Considerations for an Alternative Site of Islet Cell Transplantation.

Islet cell transplantation has been limited most by poor graft survival. Optimizing the site of transplantation could improve clinical outcomes by minimizing required donor cells, increasing graft integration, and simplifying the transplantation and monitoring process. In this article, we review the history and significant human and animal data for clinically relevant sites, including the liver, spleen, and kidney subcapsule, and identify promising new sites for further research. While the liver was the first studied site and has been used the most in clinical practice, the majority of transplanted islets become necrotic. We review the potential causes for graft death, including the instant blood-mediated inflammatory reaction, exposure to immunosuppressive agents, and low oxygen tension. Significant research exists on alternative sites for islet cell transplantation, suggesting a promising future for patients undergoing pancreatectomy.

Robot-assisted orthotopic and heterotopic ovarian tissue transplantation techniques: surgical advances since our first success in 2000.

OBJECTIVE: To demonstrate the technical advances since the time we reported the first successful case in 2000 and our modern approach to autologous transplantation of frozen-thawed human ovarian tissue. DESIGN: A step-by-step video demonstration of three surgical approaches was created by editing the surgical footage obtained during ovarian transplantation procedures. SETTING: Academic. PATIENT(S): Three patients who previously underwent ovarian tissue harvesting and cryopreservation before gonadotoxic cancer treatments or radical cancer surgery are presented. INTERVENTION(S): The illustrated techniques include robot-assisted orthotopic (technique 1) and heterotopic (technique 2) approaches using the da Vinci Xi (Intuitive Surgical) robotic system and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp.) as a tissue scaffold, as well as a percutaneous autotransplantation approach (technique 3). MAIN OUTCOME MEASURE(S): Successful completion of procedures without complications and ovarian graft function with demonstration of E2 production and follicle development. RESULT(S): All cases were completed without complications. Ovarian graft function was confirmed by E2 production, follicle growth by 10-14 weeks after transplantation, and later embryo development. CONCLUSION(S): Since our first report of successful restoration of ovarian function after orthotopic transplantation of frozen-banked ovarian tissue in 2000 (1), followed by our first reports of subcutaneous heterotopic transplantation techniques (2, 3), ovarian tissue cryopreservation followed by subsequent transplantation has become a promising fertility preservation option for young women with cancer who do not have sufficient time to undergo oocyte or embryo cryopreservation and for prepubertal girls (4, 5). The same approach also has the advantage of restoring ovarian endocrine function and fertility without a need for assisted reproduction (6, 7). In the very first successful procedure that we reported in 2000, we used conventional laparoscopy, and the tissues were reconstructed and mounted on a polycellulose scaffold (Surgicel) (1, 7). Since then, we have made significant modifications in our surgical approach with potential improvements in outcomes. Here we illustrate three main techniques of ovarian tissue transplantation resulting in the restoration of ovarian function in all cases. In the first two cases, we illustrated the robot-assisted orthotopic and heterotopic approaches using Alloderm. Robotic ovarian transplantation may increase precision, provide more delicate graft handling, and reduce the time from tissue thawing to transplantation (6, 8). Alloderm is regenerated de-epithelized human cadaver skin, which consists of several extracellular matrix components. It has been safely used in the surgery and dentistry fields for enhancing tissue regeneration and vascularization (9, 10). Furthermore, our earlier laboratory work indicated the critical role of extracellular matrix in primordial follicle growth initiation and preantral follicle growth (11, 12). Prior to our use of Alloderm as part of ovarian transplant procedures, we tested it in human ovarian xenograft models and found Alloderm to incorporate well with ovarian tissue (8). Only after that test did we adopt it for use in ovarian transplants. The utility of the extracellular tissue matrix may thus enhance our ovarian autotransplantation techniques by facilitating ovarian reconstruction and potentially improving neovascularization. In fact, we have seen improved follicle growth and response to ovarian stimulation with the use of Alloderm in our first cases (8). We use heterotopic ovarian transplantation when the pelvis is not suitable for autotransplantation due to past radiation or scarring or when there are other medical contraindications for transplantation in the pelvis. The third technique we illustrated was percutaneous heterotopic ovarian autotransplantation. This is a simple approach that can be used in surgically high-risk patients, as it is done with local anesthesia or IV sedation and without entering abdominal cavity. Additionally, same approach can be utilized when there is heightened concern that the ovarian tissue may harbor a disease that can recur, requiring close surveillance and easier removal of the ovarian graft. While ovarian endocrine function and follicle growth are restored with efficiency using the percutaneous ovarian transplants, our initial experience suggests that oocyte quality may be impaired in SC locations (2, 3, 13). Hence that technique may be more suitable when the only purpose is restoration of ovarian endocrine function. However, we have encountered recurrent live births from spontaneous conceptions following SC ovarian transplants, prompting the question of whether the grafted tissue can augment the function of in situ menopausal ovary (13, 14). While ovarian cryopreservation and transplantation may no longer be considered experimental, there are many exciting questions remaining to be answered on the full potential of this procedure.

Accessory cells for ß-cell transplantation.

Despite recent advances, insulin therapy remains a treatment, not a cure, for diabetes mellitus with persistent risk of glycaemic alterations and life-threatening complications. Restoration of the endogenous ß-cell mass through regeneration or transplantation offers an attractive alternative. Unfortunately, signals that drive ß-cell regeneration remain enigmatic and ß-cell replacement therapy still faces major hurdles that prevent its widespread application. Co-transplantation of accessory non-islet cells with islet cells has been shown to improve the outcome of experimental islet transplantation. This review will highlight current travails in ß-cell therapy and focuses on the potential benefits of accessory cells for islet transplantation in diabetes.

Current status of encapsulated islet transplantation.

Islet transplantation is a treatment modality for diabetes mellitus that can maintain insulin levels within a physiologically appropriate range. However, wider clinical application is limited by insufficient donor numbers and a need for lifelong immunosuppression. Despite various clinical and preclinical trials, there is no single standard immunosuppressive regimen that can suppress acute and chronic immune reactions with lower toxicity to grafted islets. One of the strategies for overcoming lifelong immunosuppression is the incorporation of encapsulation technology, which can provide a physical immune barrier by keeping out high molecular weight immune system components, while still allowing low molecular weight oxygen, insulin and nutrients to pass through. Encapsulated islet transplantation approaches that have been studied so far include macroencapsulation, microencapsulation, conformal coating and nanoencapsulation. Herein we will review the basic concepts of islet encapsulation technique, earlier works to recent progress related to clinical studies and corporate investigations on encapsulated islet transplantation.

Gammagrafía con hematíes desnaturalizados en el diagnóstico de esplenosis peritoneal en paciente con antecedente de hepatocarcinoma. A propósito de un caso / Usefulness of Tc-99m labelled heat-denatured red blood cell scintigraphy for diagnosis of peritoneal splenosis in a patient with hepatocellular cancer: a case report

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Islet and stem cell encapsulation for clinical transplantation.

Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues.

Heterotopic heart transplantation: the United States experience.

INTRODUCTION: More than 3 decades have passed since the first heterotopic heart transplantation (HHT) was reported. Nowadays, this surgical technique is used rarely, and only in patients who do not qualify for standard orthotopic heart transplantation (OHT). Current indications mainly comprise refractory pulmonary hypertension and a donor-recipient size mismatch (>20%). The objective of this study was to analyze the United States experience with HHT. PATIENTS AND METHODS: The United Network for Organ Sharing (UNOS) database between 1987 and 2007 was analyzed. Patients who underwent heart transplantation were enrolled in this study. Patients with missing transplant dates or history of retransplantation were excluded. RESULTS: A total of 41,379 patients underwent OHT and 178 HHT; 32,361 and 111 patients, respectively, were enrolled. Overall 1-, 5-, and 10-year survival was significantly (P < .001) better in OHT (87.7%, 74.4%, 54.4%) than HHT patients (83.8%, 59%, 35.1%). Survival in patients with transpulmonary gradients (TPG) >15 mmHg was 86.6 %, 73.3%, and 57.4% in the OHT and 93.8%, 64.8%, and 48.6% in the HHT group (P = .35). Pretransplant criteria (HHT versus OHT) with statistically significant differences (P < .05) were as follows (mean + SD): recipient weight, 78.9 + 19.9 versus 74.1 + 23.4 kg; recipient height, 174.9 + 13.9 versus 168 + 25.1 cm; and TPG 12.1 + 7.2 versus 9.6 + 6.3 mmHg. CONCLUSIONS: The results show that HHT remains a feasible option in a highly selected patient population, with overall good results.

Heterotopic heart transplantation: an expanding role in the twenty-first century?

BACKGROUND: Heterotopic heart transplantation was first performed in humans in 1974, the main advantage being the continuing function of the patient's native heart, in the event of life-threatening acute rejection. The effect of cyclosporine on acute rejection saw the heterotopic transplantation technique wane. Our unit revisited heterotopic transplantation in response to a growing number of waiting list patients with high pulmonary artery pressures. We also anticipated an increased cardiac allograft utilization, and improvement of our waiting list times. METHODS: We retrospectively analyzed 151 patients undergoing heart transplantation by our unit between August 1997 and September 2003. Twenty received allografts in the heterotopic position. This cohort was compared with the 131 contemporary orthotopic heart transplant recipients with respect to their outcomes. RESULTS: The indication for transplantation was ischemic cardiomyopathy in 14 (70%) of the heterotopic cohort and 47 (36%) of the orthotopic cohort (p = 0.004), and dilated cardiomyopathy in 3 (15%) and 48 (37%) in the heterotopic and orthotopic groups, respectively (p = 0.06). Heterotopic recipients were significantly older than orthotopic recipients, and they had higher pulmonary artery pressures. The heterotopic donors were also older and the ischemic times were longer. A subgroup analysis was made among those patients who had high pulmonary artery pressures as these groups were better matched. Major morbidity in the heterotopic heart transplantation group consisted of reversible allograft dysfunction in 4 patients, renal dysfunction requiring hemofiltration in 3 patients, profound myopathy in 4 patients, and cerebrovascular events in 2 patients. There were two early deaths in the heterotopic transplant group and eight in the orthotopic group (p = 0.87). Kaplan-Meier survival analysis of survival was performed. CONCLUSIONS: Heterotopic heart transplantation is a viable transplant option for selected high-risk heart transplant recipients in spite of somewhat poorer outcomes.