An Initial Analysis of the Baseline Levels of Dd-cfDNA After Pancreas Transplantation: A Prospective Study From High-volume Centers in the United States.

Pancreas transplantation offers patients with diabetes an opportunity for glucose homeostasis. Current blood tests to surveil for rejection have poor sensitivity and specificity for identifying rejection, and pancreas biopsies are challenging and associated with morbidity and graft loss. Donor-derived cell-free DNA (dd-cfDNA) is shed from transplanted organs and detectable in peripheral blood. Thus, a potential dd-cfDNA blood test assessing rejection would be clinically advantageous. Methods: One hundred eighty-one dd-cfDNA samples (n) were collected from 77 patients (N) up to 132 mo posttransplant. Results: The median dd-cfDNA level among all subjects was 0.28% (0.13%, 0.71%). In simultaneous pancreas-kidney (SPK) transplant recipients, the median dd-cfDNA level was 0.29% (0.13%, 0.71%), and it was 0.23% (0.08%, 0.71%) in pancreas transplant alone (PTA) recipients. When isolating for when without infection or rejection, the median dd-cfDNA level was 0.28% (0.13%, 0.64%) for SPK and 0.20% (0.00%, 0.32%) for PTA. Both transplant types approached 1.0% ≤1 mo posttransplant followed by a decrease in median dd-cfDNA. During episodes of rejection or infection, median dd-cfDNA levels were greater among all transplant types. Conclusions: The mean dd-cfDNA level for all pancreas transplant recipients is <1.0%, consistent with the published kidney transplant rejection threshold (>1.0%), regardless of SPK or PTA. Early posttransplant dd-cfDNA levels are transiently higher than later measurements. Dd-cfDNA elevation also correlates with rejection and infection and thus is a promising biomarker for surveilling pancreas transplant dysfunction.

Interfacility Transfer for Nonelective Cholecystectomy in High MELD Patients: An ACS-NSQIP Analysis.

INTRODUCTION: Interfacility transfer to a referral center is often considered for patients with liver disease undergoing nonelective cholecystectomy given management complexities and perioperative risk. We sought to determine the association between the Model for End Stage Liver Disease (MELD) score, transfer frequency, and outcomes in those patients using a national database. MATERIALS AND METHODS: The ACS-NSQIP participant use files were queried for nonelective open or laparoscopic cholecystectomy from 2016 to 2018. Patients were grouped according to low (6-11), intermediate (12-18), or high (>18) MELD. In the high MELD group, patient characteristics and outcomes were compared between transferred and nontransferred patients and multivariate regression was performed to evaluate independent predictors of outcomes. Outcomes included in-hospital mortality, complications, length-of-stay (LOS), and 30-d reoperation and readmission. RESULTS: 30,171 subjects were included. Transfer was more likely as MELD increased (19.5% high versus 12.1% low, P < 0.001). High MELD patients had increased LOS, reoperation, readmission, and mortality rates compared to low MELD. In high MELD patients (n = 1016), those transferred were more likely older, white, obese, and septic. Transferred patients had increased mortality (7.6% versus 4.2%, P = 0.044), LOS, reoperation, and complications. After controlling for differences between transferred and nontransferred patients, transfer status was not independently associated with mortality (OR = 1.593, P = 0.177), postoperative complications or LOS, but was associated with increased risk for reoperation. Sepsis and laparoscopic surgery were independently associated with higher and lower mortality, respectively. CONCLUSIONS: Transfer status is not independently associated with mortality, postoperative complications, or prolonged LOS, suggesting patients with advanced liver disease undergoing acute cholecystectomy may not benefit from interfacility transfer.

Surgical Management of Lower Extremity Wounds in the Solid Organ Transplant Patient Population: Surgeon Beware.

Objective: To evaluate our institutional outcomes of surgical management of lower extremity (LE) wounds in the solid organ transplant recipient population. Approach: An 8-year retrospective review was conducted for all solid organ transplantation (SOT) recipients with LE wounds necessitating surgical management at our tertiary limb salvage center. Outcomes of interest included wound healing, surgical treatment, progression to amputation, and amputation level. Factors contributing to amputation progression were analyzed. The article adheres to the Strengthening the Reporting of Observational Studies in Epidemiology statement. Results: Sixty-four SOT recipients underwent surgical management for their LE wounds between 2010 and 2018. Median number of surgeries per patient was 5 (interquartile range = 2-8); 47 of 64 patients (73.4%) underwent amputation, and 17 of 64 patients (26.6%) underwent nonamputation surgical management. In the amputation group, the majority of primary amputations were minor (42/47, 89.4%); 24 of 42 (57.1%) patients progressed to a higher amputation level, 16 of 42 (38.1%) healed after their index procedure, and 2 of 42 (4.8%) were lost to follow-up (LTFU) after their primary minor amputation. Five of 47 (10.6%) patients undergoing amputations required primary below-knee amputations. In the nonamputation group, 15 of 17 (88.2%) healed, 1 of 17 (5.9%) expired, and 1 of 17 (5.9%) was LTFU. Innovation: To identify the outcomes of patients undergoing surgical management for LE wounds after SOT and elucidate clinical factors that impact the rate of limb salvage. Conclusions: This is the first comprehensive analysis of LE wounds in the transplant population. Our analysis indicates high rates of failed minor amputation, and frequent progression to major amputation in SOT patients. Preexisting comorbidities and immunosuppressive regimens complicate limb salvage; therefore, further research is warranted to optimize surgical LE wound management in this population.

Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting.

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

The incidence of fungal infections in pancreas transplant recipients in the absence of systemic antifungal prophylaxis.

BACKGROUND: There is a lack of high-level evidence identifying meaningful outcomes and the place in therapy for systemic perioperative antifungal prophylaxis (ppx) in pancreas transplant recipients. As our program does not routinely utilize systemic perioperative antifungal ppx in pancreas transplant recipients, we assessed the incidence of post-transplant infectious complications. METHODS: This was a single-center, retrospective cohort study of consecutive adult pancreas transplant recipients between 01/2016 and 04/2018 to describe the incidence of fungal infections. Patients with a history of previous simultaneous pancreas-kidney (SPK) transplant, HIV, or unexplained use of antifungal ppx after transplantation were excluded. The primary outcome was the incidence of fungal infections within 3 months after transplantation. RESULTS: After screening 60 patients, 56 met inclusion criteria. Within 3 months post-transplantation, two (3.6%) patients had a positive fungal culture requiring systemic antifungal treatment. The sources for infection in both cases were intra-abdominal fluid cultures, positive for Candida albicans. Both patients were treated with fluconazole. Allograft-related outcomes included a 6-month pancreas graft survival of 91.1% and pancreas transplant rejection incidence of 10.7%. CONCLUSION: In this single-center experience, pancreas transplant recipients not receiving systemic antifungal ppx had similar infectious and graft-related outcomes to what is reported in literature.