Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model.

Sensitized patients, those who had prior exposure to foreign human leukocyte antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and interleukin (IL)-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model. All animals were sensitized using two sequential skin transplants from maximally major histocompatibility complex-mismatched donors. Carfilzomib (CFZ)/tocilizumab (TCZ) desensitization (N = 6) successfully decreased donor-specific antibody (DSA) titers and prevented the expansion of B cells compared to CFZ monotherapy (N = 3). Dual desensitization further delayed, but did not prevent humoral rebound, as evidenced by a delayed increase in post-kidney transplant DSA titers. Accordingly, CFZ/TCZ desensitization conferred a significant survival advantage over CFZ monotherapy. A trend toward increased T follicular helper cells was also observed in the dual therapy group along the same timeline as an increase in DSA and subsequent graft loss. Cytomegalovirus reactivation also occurred in the CFZ/TCZ group but was prevented with ganciclovir prophylaxis. In accordance with prior studies of CFZ-based dual desensitization strategies, the addition of IL-6 receptor blockade resulted in desensitization with further suppression of posttransplant humoral response compared to CFZ monotherapy.

Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m2 IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27-CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.

Anti-thymoglobulin induction improves neonatal porcine xenoislet engraftment and survival.

Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets and transplanted via portal vein infusion in diabetic rhesus macaques. Induction therapy consisted of either basiliximab (n = 6) or rhesus-specific anti-thymocyte globulin (rhATG, n = 6), combined with a maintenance regimen using B7 costimulation blockade, tacrolimus with a delayed transition to sirolimus, and mycophenolate mofetil. Xenografts were monitored by blood glucose levels and porcine C-peptide measurements. Of the six receiving basiliximab induction, engraftment was achieved in 4 with median graft survival of 14 days. All six receiving rhATG induction engrafted with significantly longer xenograft survival at 40.5 days (P = 0.03). These data suggest that depletional induction provides superior xenograft survival to nondepletional induction, in the setting of a costimulation blockade-based maintenance regimen.

Evolution of minimally invasive surgery for rectal cancer: update from the national cancer database.

BACKGROUND: As the use of minimally invasive techniques in colorectal surgery has become increasingly prevalent, concerns remain about the oncologic effectiveness and long-term outcomes of minimally invasive low anterior resection (MI-LAR) for the treatment of rectal cancer. STUDY DESIGN: The 2010-2015 National Cancer Database (NCDB) Participant Data Use File was queried for patients undergoing elective open LAR (OLAR) or MI-LAR for rectal adenocarcinoma. A 1:1 propensity match was performed on the basis of demographics, comorbidity, and tumor characteristics. Outcomes were compared between groups and Cox proportional hazard modeling was performed to identify independent predictors of mortality. A subset analysis was performed on high-volume academic centers. RESULTS: 35,809 patients undergoing LAR were identified of whom 18,265 (51.0%) underwent MI-LAR. After propensity matching, patients receiving MI-LAR were less likely to have a positive circumferential radial margin (CRM) (5.5% vs. 6.6%, p = 0.0094) or a positive distal margin (3.6% vs. 4.6%, p = 0.0022) and had decreased 90-day all-cause mortality (2.0% vs. 2.6%, p = 0.0238). MI-LAR resulted in decreased hospital length of stay (5 vs. 6 days, p < 0.0001) but a greater rate of 30-day readmission (7.6% vs. 6.5%, p = 0.0054). Long-term overall survival was improved with MI-LAR (79% vs. 76%, p < 0.0001). Cox proportional hazard modeling demonstrated a decreased risk of mortality with MI-LAR (HR 0.859, 95% CI 0.788-0.937). CONCLUSION: MI-LAR is associated with improvement in CRM clearance and long-term survival. In the hands of experienced surgeons with advanced laparoscopy skills, MI-LAR appears safe and effective technique for the management of rectal cancer.

Decline of increased risk donor offers increases waitlist mortality in paediatric heart transplantation.

BACKGROUND: Increased risk donors in paediatric heart transplantation have characteristics that may increase the risk of infectious disease transmission despite negative serologic testing. However, the risk of disease transmission is low, and refusing an IRD offer may increase waitlist mortality. We sought to determine the risks of declining an initial IRD organ offer. METHODS AND RESULTS: We performed a retrospective analysis of candidates waitlisted for isolated PHT using 20072017 United Network of Organ Sharing datasets. Match runs identified candidates receiving IRD offers. Competing risks analysis was used to determine mortality risk for those that declined an initial IRD offer with stratified Cox regression to estimate the survival benefit associated with accepting initial IRD offers. Overall, 238/1067 (22.3%) initial IRD offers were accepted. Candidates accepting an IRD offer were younger (7.2 versus 9.8 years, p < 0.001), more often female (50 versus 41%, p = 0.021), more often listed status 1A (75.6 versus 61.9%, p < 0.001), and less likely to require mechanical bridge to PHT (16% versus 23%, p = 0.036). At 1- and 5-year follow-up, cumulative mortality was significantly lower for candidates who accepted compared to those that declined (6% versus 13% 1-year mortality and 15% versus 25% 5-year mortality, p = 0.0033). Decline of an IRD offer was associated with an adjusted hazard ratio for mortality of 1.87 (95% CI 1.24, 2.81, p < 0.003). CONCLUSIONS: IRD organ acceptance is associated with a substantial survival benefit. Increasing acceptance of IRD organs may provide a targetable opportunity to decrease waitlist mortality in PHT.

Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients.

BACKGROUND: Patients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact. METHODS: To investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation. RESULTS: The group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection. CONCLUSIONS: Desensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use.

BACKGROUND: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. METHODS: To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. RESULTS: The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. CONCLUSIONS: Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study.

Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule-focused therapies.

Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients.

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy-mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

Improved survival in simultaneous lung-liver recipients and candidates in the modern era of lung allocation.

BACKGROUND: Liver-lung transplantation (LLT) is a rare procedure performed for patients with end-stage liver and lung disease. The lung allocation score (LAS), introduced in 2005, guides lung allocation including those receiving LLT. However, the impact of the LAS on outcomes in LLT is currently unknown. MATERIALS AND METHODS: The OPTN/United Network for Organ Sharing STAR file was queried for LLT candidates and recipients from 1988 to 2016. Demographic characteristics before (historic) and after (modern) the LAS were compared. Survival was analyzed with the Kaplan-Meier method and log-rank test. RESULTS: In total, 167 candidates were listed for LLT, and 62 underwent LLT. The historic cohort had a higher FEV1% (48.22% versus 29.82%, P = 0.014), higher creatinine (1.22 versus 0.72, P < 0.001), and a higher percentage with pulmonary hypertension as the indication for transplantation (40% versus 0%, P = 0.003) compared with the modern cohort. LLT candidates in the historic cohort had a lower rate of transplant per 100 candidates (10.87 versus 33.33, P < 0.0001) and worse waitlist survival (1 y: 69.6% versus 80.9%, 3 y: 39.1% versus 66.8%, P = 0.004). Post-transplant survival was significantly lower in the historic cohort (1 y: 50.0% versus 82.7%, 5 y: 40.0% versus 69.0%, 10 y: 20.0% versus 55.5%, P = 0.0099). CONCLUSIONS: Most analyses of LLT have included patients before and after the introduction of the LAS. Our study shows that LLT candidates and recipients before the modern allocation system had distinct baseline characteristics and worse overall survival. Although many factors contributed to recent improved outcomes, these cohorts are significantly different and should be treated as such in future studies.

Local excision results in comparable survival to radical resection for early-stage rectal carcinoid.

BACKGROUND: Controversy exists regarding current National Comprehensive Cancer Network guidelines, which recommend local excision for rectal carcinoids ≤2 cm and radical resection for tumors >2 cm. Given the limited data examining optimal surgical approach for these lesions, we queried a national database to determine the impact of extent of resection on survival. METHODS: Patients undergoing treatment for clinical stage I and II rectal carcinoid (RC) were identified from the National Cancer Data Base (1998-2012). The association between extent of surgery, tumor size, and the likelihood of pathologic lymph node positivity was examined. Kaplan-Meier analysis was used to compare overall survival. RESULTS: In total, 1900 patients were identified, of whom 1644 (86.5%) were treated with local excision, and 256 (13.5%) were treated with radical resection. A significant majority of patients with tumors ≤2.0 cm (89.0%) and nearly half with tumors 2.1-4.0 cm (44.8%) or >4.0 cm (45.8%) underwent local excision. Nodal positivity was correlated with tumor size (7.1% positivity with ≤2.0 cm tumors, 31.3% with 2.1-4.0 cm tumors, and 50.0% with >4 cm tumors). However, 5-y survival was equivalent between surgical approaches for tumors ≤2 cm (93.0% versus 93.0%) and tumors 2.1-4.0 cm (76.0% versus 76.0%). CONCLUSIONS: We demonstrate in early-stage RC that nearly half of intermediate and large tumors are being treated with local excision outside National Comprehensive Cancer Network guidelines. In addition, radical resection does not appear to be associated with improved overall survival for tumors of any size. These findings suggest that the preferred approach to early-stage RCs without aggressive biological characteristics is local excision due to the decreased morbidity and mortality versus radical resection.

Comparing oncologic outcomes after minimally invasive and open surgery for pediatric neuroblastoma and Wilms tumor.

BACKGROUND: Minimally invasive surgery (MIS) has been widely adopted for common operations in pediatric surgery; however, its role in childhood tumors is limited by concerns about oncologic outcomes. We compared open and MIS approaches for pediatric neuroblastoma and Wilms tumor (WT) using a national database. METHODS: The National Cancer Data Base from 2010 to 2012 was queried for cases of neuroblastoma and WT in children ≤21 years old. Children were classified as receiving open or MIS surgery for definitive resection, with clinical outcomes compared using a propensity matching methodology (two open:one MIS). RESULTS: For children with neuroblastoma, 17% (98 of 579) underwent MIS, while only 5% of children with WT (35 of 695) had an MIS approach for tumor resection. After propensity matching, there was no difference between open and MIS surgery for either tumor for 30-day mortality, readmissions, surgical margin status, and 1- and 3-year survival. However, in both tumors, open surgery more often evaluated lymph nodes and had larger lymph node harvest. CONCLUSION: Our retrospective review suggests that the use of MIS appears to be a safe method of oncologic resection for select children with neuroblastoma and WT. Further research should clarify which children are the optimal candidates for this approach.

Improved contemporary outcomes of liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma.

PURPOSE: Improvement in outcomes of LT for pediatric HB and HCC has been reported in small series. We analyzed national outcomes and changes in donor, recipient, and perioperative factors over time that may contribute to survival differences. METHODS: The UNOS database was queried for patients age <21 years that underwent LT for a primary diagnosis of HB or HCC (1987-2017). Subjects were divided into historic (transplant before 2010) and contemporary (transplant after 2010) cohorts. Baseline characteristics were compiled and examined. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: In total, 599 children with HB received LT (320 historic vs 279 contemporary). Concurrently, 141 children with HCC received LT (92 historic vs 49 contemporary). For both tumors, waitlist time decreased (HB 56.2 days historic vs 33.2 days contemporary, P = 0.017; HCC 189.3 days historic vs 71.7 days contemporary, P = 0.012). In the historic cohorts, patients with HB had a 1-year and 5-year OS of 84.6% and 75.1%, respectively. Survival for HCC was 84.4% and 59.9%, respectively. Outcomes improved in the contemporary era to 89.1% and 82.6% for HB, and 94.7% and 80.8% for HCC, respectively (both log-rank test P < 0.0001). CONCLUSION: Outcomes of LT have improved significantly, with contemporary survival now equivalent between these tumors and exceeding 80% 5-year OS. Future studies are needed to explore whether offering LT in patients that are resectable is justifiable.

Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adults: A National Study of 369 Patients.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor in children, with current evidence limited to single-center studies. We examined treatment and clinical outcomes for pediatric and adult SPN with a national data set. METHODS: The 2004 to 2013 National Cancer Data Base was queried to identify all patients diagnosed with SPN. The cohort was stratified by age (pediatric and adult) defined as below 18 years and 18 years and above, respectively. Baseline characteristics and unadjusted outcomes were compared. RESULTS: We identified 21 pediatric and 348 adult patients with SPN. Both groups displayed similar demographic composition. Patients were commonly female (90.5% [pediatric] vs. 85.9% [adult], P=0.56) and white (66.7% vs. 68.3%, P=0.74). Tumor location was similar between adults and children. Median tumor size was similar between children and adults (5.9 vs. 4.9 cm, P=0.41). Treatment strategies did not vary between groups. Partial pancreatectomy was the most common resection strategy (71.4% vs. 53.1%, P=0.80). Both groups experienced low mortality (0.0% vs. 0.7% at 5 y, P=0.31). CONCLUSIONS: This study provides the largest comparison of pediatric and adult SPN to date. Children with SPN have similar disease severity at presentation, receive similar treatments, and demonstrate equivalent postoperative outcomes compared with their adult counterparts.

Insurance Status, Not Race, is Associated With Use of Minimally Invasive Surgical Approach for Rectal Cancer.

OBJECTIVE: To determine the impact of race and insurance on use of minimally invasive (MIS) compared with open techniques for rectal cancer in the United States. BACKGROUND: Race and socioeconomic status have been implicated in disparities of rectal cancer treatment. METHODS: Adults undergoing MIS (laparoscopic or robotic) or open rectal resections for stage I to III rectal adenocarcinoma were included from the National Cancer Database (2010-2012). Multivariate analyses were employed to examine the adjusted association of race and insurance with use of MIS versus open surgery. RESULTS: Among 23,274 patients, 39% underwent MIS and 61% open surgery. Overall, 86% were white, 8% black, and 3% Asian. Factors associated with use of open versus MIS were black race, Medicare/Medicaid insurance, and lack of insurance. However, after adjustment for patient demographic, clinical, and treatment characteristics, black race was not associated with use of MIS versus open surgery [odds ratio [OR] 0.90, P = 0.07). Compared with privately insured patients, uninsured patients (OR 0.52, P < 0.01) and those with Medicare/Medicaid (OR 0.79, P < 0.01) were less likely to receive minimally invasive resections. Lack of insurance was significantly associated with less use of MIS in black (OR 0.59, P = 0.02) or white patients (OR 0.51, P < 0.01). However, among uninsured patients, black race was not associated with lower use of MIS (OR 0.96, P = 0.59). CONCLUSIONS: Insurance status, not race, is associated with utilization of minimally invasive techniques for oncologic rectal resections. Due to the short-term benefits and cost-effectiveness of minimally invasive techniques, hospitals may need to improve access to these techniques, especially for uninsured patients.

Gallbladder abnormalities in children with metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease that leads to neurological deterioration and visceral involvement, including sulphatide deposition in the gallbladder wall. Using our institution's extensive experience in treating MLD, we examined the incidence of gallbladder abnormalities in the largest cohort of children with MLD to date. METHODS: We conducted a retrospective review of all children with MLD, adrenoleukodystrophy (ALD), or Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) at our institution between 1994 and 2015. Baseline characteristics and unadjusted outcomes were compared using the Kruskal-Wallis test for continuous variables and Pearson χ2 test for categorical variables, with significance defined as P < 0.05. RESULTS: In total, 87 children met study criteria: 29 children with MLD and 58 children with ALD or Krabbe disease. Children with MLD were more likely to demonstrate gallbladder abnormalities on imaging, both before HSCT (41.4% versus 5.2%, P < 0.001) and after HSCT (75.9% versus 41.4%, P = 0.002). Consequently, a larger proportion of children with MLD underwent surgical or interventional management of biliary disease (10.3% versus 3.4%, P = 0.03). CONCLUSIONS: Children with MLD have a significantly greater incidence of gallbladder abnormalities than children with other lysosomal storage diseases. Biliary disease should be considered in children with MLD who develop abdominal pain, and cholecystectomy should be considered for persistent, symptomatic gallbladder abnormalities.

Elevated HbA1c in donor organs from patients without a diagnosis of diabetes portends worse liver allograft survival.

Recipients of liver allografts from diabetic donors have decreased graft survival. However, limited data exist on the effects of donor HbA1c. We hypothesized that allografts from nondiabetic donors with elevated HbA1c would be associated with decreased survival. Liver transplant recipients from the UNOS database from nondiabetic donors were stratified into two groups: euglycemic (HbA1c<6.5) and hyperglycemic (HbA1c≥6.5). Propensity score matching (10:1) was used to adjust for donor and recipient characteristics. Kaplan-Meier analysis was used to assess survival. Donors of hyperglycemic allografts were older (49 vs 36, P<.001), were more likely to be non-white, had a higher BMI (29.8 vs 26.2, P<.001), were more likely to engage in heavy cigarette use (1.5% vs 1.3%, P=.004), had higher serum creatinine levels (1.3 vs 1.0, P=.002), and were more likely to be an expanded-criteria donor (35.8% vs 14.4%, P<.001). After propensity matching to account for these differences, allograft survival was significantly decreased in the recipients of hyperglycemic allografts (P=.049), and patient survival showed a trend toward reduction (P=.082). These findings suggest that HbA1c may be a simple and inexpensive test with potential utility for better organ risk stratification.

Renal medullary carcinoma: A national analysis of 159 patients.

BACKGROUND: Renal medullary carcinoma (RMC) is an aggressive malignancy seen predominantly in young males with sickle cell trait. RMC is poorly understood, with fewer than 220 cases described in the medical literature to date. We used a large national registry to define the typical presentation, treatments, and outcomes of this rare tumor. METHODS: The National Cancer Database was queried for patients under 40 years of age diagnosed with RMC from 1998 to 2011. An analysis of patient and tumor characteristics, treatment details, and overall survival (OS) was undertaken, and factors associated with mortality were identified using multivariable regression analysis. RESULTS: In total, 159 patients with RMC were identified, of whom a majority were male (71%), African American (87%), and had metastatic disease (71%). Median tumor size was 6 cm and median survival was 7.7 months. Most patients underwent surgery (60%) and chemotherapy (65%). Few patients received radiation (12%). Patients with metastatic disease had a significantly worse median survival (4.7 vs. 17.8 months, P < 0.001) and were less likely to receive surgery (42% vs. 91%, P < 0.001). Age and tumor size did not appear to impact OS. CONCLUSION: In the largest cohort to date of patients with RMC, we found a dismal median survival of less than 8 months. Age and tumor size were not associated with OS. Metastatic disease at presentation was the main negative prognostic indicator in RMC and was present in a majority of patients at the time of diagnosis.

Children Receiving Hematopoietic Stem Cell Transplantation are at Increased Risk of Onychocryptosis Requiring Surgical Management.

PURPOSE: At our institution, a high proportion of children with onychocryptosis (ingrown toenail) requiring surgical intervention were noted to have a history of hematopoietic stem cell transplantation (HSCT). We analyzed the characteristics of patients who underwent surgical intervention for onychocryptosis and examined our institutional HSCT database to determine if an association exists between onychocryptosis and HSCT. MATERIALS AND METHODS: Surgical cases for onychocryptosis performed from 2000 to 2012 were identified. Nine demographic, clinical, and perioperative variables for both patients with and without prior HSCT were assessed. In a separate analysis, the institutional HSCT database was then queried to identify the prevalence and clinical characteristics associated with onychocryptosis after HSCT. RESULTS: We identified 17 children who had undergone surgical management of onychocryptosis, of which 8 (47.1%) had previous HSCT. Children who had undergone HSCT had an aggressive form of onychocryptosis with 50.0% having bilateral great toe and nail edge involvement and 37.5% having a recurrence. In HSCT cohort analysis of 1069 children, 91 (8.5%) had onychocryptosis. Male sex, non-black race, acute graft versus host disease, and increasing age at transplantation were independently associated with onychocryptosis. CONCLUSIONS: HSCT is strongly associated with onychocryptosis requiring surgical intervention. Children with a history of HSCT may also have more aggressive toenail disease, with higher rates of surgical intervention, bilateral ingrown toenails, recurrence, and need for return to the operating room. Clinicians should perform careful screening and early treatment in these patients.

Subtotal cholecystectomy for the hostile gallbladder: failure to control the cystic duct results in significant morbidity.

BACKGROUND: Outcomes following the inability to control the cystic duct due to a hostile triangle of Calot during cholecystectomy remain unknown. The purpose of this study was to analyze the safety and efficacy of subtotal cholecystectomy, with attention to the necessity for secondary interventions. METHODS: Sixteen thousand five hundred ninety six cholecystectomies from January 2002 to August 2014 were reviewed, identifying patients managed with subtotal cholecystectomy, defined as the inability to isolate/transect the cystic duct. After propensity matching, we investigated surgical indications, perioperative outcomes, and the necessity for secondary ERCP, percutaneous drainage, and completion cholecystectomy. RESULTS: 65 (0.39%) patients underwent subtotal cholecystectomy; 54 (83.1%) began laparoscopically, of which 30 (55.6%) required conversion to laparotomy. Subtotal cholecystectomy, performed more frequently for acute cholecystitis (70.8% vs 34.6%), was associated with extended hospitalizations (4 d vs 2 d) and frequent surgical site infections (20% vs 4.6%). 25 (38.5%) subtotal cholecystectomy patients required ≥1 secondary intervention, and compared to standard cholecystectomy, underwent higher rates postoperative ERCP (30.8% vs 5.4%), percutaneous drainage (9.2% vs 1.5%), and completion cholecystectomy (6.2% vs 0%) [all P < 0.05]. DISCUSSION: Subtotal cholecystectomy fails to control the cystic duct, resulting in significant morbidity. Most do not require completion cholecystectomy; however, patients demand close observation and, frequently, secondary interventions.