Autologous Transplantation Research Articles

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Histological Properties of Adipose Tissue as an Autologous Tissue Filler Harvested from Different Donor Areas and Impact of Centrifugation.

As a burgeoning technique in reconstructive and aesthetic surgery, lipofilling's success is hindered by the unpredictability of graft integrity and quality. This study addresses the critical need to enhance consistency and reproducibility by exploring the clinical utility of adipose tissue from specific body areas, considering the influence of patient-specific factors and mechanical processing on fat graft integrity and morphology. In a prospective, randomized, single-blind study, 52 patients undergoing surgical reconstruction due to significant deformities were enrolled. Lipoaspiration from four areas was performed. Adipose tissue was compared using five parameters of tissue damage and 10 parameters of graft integrity, assessed immediately postcollection and after centrifugation. The study aimed to evaluate the structural integrity and clinical applicability of adipocytes. Morphological assessment revealed no significant differences in adipose tissue quality across donor sites, suggesting consistent graft quality regardless of the harvesting location. Centrifugation induced more morphological damage than noncentrifuged samples, but the overall graft integrity was maintained due to increased cell density. Higher graft acceptance parameters were noted in noncentrifuged samples compared with centrifuged ones. Despite centrifugation-induced morphological changes, adipose tissue integrity remains relatively unaffected, supporting a flexible approach to donor site selection. The consistent quality of adipose tissue underscores the potential for autologous fat transplantation across various clinical scenarios. Optimizing graft processing techniques is crucial for enhancing the predictability and efficacy of lipofilling.

Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP).

106 Background: Measurable residual disease (MRD) negativity is a potential marker for the absence of disease in multiple myeloma (MM), which could be used to guide treatment cessation. MRD2STOP (NCT04108624) is a prospective study investigating outcomes among patients with sustained multimodal MRD negativity who discontinue maintenance therapy. Methods: Discontinuation of maintenance was permitted if MRD negative by PET/CT, flow cytometry (limit of detection [LoD] 10-5), and NGS by clonoSEQ (threshold 10-6). Patients underwent serial blood testing along with clonoSEQ, flow, and PET/CT annually for 3 years. Concurrent BM aspirate samples also underwent CD138+ immunomagnetic enrichment analyzed using clonoSEQ to achieve MRD 10-7 sensitivity. Primary endpoints were MRD resurgence rate at the 10-6threshold, along with progression-free survival (PFS) and overall survival among those MRD negative by the standard non-enriched clonoSEQ. Results: 83 patients were screened, and 47 patients met eligibility to discontinue maintenance as of 1/21/24. Median age was 66 years (range 39-84). 17 (36%) had high-risk disease at diagnosis (8 with 1q copy abnormalities, 5 with ISS stage 3, 2 with t(4;14), 1 with t(14;16), and 3 with del17p). Most (45/47, 96%) had one line of therapy; 26 (55%) received a triplet and 19 (40%) a quadruplet. Prior autologous transplant was received by 30 (64%) and multi-drug consolidation in 36 (77%) prior to single-agent maintenance. 96% received lenalidomide as maintenance. Median duration of consolidation/maintenance therapy prior to discontinuation was 36 months (range 12-95), including 14 (30%) with <27 months. Median follow-up was 30 months. Of 47 enrolled patients, 5 (11%) experienced disease progression and an additional 6 (13%) had MRD resurgence at 10-6. Of 11 MRD resurgent events, 4 (36%) were MRD 10-7 positive at baseline, and 3 (27%) were MRD 10-7 positive 1 year prior to MRD 10-6 resurgence. 2 second hematologic cancers occurred during follow-up: 1 Hodgkin lymphoma and 1 B-ALL, the latter which resulted in the only patient death on study. The estimated 3-year PFS was 85%, including 93% for patients MRD 10-7 negative (n=40) at baseline and 31% for those MRD 10-7 positive (n=7) at baseline (logrank p<0.001). Among the MRD evaluable patients (n=45), the 3-year MRD-free survival (MRD-FS) was 68%; 78% for patients MRD 10-7 negative (n=38) and 33% for patients MRD 10-7 positive (n=7) (logrank p<0.001). There were no differences in MRD-FS or PFS when stratified by high-risk disease, receipt of transplant, consolidation, or duration of maintenance. Conclusions: Discontinuation of maintenance therapy among patients with MM and multimodal MRD-negativity results in a high rate of sustained MRD-negativity and lack of disease progression. CD138+-enriched MRD samples using the clonoSEQ assay may help to even better identify patients who can discontinue therapy. Clinical trial information: NCT04108624 .

Survival benefit of autologous transplant (ASCT) for mantle cell lymphoma (MCL) in the California Cancer Registry (CCR).

e19043 Background: Extended follow up of the prospective Nordic MCL2 cohort shows ASCT in CR1 confers a median OS (mOS) of 12.7 y (Eskelund, BJH 2016). Incorporation of BTK inhibitors in 1L MCL is challenging the role of ASCT in an ongoing prospective trial (TRIANGLE, ASH 2022). The present study aims to evaluate the role of ASCT and the impact of social determinants of health (SDH) in a diverse real-world population of MCL patients. Methods: Adult MCL patients diagnosed from January 1, 2000 to December 31, 2020 in the CCR were identified with ICD-O-3 code 9673. The study was approved by UCLA IRB. OS was estimated using KM statistics, calculated from diagnosis to death/last follow-up. Univariate Cox proportional hazards modeling for lymphoma-specific survival (LSS) was performed for variables of interest; those significant at p ≤ 0.10 were incorporated in a stepwise multivariable regression excluding patients with missing data. Socioeconomic status (SES) variables were reported using census-block group data at diagnosis. Results: 5740 ethnically diverse patients were included (NH Whites, n=4038; NH Black, n=175; Hispanic, n=1057; Asian/Pacific Islanders, n=400). Median age at diagnosis was 69 y (IQR 61–68) and 71% were males. 4096 (71%) and 1346 (23%) patients received chemoimmunotherapy and were treated at an NCI/NCCN center, respectively. With a median follow-up of 33 m (IQR 9–76), mOS of the entire cohort was 4.4 y. ASCT patients (n=652, 11%) had improved mOS compared to non-ASCT (14.2 y vs 3.7 y, respectively p<0.001), and 100-day TRM was 2.5%. In the univariable model for all subjects, age, Charlson Comorbidity Index (CCI), married, chemoimmunotherapy, ASCT, NCI/NCCN center, insurance, period of diagnosis, and community SES, poverty, and education were prognostic for LSS. Race, sex, and rural residence were not associated with LSS. Multivariable analysis of 4148 subjects showed significant predictors of LSS were age ≥ 70 y (HR 1.71, p<0.001), ASCT (HR 0.54, p<0.001), diagnosis after 2013 (HR 0.78, p<0.001), CCI (Ref 0; 1-2 HR 1.22, p<0.001; 3+ HR 1.94, p<0.001), married (HR 0.86, p=0.003), NCI/NCCN treatment center (HR 0.77, p=0.001), higher education (top 40% with high school diploma vs. bottom 20%, HR 0.70, p<0.001), higher overall SES (medium vs. low SES tertile, HR 0.81, p=0.003), and increased community poverty (middle 40% vs. bottom 20%, HR 1.14, p=0.043). Conclusions: Our data represent the largest real-world cohort describing the role of ASCT and SDH in MCL. A minority of patients received ASCT and had improved OS compared to non-ASCT patients. While follow-up of ongoing prospective studies will clarify the role of ASCT using contemporary 1L regimens, the present data suggest ASCT in select patients results in durable response with low TRM. Socially disadvantaged patients should be identified and offered supportive programs early in the disease course to mitigate inferior outcomes.

Autologous osteoperiosteal transplantation is effective in the treatment of single cystic osteochondral lesions of the talus and the prognostic impact of age should be emphasized.

To investigate the clinical efficacy and prognostic factors associated with autologous osteoperiosteal transplantation for the treatment of single cystic osteochondral lesions of the talus (OLT). The clinical data of patients with single cystic OLT undergoing autologous osteoperiosteal transplantation at the Department of Foot and Ankle Surgery of our hospital between 2018 and 2022, including complete follow-up, were retrospectively analyzed. Imaging data from each patient were imported into Mimics software to measure the surface area, volumeand depth of the lesions. Then, the talus nine-compartment partitioning method was used to partition the injury site. Preoperative and final follow-up assessments were performed using the American Orthopaedic Foot and Ankle Society (AOFAS) score, visual analogue scale (VAS) for painand 36-item Short-Form Health Survey (SF-36) to evaluate treatment efficacy and analyze prognostic factors. Of the 31 patients with single cystic OLT with a complete set of follow-up data, there were 17 males and 14 females, with a mean age of 43.3 ± 13.6 years, a mean follow-up time of 30.1 ± 14.0 monthsand a mean illness duration of 30.4 ± 20.0 months. The postoperative final follow-up AOFAS score was 90.7 ± 5.5; this represented significant improvement when compared to the preoperative score of 57.0 ± 8.5 (P < 0.001). The final postoperative follow-up VAS score was 18.5 ± 8.3; this was significantly better than the preoperative score of 57.8 ± 8.7 (P < 0.001). The physical component summary (PCS)score and mental component summary (MCS)score on the SF-36 scale showed significant improvement at the final postoperative follow-up when compared to preoperative scores (p < 0.001). No other complications were observed during follow-up, such as wound infection or pain at the donor site. One of the patients showed less improvement, which may be related to premature weight-bearing or re-sprained ankle after surgery. There was no significant correlation between the duration of illness, genderand the location, depth, surface areaand volume of the OLTand the postoperative scores. However, patient age showed a significant negative correlation with the postoperative SF-36 PCS and MCS scores. Autologous osteoperiosteal transplantation for single cystic OLT demonstrated good clinical efficacy with a low incidence of complications. Furthermore, age represents an important factor influencing prognosis. Level II.

Experience in the production and clinical application of the cell-based medicinal product Easytense® for the repair of cartilage defects of the human knee

INTRODUCTION. The current cell-based cartilage repair methods, such as autologous chondrocyte transplantation, are not sufficiently effective, and the surgery is painful and traumatic. Therefore, there is a need for a more effective cell therapy product with a minimally invasive surgical procedure for its implantation into the patient.AIM. This study aimed to develop a manufacturing technology for the production of an autologous cell-based medicinal product (CBMP) comprising three-dimensional structures (3D-spheroids) based on chondrocytes isolated from the patient’s cartilage tissue, as well as to evaluate its clinical efficacy.MATERIALS AND METHODS. Autologous chondrocytes isolated from the patient’s cartilage biopsy were propagated in monolayer culture to obtain the required number of cells. Subsequently, the chondrocytes were cultivated on plates with a non-adhesive coating to form 3D spheroids. All CBMP production steps were performed under aseptic conditions in cell culture isolators. The authors used phase-contrast microscopy and immunohistochemical staining with specific fluorescence-labelled antibodies to characterise chondrocyte phenotypes at different stages of cultivation. Genetic stability was controlled by karyotyping. The efficacy of Easytense® was evaluated in a clinical trial using specialised functional tests and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. The primary efficacy endpoint was a change in the overall score on the Knee Injury and Osteoarthritis Outcome Score (KOOS).RESULTS. A manufacturing technology without using animal sera, growth factors, cytokines, or other additives was developed for the production of the autologous CBMP Easytense®. Karyological data confirmed that the chondrocytes retained genetic stability for 3 passages in monolayer culture. When cultured as 3D spheroids, the chondrocytes produced cartilage extracellular matrix proteins (type II collagen, aggrecan), thus acquiring the ability to repair damaged cartilage. The clinical trial demonstrated a statistically significant improvement in knee cartilage 12 months after the transplantation of 3D spheroids derived from autologous chondrocytes. The mean change in the overall KOOS score was 23.8±15.9.CONCLUSIONS. The clinical trial results indicate that Easytense® is highly effective for cartilage repair. Based on these results, the CBMP has been granted marketing authorisation and introduced into clinical practice in the Russian Federation. Easytense® has the potential to replace endoprosthetics and expensive surgeries abroad.

Transplantation of Mesenchymal Stem Cells Derived from Old Rats Improves Healing and Biomechanical Properties of Vaginal Tissue Following Surgical Incision in Aged Rats.

Pelvic floor dysfunction encompasses a group of disorders that negatively affect the quality of women's lives. These include pelvic organ prolapse (POP), urinary incontinence, and sexual dysfunction. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Prolapse recurrence rates following surgery were reported to be as high as 30%. This may be attributed to ineffective healing in the elderly. Autologous stem cell transplantation during surgery may improve surgical results. In our previous studies, we showed that the transplantation of bone marrow-derived mesenchymal stem cells (MSCs) from young donor rats improved the healing of full-thickness vaginal surgical incision in the vaginal wall of old rats, demonstrated by both histological and functional analysis. In order to translate these results into the clinical reality of autologous MSC transplantation in elderly women, we sought to study whether stem cells derived from old donor animals would provide the same effect. In this study, we demonstrate that MSC transplantation attenuated the inflammatory response, increased angiogenesis, and exhibited a time-dependent impact on MMP9 localization. Most importantly, transplantation improved the restoration of the biomechanical properties of the vagina, resulting in stronger healed vaginal tissue. These results may pave the way for further translational studies focusing on the potential clinical autologous adjuvant transplantation of MSCs for POP repair for the improvement of surgical outcomes.

Theoretical aspects regarding the use of autologous and allogeneic septal cartilage transplantation in rhinologic surgical procedures

The study examines the use of autologous and allogeneic septal cartilage transplantation in rhinoplasty and rhi­no­sep­to­plasty. Innovative surgical techniques such as endoscopic and open septal cartilage harvesting were examined, high­ligh­ting advantages such as faster postoperative re­co­very and better visualization of nasal anatomy, as well as dis­ad­van­tages such as a steep learning curve and com­pli­ca­tions as­so­cia­ted with endoscopic manipulation. The postoperative out­­comes of patients undergoing rhinoplasty with auto­lo­gous car­ti­lage implants showed increased satisfaction re­gar­ding na­sal esthetic appearance and functionality. Re­gar­ding al­lo­ge­neic cartilage transplantation, risks of re­jec­tion and in­fec­tion were highlighted. Future perspectives in sep­tal car­ti­lage transplantation included improving surgical tech­­niques and optimizing outcomes, as well as exploring the use of innovative materials and technologies for cartilage tissue regeneration and remodeling. Aspects related to the in­te­gra­tion and revitalization of transplanted cartilage were studied in detail, including processes of angiogenesis, cel­lular colonization, and extracellular matrix biosynthesis. Sur­geons’ preferences regarding the use of autologous or al­lo­ge­neic cartilage were examined, highlighting the reasons and criteria underlying their choices. In conclusion, cartilage trans­plants are effective and safe in rhinologic surgical inter­ven­tions, although the study has limitations related to source avai­la­bi­lity and methodological variability.

NPTX1 Mediates the Facilitating Effects of Hypoxia-Stimulated Human Adipocytes on Adipose-Derived Stem Cell Activation and Autologous Adipose Graft Survival Rate.

Autologous adipose tissue is an ideal material for soft tissue filling and transplantation; however, high volumes of fat absorption over time lead to a relatively low overall survival percentage. The survival and differentiation of adipose-derived stem cells (ADSCs) in the transplanted microenvironment might improve adipose graft survival. Adipocytes have been reported to affect ADSC activation. However, its underlying mechanisms remain unclear. Human ADSCs were incubated in a culture medium supplemented with hypoxic or normoxic conditioned culture medium (CM) derived from human adipocytes. Neuronal Pentraxin 1 (NPTX1) was overexpressed or knocked down in human adipocytes using an overexpression vector (NPTX1 OE) or small interfering RNA (siRNA) transfection, respectively. ADSC differentiation and paracrine secretion were assessed. Nude mice were implanted with human adipocytesand ADSCs. The adipose tissue was subsequently evaluated by histological analysis. CM from hypoxic-stimulated human adipocytes significantly facilitated the differentiation ability and paracrine levels of ADSCs. NPTX1 was significantly up-regulated in human adipocytes exposed to hypoxic conditions. In vitro, CM derived from hypoxia-stimulated human adipocytes or NPTX1-overexpressing human adipocytes exposed to normoxia promoted ADSC differentiation and paracrine; after silencing NPTX1, the facilitating effects of hypoxia-treated human adipocytes on ADSC activation were eliminated. Similarly, in vivo, the NPTX1 OE + normoxia-CM group saw improved histological morphology and fat integrity, less fibrosis and inflammation, and increased vessel numbers compared with the OE NC + normoxia-CM group; the adipocyte grafts of the si-NC + hypoxia-CM group yielded the most improved histological morphology, fat integrity, and the most vessel numbers. However, these enhancements of ADSC activation and adipose graft survival were partially abolished by NPTX1 knockdown in human adipocytes. NPTX1 might mediate the facilitating effects of hypoxia-stimulated human adipocytes on ADSC activation, thereby improving adipose tissue survival rate after autologous fat transplantation and the effectiveness of autologous fat transplantation through promoting ADSC activation. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Anaesthetics reduce the viability of adipose-derived stem cells

ABSTRACT Adipose-derived stem cells (ADSCs) are characterized by their low immunogenicity and unique immunosuppressive properties, providing many opportunities for autologous transplantation in regenerative medicine and plastic surgery. These methods are characterized by low rejection rates and intense stimulation of tissue regeneration. However, procedures during which fat tissue is harvested occur under local anaesthesia. To better understand the effects and mechanisms of anaesthetic compounds in cosmetic and therapeutic procedures, the present study used a mixture of these compounds (0.1% epinephrine, 8.4% sodium bicarbonate, and 4% articaine) and examined their impact on a human adipose-derived stem cell line. The results showed anesthetics’ negative, dose-dependent effect on cell viability and proliferation, especially during the first 24 h of incubation. After extending the exposure to 48 and 72 h of incubation, cells adapted to new culture conditions. In contrast, no significant changes were observed in immunophenotype, cell cycle progression, and apoptosis. The results obtained from this study provide information on the effect of the selected mixture of anaesthetics on the characteristics and function of ASC52telo cells. The undesirable changes in the metabolic activity of cells suggest the need to search for new drugs to harvest cells with unaltered properties and higher efficacy in aesthetic medicine treatments.

Shorter long-term post-transplant life expectancy may be due to prior chemotherapy for the underlying disease: analysis of 3012 patients with acute myeloid leukemia enrolled on 9 consecutive ECOG-ACRIN trials

Several studies reported that patients with acute myeloid leukemia (AML) who remain in long-term remission after allogeneic or autologous transplant have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy alone without a transplant and there have been no comparisons with survival among the general population. The current study indicates that the life expectancy of AML patients who achieved and maintained CR for at least 3 years is shorter than expected for age in the US population. This was observed also in patients who did not undergo a transplant including those who have not relapsed during the entire long follow-up period. Thus, late relapse does not explain why patients without transplants have a shortened life expectancy. Taken together, these data strongly suggest that prior chemotherapy for the underlying AML is at least a major contributing factor for the known shortened life expectancy post-transplant.

Autologous fat transplantation prior to permanent expander implant breast reconstruction enhances the outcome after two years: a randomized controlled trial.

Radiotherapy is important in breast cancer treatment. A side effect of the treatment is fibrosis that decreases the possibility for a successful breast reconstruction with expanders and with high patient satisfaction with the result. The most common option for mastectomized, irradiated women wishing for a breast reconstruction is autologous tissue transplantation. However, some patients are not suitable for flap surgery. Fifty mastectomized and irradiated women were included in a randomized controlled trial. They underwent breast reconstruction with expanders and were allocated 1:1 to either receive pre-treatment with autologous fat transplantation (AFT) or not. Primary outcomes were frequency of reoperations and complications. Secondary outcomes were number of days in hospital, number of outpatient visits to surgeon or nurse and patient reported outcome as reported with Breast Q. Follow-up time was 2 years. Fifty-two per cent of the intervention group and 68% of the controls underwent reoperations (p = 0.611). Thirty-two per cent of the intervention group and 52% of the controls had complications (p = 0.347). The median number of consultations with the nurse was four in the intervention group and six in the control group (p = 0.002). The AFT patients were significantly more satisfied with their breasts and psychosocial well-being after 2 years. They also had higher increase in satisfaction with breasts, psychosocial well-being, and sexual well-being when comparing baseline with 2 years postoperatively. This randomized controlled trial indicates benefits of AFT prior to breast reconstruction with expanders, especially on patient reported outcome even if the study sample is small.

Targeted Therapies in the Treatment of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 versus 10.2 × 10⁶/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

AUTOLOGOUS OSTEOCHONDRAL TRANSPLANTATION FOR LARGE OSTEOCHONDRAL LESIONS OF THE TALUS IS A VIABLE OPTION IN AN ATHLETIC POPULATION

Autologous osteochondral transplantation (AOT) is an effective treatment for large Osteochondral Lesions of the Talus (OLT), however little is reported on an athletic population, who are likely to place higher demands on the reconstruction. The aim is to report the outcomes of large OLT (&gt;150mm2) within an athletic population. The study population was limited to professional or amateur athletes (Tegner score &gt;6) with an OLT of size 150mm2 or greater. The surgical intervention was AOT with a donor site from the lateral femoral condyle. Clinical outcomes at a minimum of 24 months included Return to Sport, VAS and FAOS Scores. In addition, graft incorporation was evaluated by MRI using MOCART scores at 12 months post-surgery. 38 athletes including 11 professional athletes were assessed. Mean follow-up was 46 months. Mean lesion size was 249mm2. 33 patients returned to sport at their previous level and one did not return to sport (mean return to play 8.2 months). Visual analogue scores improved from 4.53 pre-operatively to 0.63 post-operatively (p=0.002). FAOS Scores improved significantly in all domains (p&lt; 0.001). Two patients developed knee donor site pain, and both had three osteochondral plugs harvested. Univariant analysis demonstrated no association between pre-operative patient or lesion characteristics and ability to return to sport. However, there was a strong correlation between MOCART scores and ability to return to sport (AUC=0.89). Our study suggests that AOT is a viable option in the management of large osteochondral talar defects in an athletic population, with favourable return to sport levels, patient satisfaction, and FAOS/VAS scores. The ability to return to sport is predicated upon good graft incorporation and further research is required to optimise this technique. Our data also suggests that patients should be aware of the increased risk of developing knee donor site pain when three osteochondral plugs are harvested.

Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve.

JOURNAL/nrgr/04.03/01300535-202506000-00029/figure1/v/2024-08-05T133530Z/r/image-tiff Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits (tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects (typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk+ tNGCs with the tubes without holes (silk- tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk+ tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk+ group was found compared with autologous nerve transplants and silk-, accompanied by improved axon regeneration at the distal coaptation point compared with the silk- tNGCs at 7 weeks postoperatively. In the 15-mm (critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk+ tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimization of the macroscopic holes silk+ tNGC approach containing macroscopic holes might result in improved grafting technology suitable for future clinical use.

Prospective study on the impact of BEAM versus FEAM conditioning on occurrence of neutropenic enterocolitis and on transplant outcome in lymphoma patients.

Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM vs. FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did vs. patients who did not experience a NEC episode (NECe). A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis. NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM vs. FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos vs. patients NECneg. The cost analysis of NECpos vs. NECneg has been also performed.

GATA genotype and FY*B(-67T&gt;C) polymorphism as a cheap and reliable tool to evaluate ethnicity in Brazilian patients submitted to autologous transplantation

Abstract Collecting high quality data on race and ethnicity is crucial for clinical research, notably in genetic association studies, to avoid confounding by different ethnic background among patients, a bias referred to as population stratification. In Brazil, to describe race we commonly use the National Institute of Geography and Statistics (IBGE) classification, so-called “self-declared color”, but it is acknowledged that defining ancestry by phenotypic characteristics, especially in countries with highly mixed population like Brazil, can be misleading. We aimed to evaluate the relationship between the GATA FY*B(-67T&gt;C) polymorphism and self-declared race in Brazilian patients undergoing autologous transplantation and verify the feasibility of using this test as a more reliable tool to evaluate ethnicity in this population. Methods: We conducted a study to evaluate the association of candidate-gene polymorphisms and toxicities after autologous stem-cell transplantation (ASCT) in adult patients with lymphoma or myeloma from 2015 to 2021 in two Brazilian transplant centers. All patients with available DNA to study genetic polymorphisms were included. In this analysis we evaluate the association between GATA polymorphism and self-declared color in this cohort. Results: A total of 217 patients were included in this analysis. Median age at transplantation was 56 years (21-79) and 130 patients (59.9%) were male. Most patients were self-declared white (n=175, 80.6%) and the most common genotype was GATA67T/T (wild type/wild type) (n=142, 65.4%). Among the self-declared white patients, 73.1% were genotyped as GATA67T/T and 4.0% as GATA-67C/C, while among the non-white patients 21.4% were genotyped as GATA-67C/C (p&lt;.001). The allele FY*B(-67T&gt;C) frequency was 0.22 in the whole population; it was identified in 26.9% of the self-declared white patients and in 66.6% of the non-white (p&lt;.001). Twelve-month overall survival was 86.6% (95% CI 79.9 - 91.2%), with no difference according to self-declared race (86.8% vs 85.5% for white and non-white patients, respectively, p=0.81) or the presence of the allele FY*B(-67T&gt;C) (85.2% vs 89.9% for non-mutated and mutated patients, respectively, p=0.27). Conclusion: GATA FY*B(-67T&gt;C) polymorphism is associated to self-declared race in Brazilian patients submitted to ASCT. Given the importance of correctly evaluating ancestry in genetic association studies in transplantation, GATA FY*B(-67T&gt;C) polymorphism can be used as a more accurate tool in populations with mixed ethnic/racial background.

Silicon-induced biofilm improves peripheral nerve defect in rats mediated by VEGF/VEGFR2/ERK

ABSTRACT Background: Injury of peripheral nerve capable of regeneration with much poorer prognosis affects people’s life quality. The recovery of nerve function after transplantation for peripheral nerve injury remain a worldwide problem. Silicon-induced biofilms as vascularized biological conduits can promote nerve regeneration by encapsulating autologous or allogeneic nerve graft. Objective: We proposed to explore the effect of silicon-induced biofilms on nerves regeneration and whether the VEGF/VEGFR2/ERK pathway was involved in the present study. Methods: Biofilms around the transplanted nerves in peripheral nerve injury rats were induced by silicon. Vascularization and proteins related to VEGF/VEGFR2/ERK were measured. Pathology and morphology of nerves were investigated after encapsulating the transplanted nerves by silicon-induced biofilms. Results: Our results indicated that the biofilms induced by silicon for 6 weeks showed the most intensive vascularization and the optimal effect on nerve regeneration. Moreover, silicon-induced biofilms for 4, 6 and 8 weeks could significantly secrete VEGF with the highest content at week 6 after induction. VEGFR2, VEGF, p-VEGFR2, ERK1, ERK2, p-ERK1 and p-ERK2 were expressed in the biofilms. p-VEGFR2, p-ERK1 and p-ERK2 expression were different at each time point and significantly increased at week 6 compared with that at week 4 or week 8 which was consistent with that 6 week of was the optimum time for biofilms induction to improve the nerve repair after peripheral nerve injury. Conclusion: Our results suggested that combination of silicon-induced autologous vascularized biofilm and autologous transplantation may promote the repair of rat sciatic nerve defect quickly through VEGF/VEGFR2/ERK pathway.

Engineering Pancreatic Islets to Transiently Codisplay on Their Surface Thrombomodulin and CD47 Immunomodulatory Proteins as a Means of Mitigating Instant Blood-Mediated Inflammatory Reaction following Intraportal Transplantation.

Most pancreatic islets are destroyed immediately after intraportal transplantation by an instant blood-mediated inflammatory reaction (IBMIR) generated through activation of coagulation, complement, and proinflammatory pathways. Thus, effective mitigation of IBMIR may be contingent on the combined use of agents targeting these pathways for modulation. CD47 and thrombomodulin (TM) are two molecules with distinct functions in regulating coagulation and proinflammatory responses. We previously reported that the islet surface can be modified with biotin for transient display of novel forms of these two molecules chimeric with streptavidin (SA), that is, thrombomodulin chimeric with SA (SA-TM) and CD47 chimeric with SA (SA-CD47), as single agents with improved engraftment following intraportal transplantation. This study aimed to test whether islets can be coengineered with SA-TM and SA-CD47 molecules as a combinatorial approach to improve engraftment by inhibiting IBMIR. Mouse islets were effectively coengineered with both molecules without a detectable negative impact on their viability and metabolic function. Coengineered islets were refractory to destruction by IBMIR ex vivo and showed enhanced engraftment and sustained function in a marginal mass syngeneic intraportal transplantation model. Improved engraftment correlated with a reduction in intragraft innate immune infiltrates, particularly neutrophils and M1 macrophages. Moreover, transcripts for various intragraft procoagulatory and proinflammatory agents, including tissue factor, HMGB1 (high-mobility group box-1), IL-1β, IL-6, TNF-α, IFN-γ, and MIP-1α, were significantly reduced in coengineered islets. These data demonstrate that the transient codisplay of SA-TM and SA-CD47 proteins on the islet surface is a facile and effective platform to modulate procoagulatory and inflammatory responses with implications for both autologous and allogeneic islet transplantation.