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.

A novel method for in vitro culture and expansion of nonhuman primate B cells.

BACKGROUND: Given the role of B cells in sensitization and antibody-mediated rejection pathogenesis, the ability to identify, isolate, and study B cells in vitro is critical for understanding these processes and developing novel therapeutics. While in vivo nonhuman primate models have been used to this end, an in vitro nonhuman primate model of B cell activation and proliferation has not been developed. METHODS: CD20+ B cells and CD3+ T cells were isolated using magnetic bead separation from the peripheral blood of naive and skin allograft sensitized nonhuman primates. Allogeneic B and T cells were co-cultured in plates pre-coated with murine stromal cells engineered to express human CD40L and stimulated with cytokines. Cells and supernatants were harvested every 2 days for immune phenotyping and donor specific antibody quantification by flow cytometry. RESULTS: The optimized culture system consisted of MS40L cells co-cultured with B and allogenic T cells and stimulated with cytokines. This culture system resulted in increased memory cells and plasmablasts over time compared to other culture systems. Comparison of culture of naïve and sensitized nonhuman primate samples revealed faster B cell exhaustion and marginally increased plasmablast differentiation in sensitized culture. Donor-specific antibody production was not observed in either culture group. CONCLUSIONS: This study describes the first in vitro nonhuman primate model of B cell activation and proliferation using both naïve and allosensitized samples. This model provides an opportunity for exploration of B cell mechanisms and novel therapeutics and is a preliminary step in the development of an in vitro germinal center model.

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.

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.

Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization.

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.

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.

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.

Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.

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.

Elevated Donor Hemoglobin A1C Impairs Kidney Graft Survival From Deceased Donors With Diabetes Mellitus: A National Analysis.

OBJECTIVES: Kidney transplant is the optimal therapy for patients with end-stage renal disease. The presence of donor diabetes mellitus is a recognized risk factor for impaired kidney graft survival and is incorporated into the Kidney Donor Profile Index. At present, however, there are limited assessments of the severity of this risk factor. Hemoglobin A1c reflects glycemic control over the preceding 3 months, and we hypothesized that donor hemoglobin A1c levels could confer additional discriminatory power in assessments of deceased donors with diabetes mellitus. MATERIALS AND METHODS: The United Network for Organ Sharing/Organ Procurement and Organ Transplantation Network Standard Transplant Analysis Research file was queried for adult deceased-donor kidney transplants performed using allografts from donors with diabetes mellitus who had measurements of hemoglobin A1c before donation. RESULTS: The study cohort consisted of 1518 kidney transplants performed using allografts from deceased donors with diabetes mellitus. Kaplan-Meier survival analysis and log-rank test were performed to compare survival of grafts from donors with diabetes mellitus with elevated (≥ 6.5%) versus lower (< 6.5%) hemoglobin A1c levels. Graft survival at 5 years was significantly lower for recipients of donors with hemoglobin A1c ≥ 6.5% (58.9% vs 68.3%; P < .001). On multivariate analysis, hemoglobin A1c ≥ 6.5% was an independent predictor of diminished graft survival. CONCLUSIONS: Hemoglobin A1c has potential as an additional discriminatory test for estimating outcomes of grafts from donors with diabetes mellitus and should be routinely measured in this population.

Outcomes of laparoscopic resection of Meckel's diverticulum are equivalent to open laparotomy.

PURPOSE: Meckel's diverticulum (MD) is a common congenital anomaly caused by failure of involution of the omphalomesenteric duct. Enthusiasm for minimally invasive surgery (MIS) in children has burgeoned as technologies have advanced, but the outcomes of laparoscopic resection in comparison to open laparotomy for MD remain poorly defined. We queried a large national database to compare current practice patterns and clinical outcomes between surgical approaches for MD in the pediatric population. METHODS: The National Surgical Quality Improvement Program-Pediatric (NSQIP-Ped) database was queried for patients undergoing surgical intervention for MD (2011-2014). Patients were stratified by surgical approach. Baseline characteristics, intraoperative variables, and perioperative complications were compared by univariate analysis using Pearson's χ2 test for categorical variables and Kruskall-Wallis test for continuous variables. Primary outcomes of interest were length of stay (LOS), rate of readmission, and 30-day mortality. Secondary outcomes included operative time, anesthesia time, postoperative complications, and rates of reoperation. RESULTS: A total of 148 cases of MD were identified, of which 73 (49.3%) were initially managed with a laparoscopic approach and 75 (50.7%) were managed with an open approach. We found a high rate of conversion from laparoscopy to an open approach (20/73 or 27.4%). The median age of the laparoscopic group was higher than the open group (8.3 vs. 2.5years, p<0.001). Operative and anesthesia time, LOS, 30-day mortality, post-operative complications, and rates of reoperation and readmission were similar between groups (all p>0.05). CONCLUSION: Nearly half of all resections for MD in children are now approached laparoscopically. This approach has equivalent outcomes to traditional open laparotomy. More widespread use of a hybrid approach with laparoscopy and exteriorization of the small bowel through an extended port site may facilitate avoiding open laparotomy. Routine conversion to open for palpation of the MD or segmental small bowel resection should be avoided in the absence of compelling intra-operative findings or operative complications. LEVEL OF EVIDENCE: Level III (retrospective comparative study).

A Propensity-matched Survival Analysis: Do Simultaneous Liver-lung Transplant Recipients Need a Liver?

BACKGROUND: There is debate whether simultaneous lung-liver transplant (LLT) long-term outcomes warrant allocation of 2 organs to a single recipient. We hypothesized that LLT recipients would have improved posttransplant survival compared with matched single-organ lung recipients with an equivalent degree of liver dysfunction. METHODS: The Organ Procurement and Transplant Network/United Network for Organ Sharing STAR file was queried for adult candidates for LLT and isolated lung transplantation from 2006 to 2016. Waitlist mortality and transplant odds were calculated for all candidates. Donor and recipient demographic characteristics were compiled and compared. The LLT recipients were matched 1:2 with a nearest neighbor method to single-organ lung recipients. Kaplan-Meier methods with log-rank test compared long-term survival between groups. Univariate regression was used to calculate the association of LLT and mortality within 6 months of transplant. A proportional hazards model was used to calculate risk-adjusted mortality after 6 months posttransplantation. RESULTS: Thirty-eight LLT patients were matched to 75 single-organ lung recipients. After matching, no differences in baseline demographics or liver function were observed between cohorts. Length of stay was significantly longer in LLT recipients compared to isolated lung recipients (45.89 days vs 22.44 days, P < 0.001). There was no significant difference in survival probability between LLT and isolated lung transplant (1 y, 89.5% vs 86.7%; 5 y, 67.0% vs 64.6%; P = 0.20). CONCLUSIONS: After matching for patient characteristics and level of liver dysfunction, survival in simultaneous LLT was comparable to isolated lung transplantation. Although this population is unique, the clinical picture prompting liver transplant is not clear. National guidelines to better elucidate patient selection are needed.

Kidney Donor Profile Index Is a Reliable Alternative to Liver Donor Risk Index in Quantifying Graft Quality in Liver Transplantation.

BACKGROUND: The most established metric for estimating graft survival from donor characteristics in liver transplantation is the liver donor risk index (LDRI). The LDRI is calculated from donor and transplant-related variables, including cold ischemic time. Because cold ischemic time is unknown at the time of organ offer, LDRI is not available for organ acceptance decisions. In contrast, the kidney donor profile index (KDPI) is derived purely from donor variables known at the time of offer and thus calculated for every deceased donor in the United States. The similarity in donor factors included in LDRI and KDPI led us to hypothesize that KDPI would reliably approximate LDRI in estimating graft survival in liver transplantation. METHODS: The United Network of Organ Sharing registry was queried for adults who underwent deceased donor liver transplantation from 2002 to 2016. The cohort was divided into quintiles of KDPI and LDRI, and graft survival was calculated according to Kaplan Meier. Hazard ratios for LDRI and KDPI were estimated from Cox proportional hazards models, and Uno's concordance statistic was compared. RESULTS: In our analysis of 63 906 cases, KDPI closely approximated LDRI in estimating liver graft survival, with an equivalent concordance statistic of 0.56. CONCLUSIONS: We conclude that KDPI can serve as a reasonable alternative to LDRI in liver acceptance decisions.

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.

Cervical seatbelt sign is not associated with blunt cerebrovascular injury in children: A review of the national trauma databank.

BACKGROUND: Blunt cerebrovascular injury (BCVI) is a rare consequence of blunt trauma. There appears to be benefit to an aggressive approach to screening for BCVI due to catastrophic sequelae of unrecognized injury. However, screening for BCVI carries extensive cost and oncologic risk to young patients. Foundational BCVI studies examined adults primarily, leaving question to the effectiveness of these criteria in children. We sought to evaluate BCVI screening criteria developed in primarily adult populations using a nationally representative pediatric dataset. METHODS: We queried the 2008-2014 National Trauma Data Bank for patients with BCVI. Patients were stratified by age (adults>18yrs, pediatric≤18yrs). Screening factors from the Modified Denver Criteria and Modified Memphis Criteria (GCS≤8, C1C3 cervical fracture, cervical subluxation, seatbelt sign, basilar skull fracture, mid-facial fracture, mandibular fracture, significant blood loss, coma, stroke, and hanging) were examined using univariate analysis and backwards-stepwise logistic regression to verify predictors of BCVI. RESULTS: Blunt injury occurred in 2,174,244 adults and 422,181 children; 5970 adults and 809 children sustained BCVI. In univariate analysis, all screening factors correlated with BCVI in both groups (p < 0.001). When comparing BCVI patients, children more commonly experienced GCS≤8, seatbelt sign, basilar skull fracture, mid-facial fracture, mandibular fracture, and coma (p < 0.05). In multivariable analysis, seatbelt sign was not associated with pediatric BCVI. CONCLUSION: Many adult-associated BCVI risk factors apply to children. Although children more commonly experience seatbelt sign, it does not independently cause increased BCVI risk. Given the rarity of pediatric BCVI, prospective multi-institutional studies are warranted to establish screening criteria specific to children.

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.

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.

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.