers gradually increased up to 30.2±6.9 µm. Neoadventitia was represented by loose connective tissue, containing fibroblasts and CD68+ cells.

Popryaduhin-fig05.jpg

Figure 5. SEM images and histological section of PLLA-FP grafts taken in 24 months after implantation.

A, C – graft wall, cross section, B, D – longitudinal section. (c) Immunohistochemical detection (α-actin), (d) staining by Masson method (collagen stained green). Ob. 10×.

Discussion

In the current work, we report the results of experimental testing of an original two-layer PLLA-FP low-diameter vascular grafts. Their mechanical and barrier properties were investigated, hydrophobic characteristics were determined, and in vivo experiments were performed during long period of time (from 1 h to 2 years). The mechanical characteristics of the grafts were shown to be superior to those of the native rat aorta. This result is very important for development of vascular grafts (especially bioresorbable and partially bioresorbable products). Biological resorption is followed by renewal of native vascular tissues with low mechanical strength, which may be too thin to endure blood pressure. As a result, vascular aneurysms may appear. Spontaneous ruptures of such aneurysms may cause internal bleeding and threaten the patient’s life. The inner PLLA layer of implanted graft is bioresorbable; it degrades slowly being replaced with native tissues. The outer non-bioresorbable FP layer imparts mechanical strength to the newly formed vessel walls. No aneurysms were found at any time during the whole observation period, thus supporting validity of the chosen approach (Fig. 6). However, the PLLA layer did not disappear completely even 2 years after graft implantation. The polymer fibers were partially disrupted, but were able to reinforce graft walls to a certain degree.

Popryaduhin-fig06.jpg

Figure 6. Macroscopic views of PLLA-FP graft extracted 24 months after implantation. A, after explantation; B, complete clamping with a surgical instrument; C, graft reshaping after declamping

The barrier properties of two-layer PLLA-FP graft were considerably better than those of the monolayer PLLA graft. These characteristics are especially important for highly porous grafts (e.g., prepared by electrospinning). Bleeding through graft wall may lead to significant blood loss and, therefore, presenting a threat to patient’s life. Therefore, usage of two-layer PLLA-FP graft it is preferable to the monolayer PLLA prosthesis.

During the in vivo experiments, we studied thromboresistance properties of the grafts (absence of thrombi and degree of permeability) as well as biocompatibility, rate and mechanism of living tissue ingrowth into graft wall, and bioresorption of PLLA fibers were investigated. Total permeability of grafts was 96%, a very high value for the low-diameter vascular grafts (5 mm and smaller). However, we should consider implantation of the graft into abdominal aorta, where blood flow rate is higher than that in peripheral vessels, and, thus, a risk of thrombosis is lower.

High biocompatibility between the polymer grafts and living tissues was observed during the whole experiment. No pronounced inflammation (macroscopic or microscopic) was revealed in the PLLA layer (only moderate or insignificant amounts of CD68+ cells were present). In the FP layer, the reaction was more pronounced, and the layer was populated with CD68+ cells, and the MFBGC clustering was observed around its wall, being a typical in vivo response to the foreign body invasion.

Immediately after starting blood flow in the graft, its porous walls became impregnated with blood (mainly, its liquid component). Thin fibrin depositions were observed inside the graft pores and its surface, as clearly seen within the first week post-implant. One week after grafting, smooth growth of intima from aorta to the inner side of the graft was observed in the anastomosis areas. During this period, thin connective tissue interlayer was developed between PLLA and FP layers of the graft. Thickness of this layer gradually increased until the end of observation period. This interlayer improves mechanical characteristics of the graft and its barrier properties. However, it prevents cell migration and, thus, potentially inhibits resorption of the PLLA layer.

In four weeks, neointima was completely formed over the whole inner surface of the graft. It consisted of endothelial cells, subendothelial layer, and smooth muscle cells. The presence of neointima at this early stage provided thromboresistance of the graft. Moreover, no signs of neointimal hyperplasia were found throughout the experiment, thus being a very favorable prognostic sign, which also suggests high biocompatibility of the graft.

Ingrowth of native tissues into the graft started since the first week of the experiment. Across the whole width of the PLLA layer, virtually in all series and terms of experiments, we observed moderate amounts of CD68+ and α-actin-containing cells (presumably, myofibroblasts, in absence of smooth myocytes). The amounts of fibroblasts and collagen fibers gradually increased with time, while the fibers filled the space between polymer fibers and the volume that was earlier occupied with bioresorbable PLLA fibers. The FP layer was repopulated with numerous CD 68+ cells, starting from the 2nd week of the experiment.

Conclusion

The original vascular graft based on a double-layer structure (degradable and undegradable polymeric components) has demonstrated high biocompatibility, thromboresistance, mechanical strength, bioresorbability (in PLLA layer) during the 2-year experimental observation, and, thus, may be recommended for further studies and potential clinical use.

Conflict of interests

Authors do not declare any conflicts of interests.

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Попрядухин<sup>1,2</sup>, Гурий И. Попов<sup>1</sup>, Галина Ю. Юкина<sup>1</sup>, Елена Г. Сухорукова<sup>1</sup>, Елена М. Иванькова<sup>2</sup>, Валерий Н. Вавилов<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(280) "

Павел В. Попрядухин1,2, Гурий И. Попов1, Галина Ю. Юкина1, Елена Г. Сухорукова1, Елена М. Иванькова2, Валерий Н. Вавилов1

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия

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Методом электроформования были получены двуслойные нетканые трубчатые протезы диаметром 1.1 мм. Внутренний слой протезов состоял из биорезорбируемого полимера поли(L-лактида), наружный из нерезорбируемого фторполимера, который служил для укрепления стенки протеза и предотврашения развития аневризм, после полной резорбции внутреннего слоя. Протезы были имплантированы в брюшную часть аорты крысам на срок от 1 часа до 24 мес и продемонстрировали высокую биосовместимость, нетоксичность и выраженные атромбогенные свойства. Общая проходимость протезов составила 96%. Морфометрический анализ показал, что во внутреннем слое протеза происходят два параллельных процесса: биорезорбция волокон поли(L-лактида) и образование соединительной ткани. Свободный объем наружного слоя заполнен соединительной тканью, признаков его биорезорбции не выявлено. Между двумя слоями полимера образуется соединительнотканная прослойка, толщина которой постепенно увеличивается. Клеточный состав стенок протеза представлен преимущественно фибробластами, CD 68+ клетками, α-актин содержащими клетками и многоядерными клетками инородных тел. Было показано, что наружный нерезорбируемый слой надежно предотвращает появление аневризм на всех изученных сроках эксперимента.

Ключевые слова

Тканевая инженерия, сосудистый протез, сосуды малого диаметра, биоинженерия, поли(L-лактид), фторполимер, электроспиннинг, микроволокна, биорезорбция, аневризма.

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Pavel V. Popryadukhin1,2, Guriy I. Popov1, Galina Yu. Yukina1, Elena G. Sukhorukova1, Elena M. Ivan’kova2, Valery N. Vavilov1

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1 Pavlov University, St. Petersburg, Russia
2 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, Russian Academy of Sciences, 31 Bolshoy Ave, 199004,
St. Petersburg, Russia
E-mail: pavelpnru@gmail.com


Citation: Popryadukhin PV, Popov GI, Yukina GY, et al. Double layer tissue-engineered vascular graft of small diameter based on electrospun polylactide and fluoropolymer microfibers. Cell Ther Transplant 2023; 12(2): 40-50.

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Double layer non-woven tubular grafts 1.1 mm in diameter were prepared by electrospinning. The inner layer of the graft was made of bioresorbable poly(L-lactide) polymer; the outer layer consisted of a non-resorbable fluoropolymer, which served to reinforce the graft wall and to prevent appearance of aneurysm upon complete resorption of the inner layer. The grafts were implanted into rat abdominal aorta for different periods of time (from 1 hrs to 24 months); they showed no toxicity, demonstrated good biocompatibility and high athrombogenicity. Total graft permeability was equal to 96%. Morphological analysis of the samples demonstrated that two processes occurred simultaneously in the inner layer of the graft: bioresorption of poly(L-lactide) fibers and formation of connective tissue. Free volume of the outer layer was filled with connective tissue; no signs of bioresorption were revealed. An intermediate layer consisting of connective tissue was formed between the two polymer layers; thickness of this interlayer increased gradually with time. The tissues formed on the surface of graft walls included mainly fibroblasts, CD68+ cells, α-actin-containing cells and multinucleated foreign body giant cells. It was shown that the non-resorbable outer layer reliably prevented appearance of aneurysms at all the studied time points.

Keywords

Tissue engineering, vascular graft, small-diameter blood vessels, bioengineering, poly(L-lactide), fluoropolymer, electrospinning, microfibers, bioresorption, aneurysm.

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Popryadukhin<sup>1,2</sup>, Guriy I. Popov<sup>1</sup>, Galina Yu. Yukina<sup>1</sup>, Elena G. Sukhorukova<sup>1</sup>, Elena M. Ivan’kova<sup>2</sup>, Valery N. Vavilov<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(201) "

Pavel V. Popryadukhin1,2, Guriy I. Popov1, Galina Yu. Yukina1, Elena G. Sukhorukova1, Elena M. Ivan’kova2, Valery N. Vavilov1

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Pavel V. Popryadukhin1,2, Guriy I. Popov1, Galina Yu. Yukina1, Elena G. Sukhorukova1, Elena M. Ivan’kova2, Valery N. Vavilov1

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Double layer non-woven tubular grafts 1.1 mm in diameter were prepared by electrospinning. The inner layer of the graft was made of bioresorbable poly(L-lactide) polymer; the outer layer consisted of a non-resorbable fluoropolymer, which served to reinforce the graft wall and to prevent appearance of aneurysm upon complete resorption of the inner layer. The grafts were implanted into rat abdominal aorta for different periods of time (from 1 hrs to 24 months); they showed no toxicity, demonstrated good biocompatibility and high athrombogenicity. Total graft permeability was equal to 96%. Morphological analysis of the samples demonstrated that two processes occurred simultaneously in the inner layer of the graft: bioresorption of poly(L-lactide) fibers and formation of connective tissue. Free volume of the outer layer was filled with connective tissue; no signs of bioresorption were revealed. An intermediate layer consisting of connective tissue was formed between the two polymer layers; thickness of this interlayer increased gradually with time. The tissues formed on the surface of graft walls included mainly fibroblasts, CD68+ cells, α-actin-containing cells and multinucleated foreign body giant cells. It was shown that the non-resorbable outer layer reliably prevented appearance of aneurysms at all the studied time points.

Keywords

Tissue engineering, vascular graft, small-diameter blood vessels, bioengineering, poly(L-lactide), fluoropolymer, electrospinning, microfibers, bioresorption, aneurysm.

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Double layer non-woven tubular grafts 1.1 mm in diameter were prepared by electrospinning. The inner layer of the graft was made of bioresorbable poly(L-lactide) polymer; the outer layer consisted of a non-resorbable fluoropolymer, which served to reinforce the graft wall and to prevent appearance of aneurysm upon complete resorption of the inner layer. The grafts were implanted into rat abdominal aorta for different periods of time (from 1 hrs to 24 months); they showed no toxicity, demonstrated good biocompatibility and high athrombogenicity. Total graft permeability was equal to 96%. Morphological analysis of the samples demonstrated that two processes occurred simultaneously in the inner layer of the graft: bioresorption of poly(L-lactide) fibers and formation of connective tissue. Free volume of the outer layer was filled with connective tissue; no signs of bioresorption were revealed. An intermediate layer consisting of connective tissue was formed between the two polymer layers; thickness of this interlayer increased gradually with time. The tissues formed on the surface of graft walls included mainly fibroblasts, CD68+ cells, α-actin-containing cells and multinucleated foreign body giant cells. It was shown that the non-resorbable outer layer reliably prevented appearance of aneurysms at all the studied time points.

Keywords

Tissue engineering, vascular graft, small-diameter blood vessels, bioengineering, poly(L-lactide), fluoropolymer, electrospinning, microfibers, bioresorption, aneurysm.

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1 Pavlov University, St. Petersburg, Russia
2 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, Russian Academy of Sciences, 31 Bolshoy Ave, 199004,
St. Petersburg, Russia
E-mail: pavelpnru@gmail.com


Citation: Popryadukhin PV, Popov GI, Yukina GY, et al. Double layer tissue-engineered vascular graft of small diameter based on electrospun polylactide and fluoropolymer microfibers. Cell Ther Transplant 2023; 12(2): 40-50.

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1 Pavlov University, St. Petersburg, Russia
2 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, Russian Academy of Sciences, 31 Bolshoy Ave, 199004,
St. Petersburg, Russia
E-mail: pavelpnru@gmail.com


Citation: Popryadukhin PV, Popov GI, Yukina GY, et al. Double layer tissue-engineered vascular graft of small diameter based on electrospun polylactide and fluoropolymer microfibers. Cell Ther Transplant 2023; 12(2): 40-50.

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Павел В. Попрядухин1,2, Гурий И. Попов1, Галина Ю. Юкина1, Елена Г. Сухорукова1, Елена М. Иванькова2, Валерий Н. Вавилов1

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Внутренний слой протезов состоял из биорезорбируемого полимера поли(L-лактида), наружный из нерезорбируемого фторполимера, который служил для укрепления стенки протеза и предотврашения развития аневризм, после полной резорбции внутреннего слоя. Протезы были имплантированы в брюшную часть аорты крысам на срок от 1 часа до 24 мес и продемонстрировали высокую биосовместимость, нетоксичность и выраженные атромбогенные свойства. Общая проходимость протезов составила 96%. Морфометрический анализ показал, что во внутреннем слое протеза происходят два параллельных процесса: биорезорбция волокон поли(L-лактида) и образование соединительной ткани. Свободный объем наружного слоя заполнен соединительной тканью, признаков его биорезорбции не выявлено. Между двумя слоями полимера образуется соединительнотканная прослойка, толщина которой постепенно увеличивается. Клеточный состав стенок протеза представлен преимущественно фибробластами, CD 68+ клетками, α-актин содержащими клетками и многоядерными клетками инородных тел. Было показано, что наружный нерезорбируемый слой надежно предотвращает появление аневризм на всех изученных сроках эксперимента. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Тканевая инженерия, сосудистый протез, сосуды малого диаметра, биоинженерия, поли(L-лактид), фторполимер, электроспиннинг, микроволокна, биорезорбция, аневризма.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2717) "

Методом электроформования были получены двуслойные нетканые трубчатые протезы диаметром 1.1 мм. Внутренний слой протезов состоял из биорезорбируемого полимера поли(L-лактида), наружный из нерезорбируемого фторполимера, который служил для укрепления стенки протеза и предотврашения развития аневризм, после полной резорбции внутреннего слоя. Протезы были имплантированы в брюшную часть аорты крысам на срок от 1 часа до 24 мес и продемонстрировали высокую биосовместимость, нетоксичность и выраженные атромбогенные свойства. Общая проходимость протезов составила 96%. Морфометрический анализ показал, что во внутреннем слое протеза происходят два параллельных процесса: биорезорбция волокон поли(L-лактида) и образование соединительной ткани. Свободный объем наружного слоя заполнен соединительной тканью, признаков его биорезорбции не выявлено. Между двумя слоями полимера образуется соединительнотканная прослойка, толщина которой постепенно увеличивается. Клеточный состав стенок протеза представлен преимущественно фибробластами, CD 68+ клетками, α-актин содержащими клетками и многоядерными клетками инородных тел. Было показано, что наружный нерезорбируемый слой надежно предотвращает появление аневризм на всех изученных сроках эксперимента.

Ключевые слова

Тканевая инженерия, сосудистый протез, сосуды малого диаметра, биоинженерия, поли(L-лактид), фторполимер, электроспиннинг, микроволокна, биорезорбция, аневризма.

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Методом электроформования были получены двуслойные нетканые трубчатые протезы диаметром 1.1 мм. Внутренний слой протезов состоял из биорезорбируемого полимера поли(L-лактида), наружный из нерезорбируемого фторполимера, который служил для укрепления стенки протеза и предотврашения развития аневризм, после полной резорбции внутреннего слоя. Протезы были имплантированы в брюшную часть аорты крысам на срок от 1 часа до 24 мес и продемонстрировали высокую биосовместимость, нетоксичность и выраженные атромбогенные свойства. Общая проходимость протезов составила 96%. Морфометрический анализ показал, что во внутреннем слое протеза происходят два параллельных процесса: биорезорбция волокон поли(L-лактида) и образование соединительной ткани. Свободный объем наружного слоя заполнен соединительной тканью, признаков его биорезорбции не выявлено. Между двумя слоями полимера образуется соединительнотканная прослойка, толщина которой постепенно увеличивается. Клеточный состав стенок протеза представлен преимущественно фибробластами, CD 68+ клетками, α-актин содержащими клетками и многоядерными клетками инородных тел. Было показано, что наружный нерезорбируемый слой надежно предотвращает появление аневризм на всех изученных сроках эксперимента.

Ключевые слова

Тканевая инженерия, сосудистый протез, сосуды малого диаметра, биоинженерия, поли(L-лактид), фторполимер, электроспиннинг, микроволокна, биорезорбция, аневризма.

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия

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Introduction

Doxorubicin (DOX), an anthracycline antibiotic which is successfully used in treatment of different malignancies, particularly, breast cancer. The main mechanisms of DOX action upon tumor cells include: (i) intercalation of DNA molecules, thus inhibiting DNA synthesis; (ii) generation of free radicals leading to DNA damage or lipid peroxidation [1]. However, the drug has several essential drawbacks: rapid clearance, dose-dependent cardiotoxicity, hepatic damage [1] and hematological toxicity [2]. The delivery systems that are able to eliminate these problems and increase DOX efficiency are discussed in the review [3], which is focused on delivery systems based on organic and inorganic compounds. Later publications describe complex multicomponent DOX delivery systems. For example, drug synergism observed upon combined use of DOX and ruthenium complex (Δ-Ru1/DOX) manifests as a decreased DOX cardiotoxicity [4]. Aiming for effective suppression of tumor growth, DOX is introduced into the specially prepared conjugates of nanoparticles of poly(lactic-co-glycolic acid) with chondroitin sulfate A [5]. The authors used simultaneous encapsulation of DOX and photosensitizer Indocyanine Green, in order to enhance the effect of chemo-photothermal cancer therapy [6].

The porous particles of calcium carbonate (CaCO3) vaterites are used as delivery systems (DS) for various drugs. They draw attention of researchers due to their biocompatibility, biodegradability, non-toxicity, low cost, and ease of preparation. A comprehensive review [7] discusses the recent successful applications of the CaCO3 vaterites to the delivery (in vivo and in vitro) of various diagnostic agents and therapeutic drugs. Special attention to the use of СаСО3 as carriers for antitumor preparations (in particular, with DOX) has been given elsewhere [8]. In the present work, DOX was encapsulated in the delivery systems on the basis of СаСО3 cores doped with DexS polyanions (CaCO3+DexS). DOX in the form of hydrochloride (thus creating acidic medium) is introduced into carbonate cores, thus causing re-crystallization of vaterites into non-porous calcites. Vaterites are then coated with polymers to protect their porous structure [9, 10]. Dextran sulfate is a bioavailable polymer [11]. It was shown that СаСО3 doped with DexS by various methods (coating, co-precipitation) was virtually non-cytotoxic at concentrations below 0.5 mg/mL towards human dermal fibroblasts and human epidermal carcinoma A431 cells [12]. The prolonged release of DOX from delivery systems of this structure into rat blood (2-3 weeks) has been revealed in our previous publications [13] where the DS preparations were administered in two ways (intraperitoneally, or subcutaneously). Of note, the carrier-free DOX was excreted from rats as early as 2 days after its intraperitoneal administration at similar dosage. In vivo experiments [14] demonstrated that intraperitoneal administration of 2 mg of DOX in DS (based on CaCO3 vaterites covered by DexS) in rats inoculated with Seidel hepatoma resulted in a two-fold increase of their life expectancy and a 1.5-fold decrease in ascites volume.

The purpose of this study was to demonstrate growth inhibition of breast adenocarcinomas in transgenic FVВ/N mice after intraperitoneal administration of DOX loaded into the СаСО3+DexS delivery systems at different component ratios.

Materials and methods

Reagents

Doxorubicin was purchased from Veropharm (Russia) as "Doxorubicin LENS" dosage form which contained 20% of doxorubicin hydrochloride (DOX) and 80% of mannitol. Inorganic salts (CaCl2 × 2H2O, Na2CO3), acetone, and sodium dextran sulfate (Mw = 9-20 kDa) were purchased from Sigma-Aldrich (St. Louis, MO).

Preparation of the delivery system and DOX loading

The preparation techniques for porous vaterites, methods of coating vaterites with DexS polyanions and introduction of DOX into these carriers are described in [15]. In brief, porous vaterites (СаСО3 cores) were prepared by co-precipitation of equal volumes of 1 M aqueous solutions of CaCl2 × 2H2O and Na2CO3 during intensive mixing for 30 seconds. Then the suspension was filtered through Schott filter glass, washed with distilled water and acetone. The precipitate was dried in a thermostat at 40-50°C until a constant weight was achieved.

The core DS was coated with a polyanion (sodium salt of dextran sulfate, DexS). СаСО3 cores (50 mg) were added to 10 mL aqueous solution of DexS (1 mg/mL). The suspension was stirred using a Multi Bio RS-24 rotor (Biosan, Latvia) for 1 h; the solid fraction was filtered off using a Schott glass filter, washed with distilled water and dried at 30°C.

DOX was loaded into DS under continuous stirring of the mixture containing the СаСО3+DexS (DS) suspension and 1 mg/mL DOX solution for 24 hours. The weight-to-weight DOX/(CaCO3+DexS) ratios were equal to 0.40 and 0.25; thus, two sets of DOX-containing delivery systems were formed. After mixing, the suspension was centrifuged at 8000 rpm for 3 min, and the DOX amount in supernatant was determined.

DOX load (L) was calculated using the following equation: L = (mi − ms)/mP, where mi is the initial weight of DOX; ms is the weight of non-encapsulated DOX in supernatant solution; mP is the weight of DS particles. DOX concentrations were determined using the calibration curves obtained from optical density measurements at λ=480 nm in the corresponding solvents. The mean error in triplicate measurement of DOX load under similar conditions was about 8%.

Scanning electron microscopy (SEM)

The DS samples were studied with Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging. Before measurements, the samples were coated with a thin platinum layer.

In vitro experiments with DOX release

The in vitro release of DOX from both variants of DS was analyzed in human blood plasma. Incubation of DS in this media was carried out at 20°C and at constant mixing by means of programmable Multi Bio RS-24 rotator (Biosan, Riga, Latvia). Aliquots were collected from incubation mixtures every 24 hours after centrifugation of core suspension at 3000 rpm for 3 min. Content of DOX in supernatant aliquots was determined spectrophotometrically (see above). The supernatant obtained by incubating CaCO3+DexS cores without DOX under the same conditions was used as a reference solution. After the measurements, the aliquots were returned to the incubation medium. The release parameter was determined as a percentage of the of DOX contents present in the initial DS suspension. The average errors in triplicate determination of DOX release under similar conditions were about 10%.

In vivo experiments with tumor-bearing mice

Transgenic FVВ/N mice characterized by overexpression of oncogenic HER-2/neu proteins were used in the experiments. The body weight of mice ranged from 23 to 26 g. The in vivo experiments involved fourteen 16 weeks-old FVB/N female mice divided into three groups. Two experimental groups included 5 mice each. NaCl solution (0.9%, 1 mL) containing various DS compositions was administered intraperitoneally (IP) to the experimental animals. The load characteristics are given in Table 1. Each sample contained 1 mg of DOX. The mice tolerated the administration satisfactorily. The third (control) group consisted of four FVB/N mice that did not receive the treatment. 29-weeks old mice (13 weeks after administration of the DS, one animal of each group) were sacrificed for morphological study. The total experimental period lasted 50 weeks.

Table 1. Influence of DS composition on development of tumors in transgenic FVB/N mice

Sudareva-tab01.jpg

All manipulations with animals were performed under general anesthesia: Sol. Zoletil 50 (0.05 mL per 0.1 kg of body mass), Sol. Rometаrum 20 mg/mL (0.0125 mL per 0.1 kg of body mass, intramuscularly). The animals were caged (5 individuals in a cage), had free access to water and food. The animals were fed the standard diet for laboratory mice used in the vivarium (4R F18 prolonged keeping formula for rodents, Macedonia, Italy). The animals of experimental and reference groups were examined daily; consumption of water and food was registered, body temperature and weight were measured. Behavior and life expectancy of animals were estimated for 44 weeks.

All the manipulations with animals were performed in accordance with State Standard 33216-2014 "Regulations for work with laboratory rodents and rabbits".

Characteristics of the process of tumor growth

The process was characterized using the "growth inhibition" parameter. This parameter describes antitumor effect of a tested compound at a given moment of time before or during treatment.

Growth inhibition GI (%) = (Vc – Ve/ Vc) ×100, where Vc is the average volume of a tumor in the control group, and Ve is the average volume of a tumor in the experimental group [16].

Morphological studies

Tumor nodules were not observed in animals of the experimental group. However, the nodules were visible in the mice from the non-treated reference group.

The biological material (mammary glands, liver, lung, small intestine) were fixed in 10% neutral formalin in phosphate buffer (рН=7.4) for, at least, 24 hrs, dehydrated using a series of ethanol solutions at increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. To obtain comparable results, the samples were treated simultaneously under similar conditions. The paraffin sections (5 μm thick) were prepared by means of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). Microscopic analysis was performed using a Nikon Eclipse E200 light microscope (Nikon, Japan) with a 10× ocular and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Fi3 camera (Nikon, Japan).

Results

Tumor incidence

The study was performed in FVВ/N transgenic mice which develop spontaneous mammary tumors associated with overexpression of HER-2/neu proteins. HER-2 is a human epidermal growth factor receptor. Super-expression of activated HER-2/neu in a female transgenic FVB/N mouse leads to malignant transformation of epithelial cells of the breast followed by development of several breast adenocarcinomas [17]. In this work, we compared antitumor activities of DOX-containing delivery systems at various compositions administered intraperitoneally into mice; the amount of injected DOX was 1 mg per animal.

The drug carriers were based on СаСО3 vaterites doped with DexS polyanions, by coating the carbonate core surface with the DexS polymer. The two used sets of DOX carriers differed in the DOX load per unit weight of a carrier. Their characteristics are given in Table 1. Antitumor activities of various DOX-containing DS were compared using the number, time of appearance and size of the detected tumors. These characteristics are also given in Table 1.

The values of tumor volumes in mice were used to determine characteristics of the process of disease development, i.e., inhibition of tumor growth GI (%) = (159.3-52.33)/159,3=67.1% for set 1 and GI (%) = (159.3-23)/159.3=85.5% for set 2. This parameter characterizes antitumor effect of a studied preparation. The data presented in Table 1 show that the efficiency of treatment with higher DOX load in DS (set 2) seems to be more pronounced than with delivery system from the set 1. A decrease in the average tumor volume correlates with an increase in the growth inhibition index. Hence, the inhibitory trend is more pronounced in the set 2. These results suggest that the DOX-containing DS administered intraperitoneally in both experimental sets exerts a moderate antitumor action in the FVB/N mice.

Morphological studies

Visual inspection of animals from the control group (non-treated mice) revealed breast tumors; microscopic studies showed a typical pattern of infiltrative ductal cancer: cystic formations were lined with tumor cells displaying moderate nuclear atypia and mitoses. Invasion into fatty tissue and a moderate nuclear polymorphism were also visible. When examining mice of the both experimental groups (DS-treated animals), no tumors were visually observed, but microscopic studies revealed focal atypical ductal hyperplasia, tumor cells with high nuclear atypia and pathological mitoses. Thus, we observed cytostatic effect of the administered DOX-containing DS.

Sudareva-fig01.jpg

Figure 1. Fragment of a liver of an animal from the control group (А) and an animal from the experimental group (set 2) (В) studied 29 weeks after the beginning of the experiment. Staining: hematoxylin, eosin; magnification: ×200

Histological analysis of the studied material did also reveal morphological changes in liver and lungs, while the morphological picture of small intestine remained unchanged. In the liver, changes in cytoarchitectonics of hepatic lobules (manifested as disturbance of the normal structure) are observed. Sinusoidal capillaries were dilated, central veins are collapsed. Pronounced vacuolar dystrophy in the cytoplasm of the majority of hepatocytes was observed only in experimental group (Fig. 1 А, B). All vessels of the lung are varicose and plethoric; hemorrhages are visible. Interalveolar partitions are thickened and contain increased amounts of macrophages. The described morphological changes are possibly caused by toxic action of the injected preparation.

SEM patterns of different structures in the drug carriers

Figure 2 shows SEM photos of the parent CaCO3 vaterites (Fig. 2A) and vaterites doped with sodium dextran sulfate polyanion (Fig. 2B). The set 1 and set 2 delivery systems with different DOX loads are presented in Figs. 2C and 2D, correspondingly. Comparison of Figs. 2A and 2B shows that doping calcium carbonate cores with DexS causes some slight changes in the structure of carriers. DexS molecules penetrate rather deeply into the porous structure of calcium carbonate (SEM photo of doped vaterite sample chip is not presented).

Analysis of SEM images of set 1 and set 2 delivery systems with different DOX loads reveals films of different areas that cover individual particles of the carriers (Fig. 2C, two particles are covered here together), or form coatings of larger areas (Fig. 2D). One should mention again that in our work doxorubicin was used in the form of the LENS preparation, which contains mannitol, and the DOX/mannitol ratio is equal to 1/4. Mannitol is an excipient widely used as a filler/binder in pharmaceuticals due to its chemical stability, solubility and low hygroscopicity. In addition to this function, mannitol is used to prevent kidney-related side effects that arise during use of some antitumor drugs [2]. Since the DOX load in the set 1 sample is 250 µg/mg (i.e. almost 1.5 times less than that in the set 2 samples), the set 1 preparations contain less mannitol, as is evident from the SEM images (Figs. 2C and 2D). Perhaps, higher amounts of mannitol in the delivery systems of set 2 may interfere additionally with DOX release, thus prolonging its action.

Sudareva-fig02.jpg

Figure 2. SEM photos: A, parent CaCO3 vaterites; B, CaCO3 vaterites covered by DexS polyanion; C, set 1 delivery system; D, set 2 delivery system. Marker bars, 300 nm

Characteristics of carriers. In vitro experiments

The further questions concerns possible causes of differential therapeutic effects observed upon administration of the same DOX dose (1 mg) by differently loaded delivery systems. Let us compare compositions of the two used sets of delivery systems. The DOX load in set 1 DS is equal to 250 µg/mg, and in the second DS it is equal to 380 µg/mg. Therefore, the reason for the therapeutic differences may be found in the role of carriers. We have compared the in vitro behavior of DOX delivery systems. Fig. 3 shows release profiles of DOX into blood plasma from delivery systems СаСО3+DexS at different DOX load values.

One may see from Figure 3 that an increase in DOX load in the delivery systems leads to prolonged release of the drug into the ambient medium. For example, Fig. 3B (curve 1) shows almost complete release of DOX already 10 days after the beginning of the experiment. Appearance of tumors in the in vivo model can be expected at a later time. Thus, the appearance of tumors at later stages in animals treated with high-load (set 2) DOX-containing delivery systems may be explained by more prolonged DOX release.

Sudareva-fig03.jpg

Figure 3. Profiles of DOX release into blood plasma from DS at different load values. А, DOX loading in water. Load: set 1 – 250 µg/mg; set 2 – 380 µg/mg. B – DOX loading in phosphate buffer. Load: set 1 – 100 µg/mg; set 2 – 360 µg/mg. Abscissa, incubation terms, days.

Conclusions

It was demonstrated that the delivery systems (DS) for antitumor doxorubicin (DOX) preparation based on porous calcium carbonate vaterites doped with dextran sulfate polyanion exert a cytostatic effect upon intraperitoneal administration of equivalent amounts of DOX. In female FVB/N transgenic mice, these DS suppress tumor growth more efficiently in the case when higher DOX/(СаСО3+DexS) ratios are used. Taking these results into account, one may recommend usage of delivery systems with higher DOX load in further experiments.

Financial support

The study was performed within the framework of budget-supported research project №, 122012100171-8 Institute of Macromolecular Compounds, RAS.

Conflict of interests

None declared.

References

  1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56: 185-229. doi: 10.1124/pr.56.2.6
  2. Vozniy EL, Sakaeva DD. Oncologist's diary. Dinastija, Moscow, 2011,160 p. (In Russian).
  3. Matyszewska D. Drug delivery systems in the transport of doxorubicin. Inst Civil Eng Surface Innovat. 2014; 2(4): 201-210.
    doi: 10.1680/si.13.00040
  4. Tang X, Lin K, Ke G, Ron Y, Chen D, Chen Z, et al. The synergistic effect of ruthenium complex δ-ru1 and doxorubicin in a mouse breast cancer model. Recent Patents Anti-Cancer Drug Discov. 2023; 18(2): 174-186. doi: 10.2174/1574892817666220629105543
  5. Wang X-F, Ren J, He H-Q, Liang L, Xie X, Li Z-X, et al. Self-assembled nanoparticles of reduction-sensitive poly (lactic-co-glycolic acid)-conjugated chondroitin sulfate a for doxorubicin delivery: preparation, characterization and evaluation. Pharm Dev Technol. 2019;24:794-802. doi: 10.1080/10837450.2019.1599914
  6. Yu J, Wang L, Xie X, Zhu W, Lei Z, Lv L, et al. Multifunctional nanoparticles codelivering doxorubicin and amorphous calcium carbonate preloaded with indocyanine green for enhanced chemo-photothermal cancer therapy. Int J Nanomed. 2023;18: 323-337. doi: 10.2147/IJN.S394896
  7. Trushina D, Borodina T, Belyakov S, Antipina M. Calcium carbonate vaterite particles for drug delivery: Adv and challen. Mater Today Adv. 2022; 14: 100214. doi: 10.1016/j.mtadv.2022.100214
  8. Dizaj S, Sharifi S, Ahmadian E, Eftekhari A, Adibkia K, Lotfipour F. An update on calcium carbonate nanoparticles as cancer drug/gene delivery system, Exp Opin Drug Deliv. 2019; 16(4): 331-345. doi: 10.1080/17425247.2019.1587408
  9. Wang C, Liu X, Chen S, Hu F, Sun J, Yuan H. Facile preparation of phospholipid-amorphous calcium carbonate hybrid nanoparticles: toward controllable burst drug release and enhanced tumor penetration. Chem Commun. 2018; 54: 13080-13083.
    doi: 10.1039/C8CC07694D
  10. Sudareva N, Suvorova O, Saprykina N, Vlasova H, Vilesov A. Doxorubicin delivery systems based on doped CaCO3 cores and polyanion drug conjugates. J. Microencaps. 2019;38:164-176. doi: 10.1080/02652048.2021.1872724
  11. Alavi M, Rai M. Recent progress in nanoformulations of silver nanoparticles with cellulose, chitosan, and alginic acid biopolymers for antibacterial applications. Appl Microbiol Biotechnol. 2019; 103: 8669-8676. doi: 10.1007/s00253-019-10126-4
  12. Sudareva N, Suvorova O, Saprykina N, Smirnova N, Bel’tyukov P, Petunov S et al. Two-level delivery systems based on CaCO3 cores for oral administration of therapeutic peptides. J Microencaps. 2018; 35: 619-635. doi: 10.1080/02652048.2018.1559247
  13. Sudareva N, Suvorova O, Kolbe K, Suslov D, Galibin O, Vilesov A et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant. 2022; 11(3/4): 87-92.
    doi: 10.18620/ctt-1866-8836-2022-11-3-4-87-92
  14. Sudareva N, Suvorova O, Suslov D, Galibin O, Vilesov A. Dextran sulfate coated CaCO3 vaterites as the systems for regional administration of doxorubicin. Cell Ther Transplant. 2021; 10(3/4): 71-77. doi: 10.18620/ctt-1866-8836-2021-10-3-4-71-77
  15. Sudareva N, Suvorova O, Saprykina N, Tomson V, Suslov D, Galibin O et al. Morphology of hybrid doxorubicin delivery systems (dextran sulfate-coated CaCO3 vaterites) in human blood plasma. Cell Ther Transplant. 2021; 10(1): 79-85.
    doi: 10.18620/ctt-1866-8836-2021-10-1-79-85
  16. Stukov A, Vershinina S, Koziavin N, SemiglazovaT, Filatova L, Latipova D et al. Study of the effect of lomustin on HER2-positive breast cancer in FVB/N HER-2 transgenic mice. Siberian J Oncol. 2019; 18(5): 54-60. doi: 10.21294/1814-4861-2019-18-5-54-60
  17. Muller W, Ho J, Siegel P. Oncogenic activation of Neu/ErbB-2 in a transgenic mouse model for breast cancer. Biochem Soc Symp. 1998; 63: 149-157.

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Introduction

Doxorubicin (DOX), an anthracycline antibiotic which is successfully used in treatment of different malignancies, particularly, breast cancer. The main mechanisms of DOX action upon tumor cells include: (i) intercalation of DNA molecules, thus inhibiting DNA synthesis; (ii) generation of free radicals leading to DNA damage or lipid peroxidation [1]. However, the drug has several essential drawbacks: rapid clearance, dose-dependent cardiotoxicity, hepatic damage [1] and hematological toxicity [2]. The delivery systems that are able to eliminate these problems and increase DOX efficiency are discussed in the review [3], which is focused on delivery systems based on organic and inorganic compounds. Later publications describe complex multicomponent DOX delivery systems. For example, drug synergism observed upon combined use of DOX and ruthenium complex (Δ-Ru1/DOX) manifests as a decreased DOX cardiotoxicity [4]. Aiming for effective suppression of tumor growth, DOX is introduced into the specially prepared conjugates of nanoparticles of poly(lactic-co-glycolic acid) with chondroitin sulfate A [5]. The authors used simultaneous encapsulation of DOX and photosensitizer Indocyanine Green, in order to enhance the effect of chemo-photothermal cancer therapy [6].

The porous particles of calcium carbonate (CaCO3) vaterites are used as delivery systems (DS) for various drugs. They draw attention of researchers due to their biocompatibility, biodegradability, non-toxicity, low cost, and ease of preparation. A comprehensive review [7] discusses the recent successful applications of the CaCO3 vaterites to the delivery (in vivo and in vitro) of various diagnostic agents and therapeutic drugs. Special attention to the use of СаСО3 as carriers for antitumor preparations (in particular, with DOX) has been given elsewhere [8]. In the present work, DOX was encapsulated in the delivery systems on the basis of СаСО3 cores doped with DexS polyanions (CaCO3+DexS). DOX in the form of hydrochloride (thus creating acidic medium) is introduced into carbonate cores, thus causing re-crystallization of vaterites into non-porous calcites. Vaterites are then coated with polymers to protect their porous structure [9, 10]. Dextran sulfate is a bioavailable polymer [11]. It was shown that СаСО3 doped with DexS by various methods (coating, co-precipitation) was virtually non-cytotoxic at concentrations below 0.5 mg/mL towards human dermal fibroblasts and human epidermal carcinoma A431 cells [12]. The prolonged release of DOX from delivery systems of this structure into rat blood (2-3 weeks) has been revealed in our previous publications [13] where the DS preparations were administered in two ways (intraperitoneally, or subcutaneously). Of note, the carrier-free DOX was excreted from rats as early as 2 days after its intraperitoneal administration at similar dosage. In vivo experiments [14] demonstrated that intraperitoneal administration of 2 mg of DOX in DS (based on CaCO3 vaterites covered by DexS) in rats inoculated with Seidel hepatoma resulted in a two-fold increase of their life expectancy and a 1.5-fold decrease in ascites volume.

The purpose of this study was to demonstrate growth inhibition of breast adenocarcinomas in transgenic FVВ/N mice after intraperitoneal administration of DOX loaded into the СаСО3+DexS delivery systems at different component ratios.

Materials and methods

Reagents

Doxorubicin was purchased from Veropharm (Russia) as "Doxorubicin LENS" dosage form which contained 20% of doxorubicin hydrochloride (DOX) and 80% of mannitol. Inorganic salts (CaCl2 × 2H2O, Na2CO3), acetone, and sodium dextran sulfate (Mw = 9-20 kDa) were purchased from Sigma-Aldrich (St. Louis, MO).

Preparation of the delivery system and DOX loading

The preparation techniques for porous vaterites, methods of coating vaterites with DexS polyanions and introduction of DOX into these carriers are described in [15]. In brief, porous vaterites (СаСО3 cores) were prepared by co-precipitation of equal volumes of 1 M aqueous solutions of CaCl2 × 2H2O and Na2CO3 during intensive mixing for 30 seconds. Then the suspension was filtered through Schott filter glass, washed with distilled water and acetone. The precipitate was dried in a thermostat at 40-50°C until a constant weight was achieved.

The core DS was coated with a polyanion (sodium salt of dextran sulfate, DexS). СаСО3 cores (50 mg) were added to 10 mL aqueous solution of DexS (1 mg/mL). The suspension was stirred using a Multi Bio RS-24 rotor (Biosan, Latvia) for 1 h; the solid fraction was filtered off using a Schott glass filter, washed with distilled water and dried at 30°C.

DOX was loaded into DS under continuous stirring of the mixture containing the СаСО3+DexS (DS) suspension and 1 mg/mL DOX solution for 24 hours. The weight-to-weight DOX/(CaCO3+DexS) ratios were equal to 0.40 and 0.25; thus, two sets of DOX-containing delivery systems were formed. After mixing, the suspension was centrifuged at 8000 rpm for 3 min, and the DOX amount in supernatant was determined.

DOX load (L) was calculated using the following equation: L = (mi − ms)/mP, where mi is the initial weight of DOX; ms is the weight of non-encapsulated DOX in supernatant solution; mP is the weight of DS particles. DOX concentrations were determined using the calibration curves obtained from optical density measurements at λ=480 nm in the corresponding solvents. The mean error in triplicate measurement of DOX load under similar conditions was about 8%.

Scanning electron microscopy (SEM)

The DS samples were studied with Supra 55VP scanning electron microscope (Carl Zeiss, Germany) using secondary electron imaging. Before measurements, the samples were coated with a thin platinum layer.

In vitro experiments with DOX release

The in vitro release of DOX from both variants of DS was analyzed in human blood plasma. Incubation of DS in this media was carried out at 20°C and at constant mixing by means of programmable Multi Bio RS-24 rotator (Biosan, Riga, Latvia). Aliquots were collected from incubation mixtures every 24 hours after centrifugation of core suspension at 3000 rpm for 3 min. Content of DOX in supernatant aliquots was determined spectrophotometrically (see above). The supernatant obtained by incubating CaCO3+DexS cores without DOX under the same conditions was used as a reference solution. After the measurements, the aliquots were returned to the incubation medium. The release parameter was determined as a percentage of the of DOX contents present in the initial DS suspension. The average errors in triplicate determination of DOX release under similar conditions were about 10%.

In vivo experiments with tumor-bearing mice

Transgenic FVВ/N mice characterized by overexpression of oncogenic HER-2/neu proteins were used in the experiments. The body weight of mice ranged from 23 to 26 g. The in vivo experiments involved fourteen 16 weeks-old FVB/N female mice divided into three groups. Two experimental groups included 5 mice each. NaCl solution (0.9%, 1 mL) containing various DS compositions was administered intraperitoneally (IP) to the experimental animals. The load characteristics are given in Table 1. Each sample contained 1 mg of DOX. The mice tolerated the administration satisfactorily. The third (control) group consisted of four FVB/N mice that did not receive the treatment. 29-weeks old mice (13 weeks after administration of the DS, one animal of each group) were sacrificed for morphological study. The total experimental period lasted 50 weeks.

Table 1. Influence of DS composition on development of tumors in transgenic FVB/N mice

Sudareva-tab01.jpg

All manipulations with animals were performed under general anesthesia: Sol. Zoletil 50 (0.05 mL per 0.1 kg of body mass), Sol. Rometаrum 20 mg/mL (0.0125 mL per 0.1 kg of body mass, intramuscularly). The animals were caged (5 individuals in a cage), had free access to water and food. The animals were fed the standard diet for laboratory mice used in the vivarium (4R F18 prolonged keeping formula for rodents, Macedonia, Italy). The animals of experimental and reference groups were examined daily; consumption of water and food was registered, body temperature and weight were measured. Behavior and life expectancy of animals were estimated for 44 weeks.

All the manipulations with animals were performed in accordance with State Standard 33216-2014 "Regulations for work with laboratory rodents and rabbits".

Characteristics of the process of tumor growth

The process was characterized using the "growth inhibition" parameter. This parameter describes antitumor effect of a tested compound at a given moment of time before or during treatment.

Growth inhibition GI (%) = (Vc – Ve/ Vc) ×100, where Vc is the average volume of a tumor in the control group, and Ve is the average volume of a tumor in the experimental group [16].

Morphological studies

Tumor nodules were not observed in animals of the experimental group. However, the nodules were visible in the mice from the non-treated reference group.

The biological material (mammary glands, liver, lung, small intestine) were fixed in 10% neutral formalin in phosphate buffer (рН=7.4) for, at least, 24 hrs, dehydrated using a series of ethanol solutions at increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. To obtain comparable results, the samples were treated simultaneously under similar conditions. The paraffin sections (5 μm thick) were prepared by means of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). Microscopic analysis was performed using a Nikon Eclipse E200 light microscope (Nikon, Japan) with a 10× ocular and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Fi3 camera (Nikon, Japan).

Results

Tumor incidence

The study was performed in FVВ/N transgenic mice which develop spontaneous mammary tumors associated with overexpression of HER-2/neu proteins. HER-2 is a human epidermal growth factor receptor. Super-expression of activated HER-2/neu in a female transgenic FVB/N mouse leads to malignant transformation of epithelial cells of the breast followed by development of several breast adenocarcinomas [17]. In this work, we compared antitumor activities of DOX-containing delivery systems at various compositions administered intraperitoneally into mice; the amount of injected DOX was 1 mg per animal.

The drug carriers were based on СаСО3 vaterites doped with DexS polyanions, by coating the carbonate core surface with the DexS polymer. The two used sets of DOX carriers differed in the DOX load per unit weight of a carrier. Their characteristics are given in Table 1. Antitumor activities of various DOX-containing DS were compared using the number, time of appearance and size of the detected tumors. These characteristics are also given in Table 1.

The values of tumor volumes in mice were used to determine characteristics of the process of disease development, i.e., inhibition of tumor growth GI (%) = (159.3-52.33)/159,3=67.1% for set 1 and GI (%) = (159.3-23)/159.3=85.5% for set 2. This parameter characterizes antitumor effect of a studied preparation. The data presented in Table 1 show that the efficiency of treatment with higher DOX load in DS (set 2) seems to be more pronounced than with delivery system from the set 1. A decrease in the average tumor volume correlates with an increase in the growth inhibition index. Hence, the inhibitory trend is more pronounced in the set 2. These results suggest that the DOX-containing DS administered intraperitoneally in both experimental sets exerts a moderate antitumor action in the FVB/N mice.

Morphological studies

Visual inspection of animals from the control group (non-treated mice) revealed breast tumors; microscopic studies showed a typical pattern of infiltrative ductal cancer: cystic formations were lined with tumor cells displaying moderate nuclear atypia and mitoses. Invasion into fatty tissue and a moderate nuclear polymorphism were also visible. When examining mice of the both experimental groups (DS-treated animals), no tumors were visually observed, but microscopic studies revealed focal atypical ductal hyperplasia, tumor cells with high nuclear atypia and pathological mitoses. Thus, we observed cytostatic effect of the administered DOX-containing DS.

Sudareva-fig01.jpg

Figure 1. Fragment of a liver of an animal from the control group (А) and an animal from the experimental group (set 2) (В) studied 29 weeks after the beginning of the experiment. Staining: hematoxylin, eosin; magnification: ×200

Histological analysis of the studied material did also reveal morphological changes in liver and lungs, while the morphological picture of small intestine remained unchanged. In the liver, changes in cytoarchitectonics of hepatic lobules (manifested as disturbance of the normal structure) are observed. Sinusoidal capillaries were dilated, central veins are collapsed. Pronounced vacuolar dystrophy in the cytoplasm of the majority of hepatocytes was observed only in experimental group (Fig. 1 А, B). All vessels of the lung are varicose and plethoric; hemorrhages are visible. Interalveolar partitions are thickened and contain increased amounts of macrophages. The described morphological changes are possibly caused by toxic action of the injected preparation.

SEM patterns of different structures in the drug carriers

Figure 2 shows SEM photos of the parent CaCO3 vaterites (Fig. 2A) and vaterites doped with sodium dextran sulfate polyanion (Fig. 2B). The set 1 and set 2 delivery systems with different DOX loads are presented in Figs. 2C and 2D, correspondingly. Comparison of Figs. 2A and 2B shows that doping calcium carbonate cores with DexS causes some slight changes in the structure of carriers. DexS molecules penetrate rather deeply into the porous structure of calcium carbonate (SEM photo of doped vaterite sample chip is not presented).

Analysis of SEM images of set 1 and set 2 delivery systems with different DOX loads reveals films of different areas that cover individual particles of the carriers (Fig. 2C, two particles are covered here together), or form coatings of larger areas (Fig. 2D). One should mention again that in our work doxorubicin was used in the form of the LENS preparation, which contains mannitol, and the DOX/mannitol ratio is equal to 1/4. Mannitol is an excipient widely used as a filler/binder in pharmaceuticals due to its chemical stability, solubility and low hygroscopicity. In addition to this function, mannitol is used to prevent kidney-related side effects that arise during use of some antitumor drugs [2]. Since the DOX load in the set 1 sample is 250 µg/mg (i.e. almost 1.5 times less than that in the set 2 samples), the set 1 preparations contain less mannitol, as is evident from the SEM images (Figs. 2C and 2D). Perhaps, higher amounts of mannitol in the delivery systems of set 2 may interfere additionally with DOX release, thus prolonging its action.

Sudareva-fig02.jpg

Figure 2. SEM photos: A, parent CaCO3 vaterites; B, CaCO3 vaterites covered by DexS polyanion; C, set 1 delivery system; D, set 2 delivery system. Marker bars, 300 nm

Characteristics of carriers. In vitro experiments

The further questions concerns possible causes of differential therapeutic effects observed upon administration of the same DOX dose (1 mg) by differently loaded delivery systems. Let us compare compositions of the two used sets of delivery systems. The DOX load in set 1 DS is equal to 250 µg/mg, and in the second DS it is equal to 380 µg/mg. Therefore, the reason for the therapeutic differences may be found in the role of carriers. We have compared the in vitro behavior of DOX delivery systems. Fig. 3 shows release profiles of DOX into blood plasma from delivery systems СаСО3+DexS at different DOX load values.

One may see from Figure 3 that an increase in DOX load in the delivery systems leads to prolonged release of the drug into the ambient medium. For example, Fig. 3B (curve 1) shows almost complete release of DOX already 10 days after the beginning of the experiment. Appearance of tumors in the in vivo model can be expected at a later time. Thus, the appearance of tumors at later stages in animals treated with high-load (set 2) DOX-containing delivery systems may be explained by more prolonged DOX release.

Sudareva-fig03.jpg

Figure 3. Profiles of DOX release into blood plasma from DS at different load values. А, DOX loading in water. Load: set 1 – 250 µg/mg; set 2 – 380 µg/mg. B – DOX loading in phosphate buffer. Load: set 1 – 100 µg/mg; set 2 – 360 µg/mg. Abscissa, incubation terms, days.

Conclusions

It was demonstrated that the delivery systems (DS) for antitumor doxorubicin (DOX) preparation based on porous calcium carbonate vaterites doped with dextran sulfate polyanion exert a cytostatic effect upon intraperitoneal administration of equivalent amounts of DOX. In female FVB/N transgenic mice, these DS suppress tumor growth more efficiently in the case when higher DOX/(СаСО3+DexS) ratios are used. Taking these results into account, one may recommend usage of delivery systems with higher DOX load in further experiments.

Financial support

The study was performed within the framework of budget-supported research project №, 122012100171-8 Institute of Macromolecular Compounds, RAS.

Conflict of interests

None declared.

References

  1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56: 185-229. doi: 10.1124/pr.56.2.6
  2. Vozniy EL, Sakaeva DD. Oncologist's diary. Dinastija, Moscow, 2011,160 p. (In Russian).
  3. Matyszewska D. Drug delivery systems in the transport of doxorubicin. Inst Civil Eng Surface Innovat. 2014; 2(4): 201-210.
    doi: 10.1680/si.13.00040
  4. Tang X, Lin K, Ke G, Ron Y, Chen D, Chen Z, et al. The synergistic effect of ruthenium complex δ-ru1 and doxorubicin in a mouse breast cancer model. Recent Patents Anti-Cancer Drug Discov. 2023; 18(2): 174-186. doi: 10.2174/1574892817666220629105543
  5. Wang X-F, Ren J, He H-Q, Liang L, Xie X, Li Z-X, et al. Self-assembled nanoparticles of reduction-sensitive poly (lactic-co-glycolic acid)-conjugated chondroitin sulfate a for doxorubicin delivery: preparation, characterization and evaluation. Pharm Dev Technol. 2019;24:794-802. doi: 10.1080/10837450.2019.1599914
  6. Yu J, Wang L, Xie X, Zhu W, Lei Z, Lv L, et al. Multifunctional nanoparticles codelivering doxorubicin and amorphous calcium carbonate preloaded with indocyanine green for enhanced chemo-photothermal cancer therapy. Int J Nanomed. 2023;18: 323-337. doi: 10.2147/IJN.S394896
  7. Trushina D, Borodina T, Belyakov S, Antipina M. Calcium carbonate vaterite particles for drug delivery: Adv and challen. Mater Today Adv. 2022; 14: 100214. doi: 10.1016/j.mtadv.2022.100214
  8. Dizaj S, Sharifi S, Ahmadian E, Eftekhari A, Adibkia K, Lotfipour F. An update on calcium carbonate nanoparticles as cancer drug/gene delivery system, Exp Opin Drug Deliv. 2019; 16(4): 331-345. doi: 10.1080/17425247.2019.1587408
  9. Wang C, Liu X, Chen S, Hu F, Sun J, Yuan H. Facile preparation of phospholipid-amorphous calcium carbonate hybrid nanoparticles: toward controllable burst drug release and enhanced tumor penetration. Chem Commun. 2018; 54: 13080-13083.
    doi: 10.1039/C8CC07694D
  10. Sudareva N, Suvorova O, Saprykina N, Vlasova H, Vilesov A. Doxorubicin delivery systems based on doped CaCO3 cores and polyanion drug conjugates. J. Microencaps. 2019;38:164-176. doi: 10.1080/02652048.2021.1872724
  11. Alavi M, Rai M. Recent progress in nanoformulations of silver nanoparticles with cellulose, chitosan, and alginic acid biopolymers for antibacterial applications. Appl Microbiol Biotechnol. 2019; 103: 8669-8676. doi: 10.1007/s00253-019-10126-4
  12. Sudareva N, Suvorova O, Saprykina N, Smirnova N, Bel’tyukov P, Petunov S et al. Two-level delivery systems based on CaCO3 cores for oral administration of therapeutic peptides. J Microencaps. 2018; 35: 619-635. doi: 10.1080/02652048.2018.1559247
  13. Sudareva N, Suvorova O, Kolbe K, Suslov D, Galibin O, Vilesov A et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant. 2022; 11(3/4): 87-92.
    doi: 10.18620/ctt-1866-8836-2022-11-3-4-87-92
  14. Sudareva N, Suvorova O, Suslov D, Galibin O, Vilesov A. Dextran sulfate coated CaCO3 vaterites as the systems for regional administration of doxorubicin. Cell Ther Transplant. 2021; 10(3/4): 71-77. doi: 10.18620/ctt-1866-8836-2021-10-3-4-71-77
  15. Sudareva N, Suvorova O, Saprykina N, Tomson V, Suslov D, Galibin O et al. Morphology of hybrid doxorubicin delivery systems (dextran sulfate-coated CaCO3 vaterites) in human blood plasma. Cell Ther Transplant. 2021; 10(1): 79-85.
    doi: 10.18620/ctt-1866-8836-2021-10-1-79-85
  16. Stukov A, Vershinina S, Koziavin N, SemiglazovaT, Filatova L, Latipova D et al. Study of the effect of lomustin on HER2-positive breast cancer in FVB/N HER-2 transgenic mice. Siberian J Oncol. 2019; 18(5): 54-60. doi: 10.21294/1814-4861-2019-18-5-54-60
  17. Muller W, Ho J, Siegel P. Oncogenic activation of Neu/ErbB-2 in a transgenic mouse model for breast cancer. Biochem Soc Symp. 1998; 63: 149-157.

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Сударева<sup>1,2</sup>, Дмитрий Н. Суслов<sup>3</sup>, Ольга М. Суворова<sup>1</sup>, Галина Ю. Юкина<sup>2</sup>, Елена Г. Сухорукова<sup>2</sup>, Наталия Н. Сапрыкина<sup>1</sup>, Владимир Н. Анисимов<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(339) "

Наталия Н. Сударева1,2, Дмитрий Н. Суслов3, Ольга М. Суворова1, Галина Ю. Юкина2, Елена Г. Сухорукова2, Наталия Н. Сапрыкина1, Владимир Н. Анисимов3

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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Научный медицинский исследовательский центр им. Н. Н. Петрова, Санкт-Петербург, Россия

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Исследовали воздействие доксорубицина (ДОХ), инкапсулированного в системы доставки (СД) на базе пористых карбонатно-кальциевых ватеритов, допированных полианионом декстрансульфатом натрия (СаСО3+ DexS), на организмы трансгенных мышей линии FVB/N. Внутрибрюшинно вводили по 1 мг ДОХ в СД с разным соотношением компонентов. Показано, что при большем соотношении ДОХ/СД эффективность контроля над ростом опухолей у самок мышей FVB/N повышается. При этом опухоли меньшего размера и в меньшем количестве проявляются позднее при введении СД именно такого состава. В ряде случаев опухоли не выявляются вплоть до окончания эксперимента в течение 50 недель.

Ключевые слова

Доксорубицин, системы доставки лекарств, СаСО3, декстран сульфат натрия, внутрибрюшинное введение, морфология.

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Natalia N. Sudareva1,2, Dmitry N. Suslov3, Olga М. Suvorova1, Galina Y. Yukina2, Elena G. Sukhorukova2, Natalia N. Saprykina1, Vladimir N. Anisimov3

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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 N. N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds, 31 Bolshoi Ave, 199004, St. Petersburg, Russia
E-mail: nnsas@mail.ru


Citation: Sudareva NN, Suslov DN, Suvorova OM, et al. Influence of the composition of doxorubicin delivery systems on the effectiveness of cancer therapy in transgenic FVB/N mice. Cell Ther Transplant 2023; 12(2): 51-56.

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The influence of doxorubicin (DOX) encapsulated into the delivery systems (DS) based on porous calcium carbonate vaterites doped with sodium dextran sulfate polyanions (СаСО3+ DexS) was investigated in experimental model of FVB/N transgenic mice developing tumors associated with HER-2/neu overexpression. Doxorubicin (1 mg) was loaded in DS at different drug-to-DS ratios, then being administered intraperitoneally. It was demonstrated that the preparations with higher DOX/DS ratios suppressed tumor growth in female FVB/N mice more efficiently. When injecting delivery systems of these compositions, the incidence of tumors was relatively lower, they developed at later terms and were smaller in size. In some cases, the tumors were not revealed until termination of the experiment (50 weeks).

Keywords

Doxorubicin, drug delivery system, CaCO3, sodium dextran sulfate, intraperitoneal administration, morphology.

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Sudareva<sup>1,2</sup>, Dmitry N. Suslov<sup>3</sup>, Olga М. Suvorova<sup>1</sup>, Galina Y. Yukina<sup>2</sup>, Elena G. Sukhorukova<sup>2</sup>, Natalia N. Saprykina<sup>1</sup>, Vladimir N. Anisimov<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(234) "

Natalia N. Sudareva1,2, Dmitry N. Suslov3, Olga М. Suvorova1, Galina Y. Yukina2, Elena G. Sukhorukova2, Natalia N. Saprykina1, Vladimir N. Anisimov3

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Natalia N. Sudareva1,2, Dmitry N. Suslov3, Olga М. Suvorova1, Galina Y. Yukina2, Elena G. Sukhorukova2, Natalia N. Saprykina1, Vladimir N. Anisimov3

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The influence of doxorubicin (DOX) encapsulated into the delivery systems (DS) based on porous calcium carbonate vaterites doped with sodium dextran sulfate polyanions (СаСО3+ DexS) was investigated in experimental model of FVB/N transgenic mice developing tumors associated with HER-2/neu overexpression. Doxorubicin (1 mg) was loaded in DS at different drug-to-DS ratios, then being administered intraperitoneally. It was demonstrated that the preparations with higher DOX/DS ratios suppressed tumor growth in female FVB/N mice more efficiently. When injecting delivery systems of these compositions, the incidence of tumors was relatively lower, they developed at later terms and were smaller in size. In some cases, the tumors were not revealed until termination of the experiment (50 weeks).

Keywords

Doxorubicin, drug delivery system, CaCO3, sodium dextran sulfate, intraperitoneal administration, morphology.

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The influence of doxorubicin (DOX) encapsulated into the delivery systems (DS) based on porous calcium carbonate vaterites doped with sodium dextran sulfate polyanions (СаСО3+ DexS) was investigated in experimental model of FVB/N transgenic mice developing tumors associated with HER-2/neu overexpression. Doxorubicin (1 mg) was loaded in DS at different drug-to-DS ratios, then being administered intraperitoneally. It was demonstrated that the preparations with higher DOX/DS ratios suppressed tumor growth in female FVB/N mice more efficiently. When injecting delivery systems of these compositions, the incidence of tumors was relatively lower, they developed at later terms and were smaller in size. In some cases, the tumors were not revealed until termination of the experiment (50 weeks).

Keywords

Doxorubicin, drug delivery system, CaCO3, sodium dextran sulfate, intraperitoneal administration, morphology.

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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 N. N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva,