Autologous Stem Cell Research Articles

High-Dose Chemotherapy and Autologous or Allogeneic Transplantation in Aggressive B-Cell Lymphoma-Is There Still a Role?

Novel therapies such as CAR-T, BTK inhibitors and PD-1 inhibitors have changed the management of aggressive B-cell lymphomas. Nonetheless, these novel therapies have their own risk of late toxicities including second malignancies. They also create a subgroup of patients with relapse, treatment failure, or indefinite maintenance. We discuss the current role of autologous and allogeneic stem cell transplantation in this context. In patients with recurrent diffuse large B-cell lymphoma, CAR-T cell treatment has largely replaced autologous transplant. Autologous transplant should be considered in patients with late relapses and in selected patients with T-cell-rich B-cell lymphoma, where CAR-T cell therapy may be less effective. It also remains the treatment of choice for consolidation of patients with primary CNS lymphoma. In mantle cell lymphoma, intensive chemotherapy combined with BTK inhibitors and rituximab results in excellent outcomes, and the role of autologous transplantation is declining. In Hodgkin's lymphoma, autologous transplant consolidation remains the standard of care for patients who failed initial chemotherapy. Allogeneic transplantation has lower relapse rates but more complications and higher non-relapse mortality than autologous transplantation. It is usually reserved for patients who fail autologous transplantation or in whom autologous stem cells cannot be collected. It may also have an important role in patients who fail CAR-T therapies. The increasing complexity of care and evolving sequencing of therapies for patients with aggressive B-cell lymphomas only emphasizes the importance of appropriate patient selection and optimal timing of stem cell transplantation.

A Contemporary Review of Trachea, Nose, and Ear Cartilage Bioengineering and Additive Manufacturing.

The complex structure, chemical composition, and biomechanical properties of craniofacial cartilaginous structures make them challenging to reconstruct. Autologous grafts have limited tissue availability and can cause significant donor-site morbidity, homologous grafts often require immunosuppression, and alloplastic grafts may have high rates of infection or displacement. Furthermore, all these grafting techniques require a high level of surgical skill to ensure that the reconstruction matches the original structure. Current research indicates that additive manufacturing shows promise in overcoming these limitations. Autologous stem cells have been developed into cartilage when exposed to the appropriate growth factors and culture conditions, such as mechanical stress and oxygen deprivation. Additive manufacturing allows for increased precision when engineering scaffolds for stem cell cultures. Fine control over the porosity and structure of a material ensures adequate cell adhesion and fit between the graft and the defect. Several recent tissue engineering studies have focused on the trachea, nose, and ear, as these structures are often damaged by congenital conditions, trauma, and malignancy. This article reviews the limitations of current reconstructive techniques and the new developments in additive manufacturing for tracheal, nasal, and auricular cartilages.

Optimizing interleukin-6 and 8 expression, clarification and purification in plant cell packs and plants for application in advanced therapy medicinal products and cellular agriculture

Healthcare and nutrition are facing a paradigm shift in light of advanced therapy medicinal products (ATMPs) and cellular agriculture options respectively. Both options heavily rely on some sort of animal cell culture, e.g. autologous stem cells. These cultures require various growth factors, such as interleukin-6 and 8 (IL-6/8), in a pure, safe and sustainable form that can be provided in a scalable manner. Plants seem well suited for this task because purification of small proteins can be readily achieved by membrane separation, human/animal pathogens do not replicate in plants and production can be scaled up using in-door farming or agricultural practices. Here, we illustrate this capacity by first optimizing the codon usage of IL-6/8 for translation in Nicotiana spp., as well as testing the effect of untranslated regions and product targeting to different sub-cellular compartments on expression in a high-throughput plant cell pack (PCP) assay. In the chloroplast, IL-6 accumulated up to 6.9±3.8 (SD, n=2) and 14.4±7.4 mg kg−1 (SD, n=5) were observed in case of IL-8. When transferring IL-8 expression into whole plants, accumulation was 12.3±1.5 mg kg−1 (SD, n=3). After extraction and clarification, IL-8 was purified using a two-stage process consisting of an ultrafiltration/diafiltration step with 100 kDa and 10 kDa cut off membranes followed by an IMAC polishing step. The purity, yield and recovery were 97.8%, 6.6 mg kg−1 and 38%, respectively. We evaluated the ability of the proposed purification process to remove endotoxins to ensure the compatibility of plant-made growth factors with cell culture.

Meniscal repair with additive manufacture of bioresorbable polymer: From physicochemical characterization to implantation of 3D printed poly (L-co-D, L lactide-co-trimethylene carbonate) with autologous stem cells in rabbits.

Three-dimensional (3D) structures are actually the state-of-the-art technique to create porous scaffolds for tissue engineering. Since regeneration in cartilage tissue is limited due to intrinsic cellular properties this study aims to develop and characterize three-dimensional porous scaffolds of poly (L-co-D, L lactide-co-trimethylene carbonate), PLDLA-TMC, obtained by 3D fiber deposition technique. The PLDLA-TMC terpolymer scaffolds (70:30), were obtained and characterized by scanning electron microscopy, gel permeation chromatography, differential scanning calorimetry, thermal gravimetric analysis, compression mechanical testing and study on in vitro degradation, which showed its amorphous characteristics, cylindrical geometry, and interconnected pores. The in vitro degradation study showed significant loss of mechanical properties compatible with a decrease in molar mass, accompanied by changes in morphology. The histocompatibility association of mesenchymal stem cells from rabbit's bone marrow, and PLDLA-TMC scaffolds, were evaluated in the meniscus regeneration, proving the potential of cell culture at in vivo tissue regeneration. Nine New Zealand rabbits underwent total medial meniscectomy, yielding three treatments: implantation of the seeded PLDLA-TMC scaffold, implantation of the unseeded PLDLA-TMC and negative control (defect without any implant). After 24weeks, the results revealed the presence of fibrocartilage in the animals treated with polymer. However, the regeneration obtained with the seeded PLDLA-TMC scaffolds with mesenchymal stem cells had become intimal to mature fibrocartilaginous tissue of normal meniscus both macroscopically and histologically. This study demonstrated the effectiveness of the PLDLA-TMC scaffold in meniscus regeneration and the potential of mesenchymal stem cells in tissue engineering, without the use of growth factors. It is concluded that bioresorbable polymers represent a promising alternative for tissue regeneration.

(118) Treatment Postcovid Hypogonadism with Autologous Stem Cells and PRP

Abstract Introduction COVID-19 affects ACE receptors, causing autoimmune processes that damage testicular tissue, disrupting the processes of spermatogenesis and testosterone production. Recently, we have seen an increasing number of patients with erectile dysfunction ED appearing 3–6 month safter COVID-19 and prolonging for years. Objective The aim of our study was to determine effectiveness of hormone stimulating and replacement therapy, possibility of restorative therapy with autologous stem cells (ASC) and Plasma rich Platelets (PRP) –therapy in patients with hypogonadism. Methods 117 patients with ED, which appeared 3–6 months after COVID-19. All patients except ED had clinical signs of decreased testosterone: decreased libido, mental and cognitive functions, decreased performance, fatigue. Testosterone fractions (total and free), LH, Estradiol, FSH before, during and after rehabilitation therapy were studied. Patients were divided into 2 groups: 1st- 68 patients with real hypogonadism (Tm = 7.43 + 2.1 below 12 nmol / l), and 2nd - 49 patients with relative hypogonadism (Tm = 14.1 + 1.8 above 12 nmol / l). l), they were studied the sensitivity of tissue receptors to testosterone. Results First group - patients were prescribed Tribulus terrestris extract 45% - 750 mg, Fenugreek extract 50% - 25 mg twice a day for 2 months. 37 patients (54.4%), group 1a (mean age 41.6 + 4.3) responded to therapy by normalizing the level of T (more than 12 nmol/l) and improving erectile function, 31 patients (45.6%), group 1b (average age 47.3 + 5.2) without the effect of herbal medicine prescribed testosterone Omnadren 250 1 time in 3 weeks. After 2 months of hormone replacement therapy, 28 patients were diagnosed with normal T levels, but only 19 patients (61.2%) in group 1b improved their erectile function. Second group - 49 patients were also prescribed Tribulus terrestris extract 45% - 750 mg, Fenugreek extract 50% - 25 mg twice a day for 2 months and PRP therapy (intracavernous injections of 2 ml of autoplasma with a platelet concentration greater than 1 million/ml) 1 time in 10 days 8 times. 23 patients - group 2a responded to therapy with the disappearance of symptoms of hypogonadism and improvement of ED. 26 patients - group 2b – did not have significant improvements, so they received 2 courses of 5 intravenous injections of 5 million autologous stem cells (50 millionin total). 17 patients (65.4% of group 2b) improved their mental health, reduction of symptoms of hypogonadism, improvement of erectile function to normal values (IIEF -5 increased to 19.4 + 2.2). Conclusions 1. Multicenter studies of the effect of COVID-19 on fertile and androgenic function in men and the possibility of their recovery in postpartum pathology are still needed and should be prolonged. 2. A significant proportion of men with postcovid hypogonadism and ED are men with normal levels of T, but reduced sensitivity of tissue receptors to T (relative hypogonadism). 3. In the treatment of relative postcovid hypogonadism, intracavernous PRP therapy and intravenous stem cell therapy have a clinical effect and can be considered as promising treatments for this pathology. Disclosure No.

(158) Comparison Implants for Penile Girth Enlargement: PPLA Shaft vs Silicone Implant

Abstract Introduction Male dissatisfaction with the penis size is the most common manifestation of penile dysmorphophobia. Despite the diversity of penis enlargement methods a single safe technique that fully satisfies patients has not yet been developed. Objective The aim of this work is to compare the results of a combined operation on installation of a silicone implant or a porous polylactic acid (PPLA) scaffold impregnated with autologous stem cells with simultaneous ligamenotaxis to increase the length and circumference of the penis. Methods In 2017–2023 there were performed penis enlargement surgeries in 3 centers. In Ukraine and Poland 38 patients from were operated with implantation of a porous Max Pol PLLA scaffold, and in Mexico implantation of silicone implants Peniflex in 36 patients was performed. The results of penis enlargement were evaluated in the early (2 months) and long-term (36 months) periods. Results While implanting a silicone implant the majority of the patients - 31 (86.1%) are satisfied with the result, 27 (75%) patients mention an improvement in sexual life, 31 (86.1%) also mention an increase in their own self-sufficiency. At the same time, some patients mentioned the following complications: 2 (5.6%) patients mentioned displacement of the silicone matrix, 1 (2.8%) patient mentioned prolapse of the implant, 1 (2.8%) patient mentioned a decrease in erection (which did not improve after removal of the implant), in 1 (2.8%) case the silicone implant had to be removed due to the fact that the patient did not liked the appearance. While using a collagen-like matrix made of polymerized polylactic acid impregnated with autological stem cells in 38 patients, we have seen one significant complication - prolapse that caused the removal of the matrix (in men that had denied circumcision before implantation). However, 5 (13.2%) patients required additional polylactic acid gel injections between 6 and 36 months to optimize the shape or volume of the penis. 34 (89.5%) patients mentioned an improvement in the sexual function and sexual sensations of their partner, harmonization of relationships in a couple, and 36 (97.4%) men - an increase in a sense of self-sufficiency. In 3 years most of the patients 26 (68,4%) have been satisfied with particularly resolved implant but 13 (34.2) patients want to add some PLA gel as injection for penile girth recovery. Conclusions Thus, modern implants can improve the size and appearance of the penis, improve the quality of sexual life and the feeling of self-sufficiency in operated men. The use of silicone implants is simpler, it require only long drain 3–5 days. Most of operated patients were satisfied results of silicone implant. The use of a polymer matrix impregnated with autologuous stem cells requires a special biostem cell laboratory, more time for preoperative rehabilitation, but can be considered as more philological. Both methods can be considered as permanent and quite safe for penis enlargement. Disclosure No.

The Progress and Prospects of Immune Cell Therapy for the Treatment of Cancer.

Immune cell therapy as a revolutionary treatment modality, significantly transformed cancer care. It is a specialized form of immunotherapy that utilizes living immune cells as therapeutic reagents for the treatment of cancer. Unlike traditional drugs, cell therapies are considered "living drugs," and these products are currently customized and require advanced manufacturing techniques. Although chimeric antigen receptor (CAR)-T cell therapies have received tremendous attention in the industry regarding the treatment of hematologic malignancies, their effectiveness in treating solid tumors is often restricted, leading to the emergence of alternative immune cell therapies. Tumor-infiltrating lymphocytes (TIL) cell therapy, cytokine-induced killer (CIK) cell therapy, dendritic cell (DC) vaccines, and DC/CIK cell therapy are designed to use the body's natural defense mechanisms to target and eliminate cancer cells, and usually have fewer side effects or risks. On the other hand, cell therapies, such as chimeric antigen receptor-T (CAR-T) cell, T cell receptor (TCR)-T, chimeric antigen receptor-natural killer (CAR-NK), or CAR-macrophages (CAR-M) typically utilize either autologous stem cells, allogeneic or xenogeneic cells, or genetically modified cells, which require higher levels of manipulation and are considered high risk. These high-risk cell therapies typically hold special characteristics in tumor targeting and signal transduction, triggering new anti-tumor immune responses. Recently, significant advances have been achieved in both basic and clinical researches on anti-tumor mechanisms, cell therapy product designs, and technological innovations. With swift technological integration and a high innovation landscape, key future development directions have emerged. To meet the demands of cell therapy technological advancements in treating cancer, we comprehensively and systematically investigate the technological innovation and clinical progress of immune cell therapies in this study. Based on the therapeutic mechanisms and methodological features of immune cell therapies, we analyzed the main technical advantages and clinical transformation risks associated with these therapies. We also analyzed and forecasted the application prospects, providing references for relevant enterprises with the necessary information to make informed decisions regarding their R&D direction selection.

The Treatment of Burkitt Lymphoma with the Berlin-Frankfurt-Münster Protocol with Rituximab and Autologous Transplantation

Intensive treatment approaches are required for adult Burkitt lymphoma (BL), although a univocal standard of care still does not exist. The use of frontline autologous transplantation is debated. Between 2004 and 2020, 50 HIV-negative BL patients were treated with the Berlin-Frankfurt-Münster (BFM) protocol at our institution. Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, cytarabine), B (vincristine, cyclophosphamide, methotrexate, doxorubicin) and C (vindesine, methotrexate, etoposide, cytarabine), each repeated twice, every 28 days. Patients elder than 60 years did not receive block C, thus blocks A and B were repeated 3 times. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. Autologous stem cells were reinfused (ASCT) at the end of the 6-blocks after BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning, when feasible. Median age at onset was 38 years (range 16-72); 38 patients were male and 12 female. Stage III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Two patients did not receive rituximab because of adverse reaction and early death. Intrathecal prophylaxis was given in 96% of patients. Stem cell harvest was performed in 70% of patients, who all received a subsequent ASCT. The full 6-blocks treatment was completed in 70% of the patients; 8% received 5 cycles and 22% received ≤ 3 cycles. Early treatment interruption occurred because of disease progression (12%), toxicity (8%), death (4%) or other causes (4%). The overall response rate was 74%, with a complete response rate of 60%. Three patients could not be evaluated because of early progression/death. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, with both curves exhibiting a plateau (Figure). Ten-year disease-free survival was 80.3%. Eight patients had died because of disease progression (3 patients), infection or sepsis (4 patients) or cardiac arrest (1 patient). Grade 3-4 neutropenia, thrombocytopenia, anemia and mucositis were seen in 96%, 60%, 32% and 24% of patients. Infections occurred in 60% of patients; grade 4 and fatal sepsis in 14% and 8% of cases. Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe and highly effective in adult patients with BL, as confirmed by long-term survival rates.

Hypoxia improves self-renew and migration of urine-derived stem cells by upregulating autophagy and mitochondrial function through ERK signal pathway

Urine-derived stem cells (USCs) are autologous stem cells with self-renewal ability and multi-lineage differentiation potential. Our previous studies have shown that hypoxia preconditioning can improve self-renewal and migration abilities of USCs by up-regulating autophagy. The purpose of this study was to investigate the specific mechanism by which hypoxia treatment promotes the biological function of USCs. We found that hypoxia treatment upregulated the expression of phosphralated ERK protein without affecting the expression of total ERK protein. Inhibiting ERK signaling with the PD98059 inhibitor decreased cell proliferation, migration and colony formation during hypoxia treatment. Hypoxia increased ATP production, mitochondrial membrane potential and mt-DNA copy number, which were reversed by inhibiting the ERK signal. Additionally, the number of autophagosomes and autophagic lysosomes was significantly lower in PD98059 group than in the hypoxia group. PD98059 treatment inhibited the up-regulation of autophagy related proteins induced by hypoxia. Therefore, this study suggests that hypoxia improves the self-renewal and migration abilities of USCs by upregulating autophagy and mitochondrial function through ERK signaling pathway. This finding may provide a new therapeutic mechanism for hypoxia pretreated USCs as a source of stem cell transplantation.

POSTER: IBCL-099 Intensive Chemotherapy and Autologous Stem Cell (ASCT) Consolidation for Bing Neel Syndrome

POSTER: IBCL-099 Intensive Chemotherapy and Autologous Stem Cell (ASCT) Consolidation for Bing Neel Syndrome

IBCL-099 Intensive Chemotherapy and Autologous Stem Cell (ASCT) Consolidation for Bing Neel Syndrome

IBCL-099 Intensive Chemotherapy and Autologous Stem Cell (ASCT) Consolidation for Bing Neel Syndrome

Real-world data of long-term survival in patients with T-cell lymphoma who underwent stem cell transplantation

This study aimed to identify the benefits of autologous-stem cell transplantation (auto-SCT) and allogeneic-SCT (allo-SCT) in patients with aggressive T-cell lymphomas to aid in the selection of transplantation type in clinical practice. This study retrospectively analyzed data from 598 patients who underwent transplantation for T-cell lymphomas from 2010 to 2020. In total, 317 patients underwent up-front SCT as consolidation therapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 68.7% and 76.1%, respectively. Patients who underwent auto-SCT had significantly better OS (p = 0.026) than those who underwent allo-SCT; however, no statistical difference in PFS was found. Transplantation was used as a salvage therapy in 188 patients who had relapsed/refractory disease. Overall, 96 (51.1%) patients underwent auto-SCT and 92 (48.9%) patients underwent allo-SCT. Auto-SCT improved long-term survival in patients with complete remission (CR). Allo-SCT demonstrated better 3-year PFS in patients with partial remission and relapsed/refractory disease status. However, >50% of patients died within 1 year of allo-SCT. As a consolidative therapy, up-front auto-SCT demonstrated a survival benefit. Auto-SCT was also effective in patients who achieved CR after salvage therapy. If the disease persists or cannot be controlled, allo-SCT may be considered with reduced intensity conditioning.

Assessment of the effects of intrastromal injection of adipose-derived stem cells in keratoconus patients.

To evaluate the efficacy and safety of intrastromal transplantation of adipose-derived stem cells (ASCs) in keratoconus patients. This study was conducted on 8 eyes of 8 patients with moderate to severe keratoconus. In the patients, ophthalmic assessments including visual acuity, refraction, slit lamp examination, fundoscopy, corneal topography, and confocal microscopy were performed. Autologous stem cells were used. The isolated stem cells were injected into the corneal stroma by using femtosecond laser. Surgical procedure was similar to intracorneal ring implantation. All patients were re-assessed 1, 3, and 6mo after surgery. The baseline mean visual acuity was 0.48±0.18 and improved to 0.66±0.17 after surgery and final acuity increased by 1.85±0.80 lines (P=0.001). The mean spherical refraction of patients improved 0.34±0.35 D (P=0.039), and the mean cylindrical refraction of patients improved 0.84±0.23 D (P=0.016). The mean flat keratometry decreased 0.78±0.71 D (P=0.017), and the mean steep keratometry decreased 0.59±0.68 D (P=0.023). The mean central corneal thickness of patients improved of 6.29±4.47 µm (P=0.03). The mean keratocyte density at the anterior and middle stroma of cornea increased (P<0.05) but remained stable at the posterior stroma after 6mo. All patients had no complications and their corneas remained transparent. Intrastromal transplantation of ASCs has positive effects on vision and refractive parameters in most patients with keratoconus. After six months, visual acuity improved moderately, corneal parameters reduced slightly, and stromal keratocytes density increased. This modality is safe, and patients do not have any complications.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma; because of its fast growing rate, it often represents a clinical emergency. Intensive treatment approaches are required for adult BL, although a univocal standard of care still does not exist. The use of frontline autologous transplantation (ASCT) is debated. Methods: Between 2004 and 2020, 50 HIV-negative BL patients were treated with the Berlin-Frankfurt-Münster (BFM) protocol at our institution. Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, cytarabine), B (vincristine, cyclophosphamide, methotrexate, doxorubicin) and C (vindesine, methotrexate, etoposide, cytarabine), each repeated twice, every 28 days. Patients elder than 60 years did not receive block C, thus blocks A and B were repeated 3 times. Rituximab was given at day 1 each block. Central nervous system (CNS) prophylaxis with intrathecal cytarabine, methotrexate and dexamethasone was given once per each block. Autologous stem cells were harvested after the 4th or 5th cycles, with reinfusion (ASCT) at the end of the 6-blocks after BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning, when feasible. Results: Median age at onset was 38 years (range 16–72); 387 patients were male and 12 female. Stage III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Two patients did not receive rituximab because of adverse reaction and early death. Intrathecal prophylaxis was given in 96% of patients. Stem cell harvest was performed in 70% of patients, who all received a subsequent ASCT. The full 6-blocks treatment was completed in 70% of the patients; 8% received 5 cycles and 22% received ≤3 cycles. Early treatment interruption occurred because of disease progression (12%), toxicity (8%), death (4%) or other causes (4%). The overall response rate was 74%, with a complete response rate of 60%. Three patients could not be evaluated because of early progression/death. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, with both curves exhibiting a plateau. Likewise, 10-year disease-free survival was 80.3%. Eight patients had died because of disease progression (3 patients), infection or sepsis (4 patients) or cardiac arrest (1 patient). Grade 3–4 neutropenia, thrombocytopenia, anemia and mucositis were seen in 96%, 60%, 32% and 24% of patients, respectively. Infections occurred in 60% of patients, with grade 4 and fatal sepsis in 14% and 8% of cases, respectively. Methotrexate-related hepatic and renal toxicity occurred in 16% and 12% of patients, respectively, with complete recovery in all cases. Keywords: Chemotherapy, Immunotherapy, Stem Cell Transplant No conflicts of interests pertinent to the abstract.

(486) Different Methods Penile Girth Enlargement

Abstract Introduction Male dissatisfaction with the size of the penis is the most common manifestation of penile dysmorphophobia. Despite the variety of penis girth enlargement methods, a single safe technique that satisfies patients has not yet been developed. Objective The aim of the work was to compare the results of a combined operation to install a collagen-like matrix impregnated with autologous stem cells with simultaneous ligamentotomy to increase the circumference of the penis and Polylactic Gel injection. Methods In 2017-2022, penis enlargement surgeries were performed in 2 centers. In 38 patients from Ukraine and Poland, . performed the implantation of the Max Pol porous matrix, and injections of the polylactic acid gel were performed at the other Clinic. The results of penis enlargement were evaluated in the early (2 months) and long-term (36 months) terms. Results When using a collagen-like matrix -Scaffolf made of polymerized polylactic acid impregnated with own stem cells in 38 patients, we did not encounter complications that caused the removal of the matrix. However, 5 patients required additional polylactic acid gel injections between 6 and 36 months to optimize the shape or volume of the penis. In 4 cases (10.5%), patients underwent circumcision in the period up to 3 years, as the head did not open well due to the enlarged trunk. 34 (89.5%) patients noted an improvement in the sexual function and sexual sensations of their partner, harmonization of relationships in a couple, and 36 (94.7%) men - an increase in a sense of self-sufficiency and self-confidence. In 68 patients, Polylactic Acid Gel was used to enlarge the penis. It was injected under the skin of the penis in a volume of 15 ml per 1 procedure. As a rule, we performed 2-4 treatments (30-60 ml) with an interval of 1 month. No significant complications were noted. In 11 cases (16.4%), patients had to undergo circumcision within 3 years, due to the impossibility of retracting the foreskin. Most of patients noted an improvement in the sexual function and sexual sensations of their partner, harmonization of relationships in a couple, and 61 (91.%) men - an increase in a sense of self-sufficiency and self-confidence. Conclusions Thus, modern implants can improve the size and appearance of the penis, improve the quality of sexual life and the feeling of self-sufficiency in operated men. The use of a polymer matrix impregnated with one's own stem cells requires a special laboratory, more time for perioperative preparation and postoperative rehabilitation. The use of polylactic acid gel injections does not require anesthesia, operating room, is more physiological, and can be considered as the standard of safe penis enlargement. The frequency of the need for circumcision after gel injection is slightly higher at 3 years of follow-up compare with scaffold implantation, possibly due to the greater addition of penile volume. Disclosure No

Long-Term Activity of Combining CNCT19 with HDT/ASCT in Refractory Large B-Cell Lymphoma: Two-Year Follow-up of a Prospective Phase 1/2 Clinical Trial

Background: We have previously reported the preliminary results of a phase 1/2 clinical trial of administrating CNCT19 (a second-generation anti-CD19 CAR T-cell) following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in large B-cell lymphoma (LBCL) patients with diseases refractory to first-line and/or subsequent lines of chemotherapy. Eight of 10 (80%) patients achieved complete response (CR), and the estimated proportion of progression-free survival (PFS) and overall survival (OS) at 12 months was 66.7% and 77.1%, respectively (Wei liu et al. ASH 2019, 2020). Here we reported this study's updated enrollment, efficacy, and follow-up. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with LBCL with a history of refractory to first-line rituximab-containing anthracycline-based chemotherapy and/or subsequent salvage chemotherapy were eligible for this study. Conditioning regimen of GBC/M (Gemcitabine 600 mg/m2/h, infused for 3 hours with loading bolus of 75 mg/m2, day -7, -3, busulfan 105 mg/m2, day -7 until -5, cyclophosphamide 45mg/kg or melphalan 60 mg/m2, day -3, -2) was administered once the CNCT19 product was available. Autologous stem cells were infused on day 0, and CNCT19 cells were infused on day +3 (±1 day). Cytokine release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) were graded according to the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group criteria. Results: From December 2017 through May 2021, 21 subjects were consecutively enrolled in this study. CNCT19 cells were successfully manufactured for 20 subjects and administered to 18 subjects. The median age was 44 (range 23 to 64), and 56% were male. Patients included 11 (67%) with diffuse large B-cell lymphoma (not otherwise specified), 4 (22%) with high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement, 2 (11%) with primary mediastinal large B-cell lymphoma and 1 (6%) with transformed follicular lymphoma. The median number of lines of prior therapy was 3 (range, 2 to 5). Eighty-nine percent of patients had a history of refractory to first-line immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) or R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and 72% were refractory to subsequent platinum-based salvage therapy. TP53 deletion and/or mutation were detected in 7 of 11 (64%) patients. The median dose of infused stem cells was 2.6×106 (range, 1.8~8.7×106) per kilogram of body weight and the median dose of infused CNCT19 cells was 2×106 (range, 1.6~4.0×106) per kilogram of body weight. The CRS occurred in 16 patients (89%), and all were low grades (grade 1, 83%; grade 2, 6%). CRES occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved completely after glucocorticoids treatment. We did not observe any unexpected toxicity or treatment-related death throughout the therapy. The median times to neutrophil and platelet recovery were ten days (range, 8 to 30 days) and 16.5 days (range, 8 to 265 days) after stem cells reinfusion, respectively. As of July 26, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 28.2 (95% CI 16.9-39.1) months. The best overall response rate was 94.4%, with a best CR rate of 72.2%. The median PFS, duration of response (DOR), disease-free survival (DFS) and OS were not reached, and the probability of 2-year PFS, DOR, DFS and OS were 59.3% (95% CI 32.5%-78.4%), 63.5% (95% CI 35.9%-81.8%), 74.1% (95% CI 39.1%-90.9%) and 64.2% (95% CI 36.2%-82.4%), respectively. Of the patients who were in durable response at three months or six months post CNCT19 infusion, 66.7% and 83.3% were in ongoing response at the date of data cutoff, respectively. Conclusions: CNCT19 could be safely administered following HDT/ASCT in patients with relapsed or refractory LBCL. The strategy of combining CAR T-cell therapy with HDT/ASCT might improve response rate and prolong survival compared to CAR T-cell therapy alone.

κ-Carrageenan and PVA blends as bioinks to 3D print scaffolds for cartilage reconstruction

3D printing of polymeric scaffolds and autologous stem cells is a promising tool for damaged facial cartilage reconstruction surgeries. To this end, suitable bioinks are needed to generate scaffolds with the required morphological and functional features. We formulated hydrogel bioinks using k-Carrageen (kC) and poly(vinyl alcohol) (PVA) in three different weight ratios. The kC gives the systems the ability to undergo rapid sol-to-gel transitions upon cooling from 60 °C and above to body temperature, while the PVA is used as rheology modifier and porogen. The latter is crosslinked after molding or printing by freeze-thaw cycling for 1 day (FT1) or 5 days (FT5). To select the most suitable formulation for 3D printing, the sol-to-gel transition and the physico-chemical, mechanical and morphological properties of obtained hydrogels were studied. Moreover, the absence of cytotoxic effects of the material on SASCs was assessed in both stemness-preserving or chondro-inductive media. Printing trials were performed to identify optimal process parameters and co-printing and post-printing seeding approaches of SASCs were evaluated. Cells were found to be viable after co-printing and also after the FT1 treatment. Viable adherent cells were also found in the FT5 system, where cells were plated after freezing and thawing treatment.

S191 Efficacy and Safety of Adipose-Derived Stem Cell Therapy for the Treatment of Complex Perianal Fistula Not Associated With Crohn’s Disease: A Systematic Review and Meta-Analysis

Introduction: Given the high recurrence rate and the risk of fecal incontinence with surgical options, Injection of adipose tissue-derived stem cells (ASC) has been arising as a novel method for treating complex perianal fistulas (CPAF). Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of ASC in the management of CPAF not associated with Crohn’s disease. Methods: We systematically searched Medline and Embase databases through April 20, 2022, for all studies that assessed the efficacy and safety of ASC for the treatment of CPAF not associated with Crohn’s disease. We excluded patients with rectovaginal fistulas and perianal fistulas associated with Crohn’s disease. Our primary outcome was the complete closure. The secondary outcomes included overall nonserious adverse events (NSAE), serious adverse events (SAE), and perianal abscess rate. All meta-analyses were conducted using a random-effect model. The publication bias was assessed by Egger’s test. Results: Ten studies (eight clinical trials and two observational studies) with 271 patients were included in the pooled analysis. Eight studies used autologous stem cells, one used allogeneic stem cells, and one did not report the source of stem cells. The mean age of the patients was 43.7 years. The follow-up period ranged from 3 months to 2 years. The pooled complete closure rate was 59.7% (95% confidence interval (CI): 0.46-0.73, Figure 1A). On subgroup analysis based on country of origin, six studies with 213 patients were conducted in European countries, and four studies with 58 patients were conducted in non-European countries. The complete closure rate was higher in European countries than non-European countries, 64.1% vs. 52.6%. Eight studies reported overall NSAEs with the pooled NSAE rate of 22.5% (95% CI: 0.11-0.34, Figure 1B). Seven studies reported SAEs with the pooled SAE rate of 1.7% (95% CI: 0.001-0.034, Figure 1C). Seven studies reported the perianal abscess rate with a pooled perianal abscess rate of 7.1% (95% CI: 0.016-0.125, Figure 1D). No evidence of publication bias was found (Egger’s test: P=0.36). Conclusion: Our meta-analysis demonstrated that ASC is a promising therapeutic option for CPAF not associated with Crohn’s disease with a clinically adequate efficacy and low rate of adverse events. However, more studies with larger sample sizes are needed to provide a definitive assessment of the effectiveness of ASCs for CPAF not associated with Crohn’s disease.Figure 1

Experience of successful autologous hematopoietic stem cell transplantation in patients with an unfavorable prognosis of systemic scleroderma

One of the methods of treating severe forms of systemic scleroderma is hematopoietic stem-cell autotransplantation (auto-HSCT). The article describes two clinical cases of auto-HSCT followed by rituximab (RTM) therapy in patients with diffuse systemic scleroderma with progressive interstitial lung disease (ILD), high immunological activity, high skin score, and an unfavorable prognosis. The assessment of the course of these diseases was carried out in the course of dynamic observation of patients for 10–11 years. In all cases, auto-HSCT followed by RTM made it possible to achieve remission / low activity, as well as to stabilize the progressive of ILD.

Comparison of implant methods for penis enlargement

Male dissatisfaction with the penis size is the most common manifestation of penile dysmorphophobia. Despite the diversity of penis enlargement methods a single safe technique that fully satisfies patients has not yet been developed.The aim of this work is to compare the results of a combined operation on installation of a silicone implant or a collagen matrix impregnated with autologous stem cells with simultaneous ligamentotomy to increase the length and circumference of the penis.In 2017–2022 there were performed penis enlargement surgeries in 2 centers. In Public Non-Profit Organization Of The Kharkiv District Council «Kharkiv Regional Clinical Center Of Urology And Nephrology Named After V.I.Shapoval (Kharkiv, Ukraine) 38 patients from Ukraine and Poland were operated by Professor Knigavko O.V. with implantation of a porous Max Pol matrix (manufactured by Dersmithson, M.D. Choi), and in the “Mexico phalloplastic center” (Mexico city, Mexico) by Dr. Aguilar I.E. implantation of non-absorbable silicone implants in 36 patients was perfomed. The results of penis enlargement were evaluated in the early (2 months) and long-term (6 months) terms.While implanting a silicone implant the majority of the patients – 31 (86.1%) are satisfied with the result, 27 (75%) patients mention an improvement in sexual life, 31 (86.1%) also mention an increase in their own self-sufficiency. At the same time, some patients mentioned the following complications: 2 (5.6%) patients mentioned displacement of the silicone matrix, 1 (2.8%) patient mentioned prolapse of the matrix, 1 (2.8%) patient mentioned a decrease in erection (which did not improve after removal of the matrix), in 1 (2.8%) case the silicone implant had to be removed due to the fact that the patient did not liked the appearance.While using a collagen-like matrix made of polymerized polylactic acid impregnated with own stem cells in 38 patients, we haven’t seen any complications that caused the removal of the matrix. However, 5 (13.2%) patients required additional polylactic acid gel injections between 6 and 36 (97.4%) months to optimize the shape or volume of the penis. 34 (89.5%) patients mentioned an improvement in the sexual function and sexual sensations of their partner, harmonization of relationships in a couple, and 36 (97.4%) men – an increase in a sense of self-sufficiency.Thus, modern implants can improve the size and appearance of the penis, improve the quality of sexual life and the feeling of self-sufficiency in operated men. The use of silicone implants is simpler, almost does not require specific rehabilitation after surgery, however, in a small part of patients prolapse of the prosthesis and dissatisfaction with the final result are present. Most of operated patients were satisficed results of silicone implant. The use of a polymer matrix impregnated with own stem cells requires a special laboratory, more time for preoperative and postoperative rehabilitation, however, it is more physiological and can be considered as a standard for safe penis enlargement.