Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation.

BACKGROUND: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation. METHODS: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays. RESULTS: High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR. CONCLUSIONS: Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.

Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

Physiological basis for xenotransplantation from genetically modified pigs to humans.

The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-nonhuman primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pigs with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes), whose hearts and kidneys have now been studied in preclinical human xenotransplantation models with brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed with hearts from this 10 GE pig at the University of Maryland. Although this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.

Vascularized Islet Transplantation as Composite Islet-Kidney Grafts with Nanoparticle-Labeled Islets in Large Animal Preclinical Transplant Models.

Although there are many patients with diabetes and end-stage renal failure (DM/ESRD) who would benefit from a transplantation strategy that addresses both their ESRD and its underlying cause, current methods of islet and kidney transplantation using live donors have had only limited success. The first major obstacle is that the number of islets obtained from a live donor partial pancreatectomy is generally insufficient to cure diabetes in recipients, as large numbers of intraportally administered islets are lost due to ischemia before they are engrafted and vascularized in the recipient liver. To overcome this hurdle, we have developed a strategy to transplant islets as a vascularized graft. Autologous prevascularization of donor islets under the donor's own renal capsule prior to transplantation preserves islets and thus achieves normal glycemic control in diabetic recipients in our preclinical transplant models with a limited donor pancreas resection. In addition, from an immunological perspective, the innate tolerogenic qualities of the kidney provide immunoprotection for the engrafted, vascularized islets when they are transplanted as part of the composite islet-kidney (I-K) grafts. This "Trojan Horse" approach of transplanting a composite I-K eliminates the lengthy time which is otherwise required for vascularization of intraportally administered free islets, minimizing loss of islets to ischemic damage and facilitating the induction of tolerance. We have also recently developed a strategy to further minimize the required size of resected donor pancreas to prepare composite I-K graft using a novel, synthesized, small interfering RNA (siRNA)-nanoparticle probe. In this chapter, we introduce our living donor transplantation strategy to cure diabetic nephropathy using composite I-K graft.

Progress in Xenotransplantation: Immunologic Barriers, Advances in Gene Editing, and Successful Tolerance Induction Strategies in Pig-To-Primate Transplantation.

Organ transplantation is the most effective treatment for end stage organ failure, but there are not enough organs to meet burgeoning demand. One potential solution to this organ shortage is xenotransplantation using pig tissues. Decades of progress in xenotransplantation, accelerated by the development of rapid genome editing tools, particularly the advent of CRISPR-Cas9 gene editing technologies, have enabled remarkable advances in kidney and heart xenotransplantation in pig-to-nonhuman primates. These breakthroughs in large animal preclinical models laid the foundation for three recent pig-to-human transplants by three different groups: two kidney xenografts in brain dead recipients deemed ineligible for transplant, and one heart xenograft in the first clinical grade study of pig-to-human transplantation. However, despite tremendous progress, recent data including the first clinical case suggest that gene-modification alone will not overcome all xenogeneic immunologic barriers, and thus an active and innovative immunologic strategy is required for successful xenotransplantation. This review highlights xenogeneic immunologic barriers, advances in gene editing, and tolerance-inducing strategies in pig-to-human xenotransplantation.

Progress in islet xenotransplantation: Immunologic barriers, advances in gene editing, and tolerance induction strategies for xenogeneic islets in pig-to-primate transplantation.

Islet transplantation has emerged as a curative therapy for diabetes in select patients but remains rare due to shortage of suitable donor pancreases. Islet transplantation using porcine islets has long been proposed as a solution to this organ shortage. There have already been several small clinical trials using porcine islets in humans, but results have been mixed and further trials limited by calls for more rigorous pre-clinical data. Recent progress in heart and kidney xenograft transplant, including three studies of pig-to-human xenograft transplant, have recaptured popular imagination and renewed interest in clinical islet xenotransplantation. This review outlines immunologic barriers to islet transplantation, summarizes current strategies to overcome these barriers with a particular focus on approaches to induce tolerance, and describes an innovative strategy for treatment of diabetic nephropathy with composite islet-kidney transplantation.

Failure to Rescue in Geriatric Trauma: The Impact of Any Complication Increases with Age and Injury Severity in Elderly Trauma Patients.

INTRODUCTION: The interaction of increasing age, Injury Severity Score (ISS), and complications is not well described in geriatric trauma patients. We hypothesized that failure to rescue rate from any complication worsens with age and injury severity. METHODS: The National Trauma Data Bank (NTDB) was queried for injured patients aged 65 years or older from January 1, 2013 through December 31, 2016. Demographics and injury characteristics were used to compare groups. Mortality rates were calculated across subgroups of age and ISS, and captured with heatmaps. Multivariable logistic regression was performed to identify independent predictors of mortality. RESULTS: 614,496 geriatric trauma patients were included; 151,880 (24.7%) experienced a complication. Those with complications tended to be older, female, non-white, have non-blunt mechanism, higher ISS, and hypotension on arrival. Overall mortality was highest (19%) in the oldest (≥86 years old) and most severely injured (ISS ≥ 25) patients, with constant age increasing across each ISS group was associated with a 157% increase in overall mortality (P < .001, 95% CI: 148-167%). Holding ISS stable, increasing age group was associated with a 48% increase in overall mortality (P < .001, 95% CI: 44-52%). After controlling for standard demographic variables at presentation, the existence of any complication was an independent predictor of overall mortality in geriatric patients (OR: 2.3; 95% CI: 2.2-2.4). CONCLUSIONS: Any complication was an independent risk factor for mortality, and scaled with increasing age and ISS in geriatric patients. Differences in failure to rescue between populations may reflect critical differences in physiologic vulnerability that could represent targets for interventions.

The Impact of Increasing Surgical Capacity at a Tertiary Hospital in Southern Haiti.

BACKGROUND: St. Boniface Hospital (SBH) plays a critical role in providing safe, accessible surgery in rural southern Haiti. We examine the impact of SBH increasing surgical capacity on case volume, patient complexity, and inpatient mortality across three phases. MATERIALS AND METHODS: A retrospective review and geospatial analysis of all surgical cases performed at SBH between 2015 and 2017 were performed. Inpatient mortality was defined by in-hospital deaths divided by the number of procedures performed. RESULTS: Between February 2015 and August 2017, over 2000 procedures were performed. The average number of surgeries per week was 3.1 with visiting surgical teams in phase 1 (P1), 10.4 with a single general surgeon in phase 2 (P2), and 20.1 with two surgeons and a resident in phase 3 (P3). There was a six-fold increase in surgical volume between P1 and P3 and a significant increase in case complexity. The distribution of American Society of Anesthesiologists scores of 1, 2, 3, and 4 during P2 was 81.05%, 14.74%, 3.42%, and 0.79%, respectively, whereas in P3, the distribution was 68.91%, 22.55%, 7.70%, and 0.84%. Surgical mortality was 0%, 1.2%, and 1.67% across phases. CONCLUSIONS: Increasing resources and surgical staff at SBH allowed for greater delivery of safe surgical care. This study highlights that investing in surgery has a significant impact in regions of great surgical need.

Unusual Mechanism for Superior Mesenteric Artery Syndrome after Scoliosis Surgery.

t Superior Mesenteric Artery (SMA) syndrome is an uncommon condition caused by mechanical obstruction of the distal third of the duodenum between the superior mesenteric artery and the abdominal aorta. SMA syndrome is associated with both operative and non-operative corrections of scoliosis, as well as anorexia nervosa, severe weight loss, tumors, burns, and other traumas.[1-4] We report an unusual case of SMA syndrome following corrective surgery for scoliosis in which post-operative gastric distension caused duodenal compression that subsequently resolved with gastric decompression, as opposed to the conventional, reverse series of events in which SMA syndrome causes the gastric dilatation. [Full article available at http://rimed.org/rimedicaljournal-2017-08.asp].

Intraoperative Femur Fracture Risk During Primary Direct Anterior Approach Cementless Total Hip Arthroplasty With and Without a Fracture Table.

BACKGROUND: There is no study to date comparing intraoperative femur fractures (IFFs) in the direct anterior approach (DAA) with and without a fracture table. We hypothesize that there is no significant difference in the IFF with and without a fracture table when performed by experienced DAA hip surgeons. METHODS: This study is a 1-year retrospective review of patients who underwent DAA total hip arthroplasty by 2 surgeons: one surgeon uses a flat table and manually elevates the femur with a large bone hook, while the other surgeon uses a fracture table and a mechanical femoral elevator. Exclusion criteria included cemented femoral implants, femoral neck fractures, and lack of 6-month follow-up. RESULTS: We identified 487 patients for analysis (220 male and 267 female, average age 66.55 years). There were 12 total IFFs (2.46%): 8 female and 4 male patients. The average age of IFF patients was 70.67 years and in nonfracture patients was 66.00 years. There was no difference in gender (P = .2981) or age (P = .2099) between IFF and nonfracture patients. In the fracture table group, there were 6 IFFs (2.22%) in 271 patients; in the nonfracture table group, there were 6 IFFs (2.76%) in 216 patients. There was no statistical difference in IFF between the 2 groups (P = .6973). We observed just 2 patients (0.4%) in this series where the IFFs changed management requiring a revision femoral stem. CONCLUSION: There was no statistical difference in IFF with or without the use of fracture table. Both DAA surgical technique variations are felt to be equivalent regarding the risk for IFF during DAA cementless total hip arthroplasty.

Fournier's gangrene of the penis in a 12-year-old patient secondary to phimosis.

We report a case of Fournier's gangrene in a 12-year-old boy from St. Boniface Hospital in Fond-des-Blancs, Haiti. Fournier's gangrene, a fulminant necrotizing fasciitis of the penis and scrotum, is a rare and life-threatening infection that requires hospitalization, broad-spectrum antibiotics, and surgical debridement.1-3 It is usually associated with impaired cellular immunity due to systemic disorders such as diabetes and liver disease.4,5 This patient had none of those risk factors, but had severe, longstanding phimosis, for which circumcision had been recommended many years before. This case illustrates how lack of access to basic surgical care for an easily treatable condition leads to advanced presentation of a severe disease process. [Full article available at http://rimed.org/rimedicaljournal-2016-12.asp].

Passenger deletions generate therapeutic vulnerabilities in cancer.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.