Criteria, Challenges, and Opportunities for Acellularized Allogeneic/Xenogeneic Bone Grafts in Bone Repairing.

As bone grafts become more commonly needed by patients and as donors become scarcer, acellularized bone grafts (ABGs) are becoming more popular for restorative purposes. While autogeneic grafts are reliable as a gold standard, allogeneic and xenogeneic ABGs have been shown to be of particular interest due to the limited availability of autogeneic resources and reduced patient well-being in long-term surgeries. Because of the complete similarity of their structures with native bone, excellent mechanical properties, high biocompatibility, and similarities of biological behaviors (osteoinductive and osteoconductive) with local bones, successful outcomes of allogeneic and xenogeneic ABGs in both in vitro and in vivo research have raised hopes of repairing patients' bone injuries in clinical applications. However, clinical trials have been delayed due to a lack of standardized protocols pertaining to acellularization, cell seeding, maintenance, and diversity of ABG evaluation criteria. This study sought to uncover these factors by exploring the bone structures, ossification properties of ABGs, sources, benefits, and challenges of acellularization approaches (physical, chemical, and enzymatic), cell loading, and type of cells used and effects of each of the above items on the regenerative technologies. To gain a perspective on the repair and commercialization of products before implementing new research activities, this study describes the differences between ABGs created by various techniques and methods applied to them. With a comprehensive understanding of ABG behavior, future research focused on treating bone defects could provide a better way to combine the treatment approaches needed to treat bone defects.

Study on feasibility of the partial meniscal allograft transplantation.

Since the meniscus is an important stabilizing structure of the knee joint and has a significant role in load-bearing and shock absorption, so the complete structural and functional reconstructions of the teared menisci should be done not only after partial meniscectomy but also post total meniscectomy. So far, animal experiments and good clinical practice have showed that TMAT after total meniscectomy has partially solved the problem of structural and functional reconstructions after total meniscectomy. However, partial meniscectomy will also lead to accelerated knee degeneration, and its proportion is much higher than that of patients with total meniscectomy. Herein, the feasibility of PMAT after partial meniscectomy was investigated for the first time by using the 40% posterior horn meniscectomy model of the medial meniscus in Beagle dogs, and also for the first time, TMAT group and the total meniscectomy group were used as control groups. Compared with the TMAT, the transcriptomics evaluation, scanning electron microscope observation, histological regeneration and structure, biomechanical property, inflammation environment, and the knee function post PMAT were more similar to that of normal meniscus was first reported. This study provides a PMAT scheme with clinical translational value for the complete structural and functional reconstruction of the patients with partial meniscectomy and fills the gap in the field of teared meniscus therapy on the basis of quite well clinical applications of the meniscus repair and the TMAT.

Avoiding delays in time to renal transplantation: Pretransplant thyroid malignancy does not affect patient or graft survival after renal transplantation.

BACKGROUND: Pretransplant malignancy is associated with decreased patient and graft survival. Current US guidelines recommend a 2- to 5-year, tumor-free waiting period before transplantation. No large studies have examined the specific, modern day risk of pretransplant thyroid malignancy on patient and graft survival after renal transplant. METHODS: The United Network for Organ Sharing database was queried for all adult isolated renal transplant recipients between 2003 and 2019. Patient characteristics, rates of post-transplant malignancy, and survival were compared between patients with pretransplant thyroid malignancy and without pretransplant thyroid malignancy. RESULTS: Eighty-six patients had pretransplant thyroid malignancy diagnosed after listing and before renal transplantation. Both overall and graft survival were similar between cohorts (P > .05). There was no significant association between pretransplant thyroid malignancy and patient (hazard ratio: 0.66; P = .31) or graft (hazard ratio:0.32; P = .11) survival on multivariate analysis. Waitlist duration for pretransplant thyroid malignancy patients was significantly increased (1,444 vs 438 days; P < .01), which translated to increased dialysis duration (2,234 vs 1,201 days, P < .01). Pretransplant thyroid malignancy patients did not experience increased post-transplant malignancy (P = .21). CONCLUSION: Given no association with decreased patient or allograft survival, our findings suggest that pretransplant thyroid malignancy patients are unnecessarily subjected to increased wait-list duration before transplant. We recommend an individualized approach for pretransplant thyroid malignancy patients diagnosed before or after listing.

Corneal Allografts: Factors for and against Acceptance.

Cornea is one of the most commonly transplanted tissues worldwide. However, it is usually omitted in the field of transplantology. Transplantation of the cornea is performed to treat many ocular diseases. It restores eyesight significantly improving the quality of life. Advancements in banking of explanted corneas and progressive surgical techniques increased availability and outcomes of transplantation. Despite the vast growth in the field of transplantation laboratory testing, standards for corneal transplantation still do not include HLA typing or alloantibody detection. This standard practice is based on immune privilege dogma that accounts for high success rates of corneal transplantation. However, the increasing need for retransplantation in high-risk patients with markedly higher risk of rejection causes ophthalmology transplantation centers to reevaluate their standard algorithms. In this review we discuss immune privilege mechanisms influencing the allograft acceptance and factors disrupting the natural immunosuppressive environment of the eye. Current developments in testing and immunosuppressive treatments (including cell therapies), when applied in corneal transplantation, may give very good results, decrease the possibility of rejection, and reduce the need for retransplantation, which is fairly frequent nowadays.

Evolution of a Novel Tissue Preservation Protocol to Optimize Osteochondral Transplantation Outcomes.

OBJECTIVE: Osteochondral allograft transplantation is a procedure to treat focal osteochondral lesions (OCLs), but is limited by tissue availability, the quality of transplanted tissue, and inconsistent storage protocols. The objective of this study was to assess the clinical outcomes of a novel tissue procurement, storage, and quality control protocol in treating OCLs. DESIGN: Prospective case series. Donor cadaveric tissue was processed, stored, and the tissue quality analyzed using the unique tissue preservation protocol developed at our institution. Advanced cross-sectional imaging was used to size match donor tissue with recipient patients. Osteochondral allografts were transplanted using the Arthrex Allograft OATS. Patients were evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS), and 36-Item Short Form Survey (SF-36) preoperatively and at 1 year and 2 years postoperatively. RESULTS: Twenty patients (17 knees, 3 shoulders) were included in the study. There was a significant improvement in the following scores: overall WOMAC score, WOMAC function and pain subcategories; KOOS pain, knee-related symptoms, activities of daily living, sports and recreation, and quality of life; SF-36 physical functioning, physical role, pain, and social functioning subcategories; and VAS at all time points postoperatively. There was a significant improvement in WOMAC stiffness at 2 years postoperatively. There were 2 failures, defined by graft subsidence and persistent pain requiring reoperation. CONCLUSION: The protocol developed at our institution for OAT resulted in significant clinical improvement in patients with OCLs and is an improvement on existing tissue storage techniques.

GMP Tiered Cell Banking of Non-enzymatically Isolated Dermal Progenitor Fibroblasts for Allogenic Regenerative Medicine.

Non-enzymatically isolated primary dermal progenitor fibroblasts derived from fetal organ donations are ideal cell types for allogenic musculoskeletal regenerative therapeutic applications. These cell types are differentiated, highly proliferative in standard in vitro culture conditions and extremely stable throughout their defined lifespans. Technical simplicity, robustness of bioprocessing and relatively small therapeutic dose requirements enable pragmatic and efficient production of clinical progenitor fibroblast lots under cGMP standards. Herein we describe optimized and standardized monolayer culture expansion protocols using dermal progenitor fibroblasts isolated under a Fetal Transplantation Program for the establishment of GMP tiered Master, Working and End of Production cryopreserved Cell Banks. Safety, stability and quality parameters are assessed through stringent testing of progeny biological materials, in view of clinical application to human patients suffering from diverse cutaneous chronic and acute affections. These methods and approaches, coupled to adequate cell source optimization, enable the obtention of a virtually limitless source of highly consistent and safe biological therapeutic material to be used for innovative regenerative medicine applications.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Impact of Guideline-Driven Approach in Follow-Up of Long-Term Complications After Allogeneic Hematopoietic Cell Transplant: Single Center Experience.

OBJECTIVES: After allogeneic stem cell transplant, patients may experience psychiatric, endocrinologic, pulmonary, and cardiovascular problems, as well as secondary malignancies and chronic graft-versus-host disease over the long-term follow-up. These long-term complications not only increase mortality and morbidity of transplant survivors but also decrease their quality of life. In this study, we shared our experiences with our guideline-driven approach for follow-up of long-term complications. MATERIALS AND METHODS: Our study included 91 patients who received allogeneic hematopoietic cell transplant between July 2009 and March 2016 at our medical center. In accordance with the current guidelines, a screening program was applied to all patients seen between February 2016 and February 2017. RESULTS: Median posttransplant follow-up duration was 36 months (range, 12-84 mo), and the median follow-up duration after initial diagnosis was 51 months (range, 15-109 mo). Evaluations of patients posttransplant showed ocular complications (50.6% of patients), oral complications (15.4%), respiratory complications (8.8%), cardiac complications (5.5%), metabolic syndrome (37.4%), liver complications (2.2%), skeletal complications (66.7%), endocrine complications (12.1%), secondary cancers (2.2%), psychosocial adjustment (27.7%), hypertension (5.5%), and type 2 diabetes mellitus (8.8%). CONCLUSIONS: For long-term follow-up, detailed evaluations of body organs and systems are essential. Early recognition of the aforementioned complications could decrease mortality and morbidity. For patients to be monitored by transplant centers over many years, training and awareness should be provided to ensure adequate follow-up of patients. Based on our results, we believe that the long-term follow-up guidelines used in our clinic are applicable to others.

Practical Considerations for APOL1 Genotyping in the Living Kidney Donor Evaluation.

BACKGROUND: Association between the apolipoprotein L1 gene (APOL1) and nephropathy has altered the epidemiology of chronic kidney disease. In addition, donor APOL1 genotypes play important roles in the time to allograft failure in kidneys transplanted from deceased donors and the safety of living kidney donation. METHODS: This article reviews genetic testing for inherited kidney disease in living kidney donors to improve donor safety. APOL1 genotyping in donors with recent African ancestry is considered. RESULTS: Based on current data, transplant physicians should discuss APOL1 genotyping with potential living kidney donors self-reporting recent African ancestry. Until results from APOL1 Long-term Kidney Transplant Outcomes Network ancillary studies are available, we present practical approaches from our experience for considering APOL1 genotyping in the living donor evaluation. CONCLUSIONS: Transplant physicians should inform potential living kidney donors at risk for APOL1-associated nephropathy about the gene and possibility of genetic testing early in the donor evaluation, well before scheduling the donor nephrectomy. Transplant programs must weigh risks of performing a donor nephrectomy in those with 2 APOL1 renal risk variants (high-risk genotypes), particularly younger individuals. Our program counsels kidney donors with APOL1 high-risk genotypes in the same fashion as with risk genotypes in other nephropathy genes. Because most African American kidney donor candidates lacking hypertension, proteinuria and reduced kidney function after workup will not possess APOL1 high-risk genotypes, genetic testing is unlikely to markedly increase donor declines and may reassure donors with regard to their long-term kidney outcomes, potentially increasing the number of African American donors.

Demographics and Distal Tibial Dimensions of Suitable Distal Tibial Allografts for Glenoid Reconstruction.

PURPOSE: To evaluate whether characteristics such as age, height, weight, sex, or body mass index affected the distal tibial dimensions and radius of curvature (ROC) of a potential donor for anterior glenoid augmentation. METHODS: A retrospective review of magnetic resonance imaging of ankles without bony trauma was performed, and the anteroposterior (AP) and medial-lateral (ML) distances and ROC of the tibial plafond articular surface were measured. Demographic characteristics, including age, sex, height, weight, and body mass index, were recorded. RESULTS: A total of 141 imaging studies were included (73 men and 68 women; average age, 38.2 ± 12.65 years). All potential specimens accommodated harvest of a 10 × 22-mm distal tibial allograft bone block. Men had greater ML (42.74 cm [95% confidence interval (CI), 42.09-43.39 cm] vs 38.01 cm [95% CI, 37.30-38.72 cm]; P < .001) and AP (38.16 cm [95% CI, 37.47-38.85 cm] vs 34.57 cm [95% CI, 33.97-35.17 cm]; P < .001) dimensions. Significant moderately positive correlations were found for AP dimensions with height (r = 0.584, P < .001) and weight (r = 0.383, P < .001) and for ML dimensions with height (r = 0.711, P < .001) and weight (r = 0.467, P < .001). ROC was positively correlated with height (r = 0.509, P < .001) and weight (r = 0.294, P < .001). Patient age was not related to either the AP or ML distal tibial dimensions or ROC. CONCLUSIONS: After magnetic resonance imaging analysis, all potential donors permitted harvest of a standard-sized distal tibial allograft irrespective of sex or common anthropometric measures, and 85.8% showed distal tibial morphology acceptable for glenoid augmentation. AP and ML graft dimensions and ROC correlated significantly with height and weight. LEVEL OF EVIDENCE: Level II, diagnostic study.

Comparison of Immune Reconstitution After Allogeneic Versus Autologous Stem Cell Transplantation in 182 Pediatric Recipients.

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of malignant and nonmalignant conditions. However, even if immune reconstitution after HSCT has been studied extensively, until now, data on the comparison of immune reconstitution after autologous versus allogeneic HSCT are scarce, but might provide important clinical implications. We examined immune reconstitution (T cells, B cells, and NK cells) at defined timepoints in 147 children who received 182 HSCTs. Differences in the time course of immune reconstitution were analyzed in autologous versus allogeneic HSCT. We identified a quicker immune reconstitution in the T-cell compartment, especially in the CD4 and naive subset after autologous HSCT, whereas recipients of allogeneic transplants showed a higher TCRgd proportion. B-cell reconstitution showed a delayed immune reconstitution after allogeneic HSCT in the first 2 years after HSCT. However, a reconstitution of all lymphocyte subsets after HSCT could be achieved in all patients. Children undergoing an HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and revaccinations.

[Stem cell transplantation unit: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Unité de greffe : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic cell transplantation (HCT) is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic HCT leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of HCT are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for human resources, construction and layout of a unit treating patients during the transplantation procedure and for different complications are not well defined. Here, we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of personnel and infrastructural requirements for hospitals caring for people with severe immunosuppression.

Medial patellofemoral ligament reconstruction in children: A comparative randomized short-term study of fascia lata allograft and gracilis tendon autograft reconstruction.

BACKGROUND: Many surgical procedures have been described to treat recurrent patellar dislocation, but none of these techniques has been successful in all patients. The goal of the study was to evaluate the results of medial patellofemoral ligament reconstruction in children. Two operative procedures were evaluated; a fascia lata allograft and an autologous gracilis graft. METHODS: Forty-four children (27 girls and 17 boys) between 13 and 17 years of age with unilateral recurrent patellar dislocation underwent medial patellofemoral ligament (MPFL) reconstruction. Patients were operated in two orthopedic centers. The 1st group contained 22 patients and surgery was performed using a fascia lata allograft. In the 2nd group of patients which also contained 22 children and autologous gracilis graft was used. The mean age of the patients was 14.9 years and the mean follow-up was 24 months. Preoperatively, all patients were evaluated clinically (Kujala score questionnaire) and radiologically. The same evaluation was used 18 to 30 months postoperatively to estimate the results of our treatment. RESULTS: In 1st group of children operated with cadaver allografts, the Kujala score significantly improved from 73.91 points preoperatively to 94.50 points postoperatively (P < .001). The average duration of operating procedure was 1 hour and 35 minutes. As shown by subjective symptoms, the results in 95% of patients were rated as good or very good. All children returned to full activity. Similar results were obtained in patients in 2nd group, where MPFL was reconstructed with ipsilateral gracilis tendon. Kujala score increased from 70.77 points preoperatively to 94.32 postoperatively (P < .001). Our results were estimated as good or very good in 93% of patients. All patients that were operated returned to full activity. However, median duration of operation was longer and lasted 1 hour and 55 minutes. CONCLUSIONS: Both techniques were effective in the short-term (18-30 months) in treatment of recurrent patellar dislocation. The use of cadaver allograft spares the hamstring muscles and reduces the time of surgery. Therefore, such study appears to be useful because it provides valuable information that would help to guide treatment of this condition in children. Level of evidence II-2.

Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

Renal allograft survival rates in kidneys initially declined for paediatric transplantation.

BACKGROUND: The outcome of organs which have been declined for paediatric recipients is not known. This study aimed to determine the outcome of kidneys initially declined for paediatric recipients and establish renal allograft survival in kidneys that were eventually transplanted. METHODS: Data were obtained from the UK Transplant Registry for all donation after brain death (DBD) kidneys offered and declined to paediatric recipients (< 18 years) in the UK from 2009 to 2014. RESULTS: Eighty-two percent (503/615) of kidneys initially declined for paediatric transplantation were eventually transplanted, 7% (46/615) of kidneys went to paediatric recipients and 62% (384/615) of kidneys went to adult (kidney only) recipients. The remainder were used for multiple organ transplants. In the 46 kidneys that went to paediatric recipients, 1 and 3-year renal allograft survivals were 89% (95% CI 75.8-95.3%) and 82% (95% CI 67.1-90.6%), respectively. In the 384 kidneys given to adult kidney-only recipients, 1 and 3-year renal allograft survivals were 96% (95% CI 93.5-97.6%) and 94% (95% CI 90.7-96.1%), respectively. Eighty-four percent of the 204 children who initially had an offer declined on their behalf were eventually transplanted and have a functioning graft at a median 3-year follow-up. CONCLUSIONS: This study reports acceptable short-term renal allograft survival in kidneys that were initially declined for paediatric recipients and subsequently transplanted. Evidence-based guidelines are required to ensure that the most appropriate kidneys are selected for paediatric recipients.

The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat malignant hematological neoplasms and non-malignant hematological disorders. Approximately, 5000 allo-HSCT procedures are performed in China annually. Substantial progress has been made in haploidentical HSCT (HID-HSCT), pre-transplantation risk stratification, and donor selection in allo-HSCT, especially after the establishment of the "Beijing Protocol" HID-HSCT system. Transplant indications for selected subgroups in low-risk leukemia or severe aplastic anemia (SAA) differ from those in the Western world. These unique systems developed by Chinese doctors may inspire the refining of global clinical practice. We reviewed the efficacy of allo-HSCT practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association and compared these studies to the consensus or guideline outside China. We summarized the consensus on routine practices of all-HSCT in China and focused on the recommendations of indications, conditioning regimen, and donor selection.

Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors.

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.

[Graft failure in allogeneic hematopoietic stem cell trans-plantation].

With the progress of medical technology, the development of new drugs and the improvement of the therapeutic effect of graft-versus host disease in the last two decades, the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been greatly improved. However, graft failure is still a rare but serious complication of allo-HSCT. HLA incompatibility, virus infection, elderly donor, uncontrolled primary disease, damage of bone marrow hematopoietic microenvironment, ABO blood group incompatibility, T cell depletion, reduced intensity conditioning, and low nucleated cell number are all risk factors for graft failure. In recent years, with the implementation of HLA haplo-identical hematopoietic stem cell transplantation, the role of donor-specific antibodies in graft failure has attracted attention increasingly. This article reviews the recent studies involving the mechanism, risk factors and prevention measures of graft failure in allo-HSCT.