Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Management of ectopic intestinal variceal bleeding following pancreatic transplant: Two cases.

Ectopic variceal bleeding is a potentially under recognized source of gastrointestinal (GI) hemorrhage. While vascular complications following pancreatic transplant are relatively common, the development of symptomatic ectopic venous varices has rarely been reported. We report two patients with a remote history of simultaneous kidney pancreas transplant (SPK) presenting two decades after transplant with an occult GI bleed. In both cases, a lengthy diagnostic course was required. The varices were treated with coil embolization via transhepatic approach. Our findings add to the limited literature on this topic and aid in the recognition, diagnosis, and management of this unusual presentation.

Improved survival of SARS COV-2-infected K18-hACE2 mice treated with adenosine A2AR agonist.

A life-threatening manifestation of Covid-19 infection is a cytokine storm that requires hospitalization and supplemental oxygen. Various strategies to reduce inflammatory cytokines have had some success in limiting cytokine storm and improving survival. Agonists of adenosine A2A receptors (A2AR) reduce cytokine release from most immune cells. Apadenoson is a potent and selective anti-inflammatory adenosine analog that reduces inflammation. When administered by subcutaneous osmotic pumps to mice infected with SARS CoV-2, Apadenoson was found to improve the outcomes of infection as measured by a decrease in weight loss, improved clinical symptoms, reduced levels of proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and enhanced survival of K18-hACE2 transgenic mice. These results support further examination of A2AR agonists as therapies for treating cytokine storm due to COVID-19.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.

BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. METHODS AND FINDINGS: Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4-5) were infused IV with a loading RA dose of 5 µg/kg/h for 0.5 h followed by a maintenance dose of 1.44 µg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 µg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). CONCLUSIONS: Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

Delivery of Dissociated Islets Cells within Microporous Annealed Particle Scaffold to Treat Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by the autoimmune loss of insulin-producing beta cells in the pancreas. The only clinical approach to patient management of blood glucose that doesn't require exogenous insulin is pancreas or islet transplantation. Unfortunately, donor islets are scarce and there is substantial islet loss immediately after transplantation due, in part, to the local inflammatory response. The delivery of stem cell-derived beta cells (e.g., from induced pluripotent stem cells) and dissociated islet cells hold promise as a treatment for T1D; however, these cells typically require re-aggregation in vitro prior to implantation. Microporous scaffolds have shown high potential to serve as a vehicle for organization, survival, and function of insulin-producing cells. In this study, we investigated the use of microporous annealed particle (MAP) scaffold for delivery of enzymatically dissociated islet cells, a model beta cell source, within the scaffold's interconnected pores. We found that MAP-based cell delivery enables survival and function of dissociated islets cells both in vitro and in an in vivo mouse model of T1D.

Challenges, highlights, and opportunities in cellular transplantation: A white paper of the current landscape.

Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.

Robot-assisted kidney transplantation is a safe alternative approach for morbidly obese patients with end-stage renal disease.

BACKGROUND: Many centres deny obese patients with a body mass index (BMI) >35 access to kidney transplantation due to increased intraoperative and postoperative complications. METHODS: From August 2017 to December 2019, 73 consecutive cases of kidney transplantation in morbidly obese patients were enrolled at a single university at the initiation of a robotic transplant surgery program. Outcomes of patients who underwent robotic assisted kidney transplant (RAKT) were compared to frequency-matched patients undergoing open kidney transplant (OKT). RESULTS: A total of 24 morbidly obese patients successfully underwent RAKT, and 49 obese patients received an OKT. The RAKT group developed fewer surgical site infections (SSI) than the OKT group. Graft function, creatinine, and glomerular filtration rate (GFR) were similar between groups 1 year after surgery. Graft and patient survival were 100% for both groups. CONCLUSIONS: RAKT offers a safe alternative for morbidly obese patients, who may otherwise be denied access to OKT.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Center-level Variation in HLA-incompatible Living Donor Kidney Transplantation Outcomes.

BACKGROUND: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice.

Autoimmune diseases such as type 1 diabetes (T1D) arise from unrestrained activation of effector lymphocytes that destroy target tissues. Many efforts have been made to eliminate these effector lymphocytes, but none has produced a long-term cure. An alternative to depletion therapy is to enhance endogenous immune regulation. Among these endogenous alternatives, naturally occurring Igs have been applied for inflammatory disorders but have lacked potency in antigen-specific autoimmunity. We hypothesized that naturally occurring polyclonal IgMs, which represent the majority of circulating, noninduced antibodies but are present only in low levels in therapeutic Ig preparations, possess the most potent capacity to restore immune homeostasis. Treatment of diabetes-prone NOD mice with purified IgM isolated from Swiss Webster (SW) mice (nIgMSW) reversed new-onset diabetes, eliminated autoreactive B lymphocytes, and enhanced regulatory T-cell (Treg) numbers both centrally and peripherally. Conversely, IgM from prediabetic NOD mice could not restore this endogenous regulation, which represents an unrecognized component of T1D pathogenesis. Of note, IgM derived from healthy human donors was similarly able to expand human CD4 Tregs in humanized mice and produced permanent diabetes protection in treated NOD mice. Overall, these studies demonstrate that a potent, endogenous regulatory mechanism, nIgM, is a promising option for reversing autoimmune T1D in humans.

Evidence for the Role of the Cecal Microbiome in Maintenance of Immune Regulation and Homeostasis.

OBJECTIVE (S): Our objective was to investigate alterations in the cecal microbial composition during the development of type 1 diabetes (T1D) with or without IgM therapy, and correlate these alterations with the corresponding immune profile. METHODS: (1) Female nonobese diabetic (NOD) mice treated with IgM or saline (n = 20/group) were divided into 5-week-old nondiabetic; 9 to 12-week-old prehyperglycemic stage-1; ≥13-week-old prehyperglycemic stage-2; and diabetic groups. 16S rRNA libraries were prepared from bacterial DNA and deep-sequenced. (2) New-onset diabetic mice were treated with IgM (200 µg on Days 1, 3, and 5) and their blood glucose monitored for 2 months. RESULTS: Significant dysbiosis was observed in the cecal microbiome with the progression of T1D development. The alteration in microbiome composition was characterized by an increase in the bacteroidetes:firmicutes ratio. In contrast, IgM conserved normal bacteroidetes:firmicutes ratio and this effect was long-lasting. Furthermore, oral gavage using cecal content from IgM-treated mice significantly diminished the incidence of diabetes compared with controls, indicating that IgM specifically affected mucosa-associated microbes, and that the affect was causal and not an epiphenomenon. Also, regulatory immune cell populations (myeloid-derived suppressor cells and regulatory T cells) were expanded and insulin autoantibody production diminished in the IgM-treated mice. In addition, IgM therapy reversed hyperglycemia in 70% of new-onset diabetic mice (n = 10) and the mice remained normoglycemic for the entire post-treatment observation period. CONCLUSIONS: The cecal microbiome appears to be important in maintaining immune homeostasis and normal immune responses.

A case of rhabdomyolysis after kidney transplantation successfully managed with intensive continuous dialysis.

Rhabdomyolysis is characterized by muscle cell death which can result in acute kidney injury from pigment nephropathy. We present a patient who developed rhabdomyolysis immediately after deceased donor kidney transplantation surgery and was managed with continuous renal replacement therapy that resulted in successful salvage of the kidney allograft. Patients who develop acute kidney failure requiring renal replacement therapy generally have a poor prognosis. It is worth noting that while continuous veno-venous hemofiltration (CVVHF) offers greater volume support and continuous clearance compared to hemodialysis (HD), recent studies have demonstrated no clinically significant improvement in clinical outcome between the two. Perhaps CVVHF is a better modality compared to HD in this setting to prevent further insult from pigment nephropathy to an allograft. A combination of early diagnosis and intensive continuous renal replacement therapy can be used for allograft salvage in a patient with rhabdomyolysis in the immediate post-kidney transplant period.

The successful salvage of a thrombosed pancreatic graft at the early postoperative period of a simultaneous pancreas and kidney transplantation.

INTRODUCTION: Simultaneous kidney and pancreas transplant is the preferred treatment option for end-stage renal disease due to type 1 diabetic nephropathy. Vascular complications are detrimental to graft survival and can lead to graft loss in the early postoperative phase of transplantation. Generally, duplex Doppler ultrasound is used for vascular patency monitoring and pancreatectomy followed by re-transplantation is required in the majority of cases. Recently, pancreatic graft salvage with non-operative management, including medical anticoagulation and endovascular thrombectomy, in the early postoperative period has been described with success. PRESENTATION OF CASE: We report a case of early detection of pancreas venous graft thrombosis via clinical suspicion and radiological methods, and early intervention with endovascular thrombolysis. As a result, the pancreatic graft was successfully salvaged. DISCUSSION: A limited number of studies had showed successful graft salvage in only 30-45% of thrombosed pancreatic graft with surgical thrombectomy. Our patient also had bleeding from the vascular access site and ultimately required blood transfusion, however she recovered well after procedure. CONCLUSION: Given the complexity and significance of PVGT, urgent and prompt treatment is necessary. Interpreting outcomes from our case and other small studies, it appears that endovascular pharmacomechanical thrombectomy can be a vital tool to salvage graft organs in those receiving SPK.

An engineered macroencapsulation membrane releasing FTY720 to precondition pancreatic islet transplantation.

Macroencapsulation is a powerful approach to increase the efficiency of extrahepatic pancreatic islet transplant. FTY720, a small molecule that activates signaling through sphingosine-1-phosphate receptors, is immunomodulatory and pro-angiogenic upon sustained delivery from biomaterials. While FTY720 (fingolimod, Gilenya) has been explored for organ transplantation, in the present work the effect of locally released FTY720 from novel nanofiber-based macroencapsulation membranes is explored for islet transplantation. We screened islet viability during culture with FTY720 and various biodegradable polymers. Islet viability is significantly reduced by the addition of high doses (≥500 ng/mL) of soluble FTY720. Among the polymers screened, islets have the highest viability when cultured with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). Therefore, PHBV was blended with polycaprolactone (PCL) for mechanical stability and electrospun into nanofibers. Islets had no detectable function ex vivo following 5 days or 12 h of subcutaneous implantation within our engineered device. Subsequently, we explored a preconditioning scheme in which islets are transplanted 2 weeks after FTY720-loaded nanofibers are implanted. This allows FTY720 to orchestrate a local regenerative milieu while preventing premature transplantation into avascular sites that contain high concentrations of FTY720. These results provide a foundation and motivation for further investigation into the use of FTY720 in preconditioning sites for efficacious islet transplantation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 555-568, 2018.

Post-Transfer Predictors of Poor Outcomes in Pediatric Renal Transplant Recipients.

The aims of this study were twofold: 1) to describe the post-transfer (defined as from pediatric to adult providers) incidence of predictors (medication nonadherence, acute rejection, and change in kidney function), as well as outcomes (graft loss) for adolescent and young adult kidney transplant recipients during a three-year post-transfer follow-up period; and 2) to identify variables to monitor these predictors, in the form of a clinical profile, so providers can promote early intervention for these medically at-risk adolescents. National data were used to describe predictors and outcomes for 250 youth (16 to 25 years old) three years after transfer of care. These predictors were combined with previous literature to develop a preliminary clinical profile. Using an evidence-based clinical profile with predictors for graft loss by a dedicated healthcare professional as a transition coordinator will assist in identifying those at risk for poor outcomes after transfer.

Deformability-based microfluidic separation of pancreatic islets from exocrine acinar tissue for transplant applications.

The long-term management of type-1 diabetes (T1D) is currently achieved through lifelong exogenous insulin injections. Although there is no cure for T1D, transplantation of pancreatic islets of Langerhans has the potential to restore normal endocrine function versus the morbidity of hypoglycemic unawareness that is commonly associated with sudden death among fragile diabetics. However, since endocrine islet tissues form a small proportion of the pancreas, sufficient islet numbers can be reached only by combining islets from multiple organ donors and the transplant plug contains significantly high levels of exocrine acinar tissue, thereby exacerbating immune responses. Hence, lifelong administration of immunosuppressants is required after transplantation, which can stress islet cells. The density gradient method that is currently used to separate islets from acinar tissue causes islets to be sparsely distributed over the centrifuged bins, so that the transplant sample obtained by combining multiple bins also contains significant acinar tissue levels. We show that in comparison to the significant size and density overlaps between the islet and acinar tissue populations post-organ digestion, their deformability overlaps are minimal. This feature is utilized to design a microfluidic separation strategy, wherein tangential flows enable selective deformation of acinar populations towards the bifurcating waste stream and sequential switching of hydrodynamic resistance enables the collection of rigid islets. Using 25 bifurcating daughter channels, a throughput of ∼300 islets per hour per device is obtained for enabling islet enrichment from relatively dilute starting levels to purity levels that meet the transplant criteria, as well as to further enhance islet purity from samples following density gradient enrichment. Based on confirmation of viability and functionality of the microfluidic-isolated islets using insulin secretion analysis and an angiogenesis assay, we envision utilizing this strategy to generate small-volume transplant plugs with high islet purity and significantly reduced acinar levels for minimizing immune responses after transplantation.

STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation.

OBJECTIVE: STEAP4 (six-transmembrane epithelial antigen of the prostate 4) is a metalloreductase that has been shown previously to protect cells from inflammatory damage. Genetic variants in STEAP4 have been associated with numerous metabolic disorders related to obesity, including putative defects in the acute insulin response to glucose in type 2 diabetes. PURPOSE: We examined whether obesity and/or type 2 diabetes altered STEAP4 expression in human pancreatic islets. METHODS: Human islets were isolated from deceased donors at two medical centers and processed for quantitative polymerase chain reaction. Organ donors were selected by status as non-diabetic or having type 2 diabetes. Site 1 (Edmonton): N = 13 type 2 diabetes donors (7M, 6F), N = 20 non-diabetic donors (7M, 13F). Site 2 (Virginia): N = 6 type 2 diabetes donors (6F), N = 6 non-diabetic donors (3M, 3F). RESULTS: STEAP4 showed reduced islet expression with increasing body mass index among all donors (P < 0.10) and non-diabetic donors (P < 0.05) from Site 1; STEAP4 showed reduced islet expression among type 2 diabetes donors with increasing hemoglobin A1c. Islet STEAP4 expression was also marginally higher in female donors (P < 0.10). Among type 2 diabetes donors from Site 2, islet insulin expression was reduced, STEAP4 expression was increased, and white blood cell counts were increased compared to non-diabetic donors. Islets from non-diabetic donors that were exposed overnight to 5 ng/ml IL-1ß displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling. CONCLUSIONS: These findings suggest that increased STEAP4 mRNA expression is associated with inflammatory stimuli, whereas lower STEAP4 expression is associated with obesity in human islets. Given its putative protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage.

Operative management of chronic pancreatitis: A review.

BACKGROUND: Pain secondary to chronic pancreatitis is a difficult clinical problem to manage. Many patients are treated medically or undergo endoscopic therapy and surgical intervention is often reserved for those who have failed to gain adequate pain relief from a more conservative approach. RESULTS: There have been a number of advances in the operative management of chronic pancreatitis over the last few decades and current therapies include drainage procedures (pancreaticojejunostomy, etc.), resection (pancreticoduodenectomy, etc.) and combined drainage/resection procedures (Frey procedure, etc.). Additionally, many centers currently perform total pancreatectomy with islet autotransplantation, in addition to minimally invasive options that are intended to tailor therapy to individual patients. DISCUSSION: Operative management of chronic pancreatitis often improves quality of life, and is associated with low rates of morbidity and mortality. The decision as to which procedure is optimal for each patient should be based on a combination of pathologic changes, prior interventions, and individual surgeon and center experience.