Benjamin M. Martin

A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival

The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well‐documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti‐CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell‐dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC‐mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.

Islet cell xenotransplantation: a serious look toward the clinic

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near‐physiologic function and year‐long survival in clinically relevant pig‐to‐primate model systems. These proof‐of‐concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.

Oncologic outcomes of patients undergoing videoscopic inguinal lymphadenectomy for metastatic melanoma.

BACKGROUND Open inguinal lymphadenectomy for regionally metastatic melanoma is associated with a high wound-related morbidity. Videoscopic inguinal lymphadenectomy (VIL) is a minimally invasive approach with fewer wound-related complications, yet its adoption has been hindered by a lack of oncologic outcomes data. STUDY DESIGN Data were prospectively collected on all VILs performed for melanoma from 2008 to 2012 (n = 40) and compared with a retrospective cohort of open superficial inguinal lymphadenectomies from 2005 to 2012 (n = 40). Continuous variables were analyzed with Students t-test, binomial variables with chi-square, and survival curves using log-rank comparison. RESULTS Median follow-up for patients undergoing VIL was 19.1 months compared with 33.9 months in the open inguinal lymphadenectomy group. There were no statistical differences in demographics (age, sex, body mass index, smoking status, Charlson comorbidity index) or clinicopathologic features (primary site, stage, Breslow depth, ulceration). Lymph node yield was similar (VIL, 12.6; open, 14.2; p = 0.131). Overall recurrence rates were also similar: 27.5% in the VIL group and 30.0% in the open group (p = 0.805). One patient in the VIL group and 2 in the open group suffered recurrence in the nodal basin. Although median survival was not reached in the VIL group, Kaplan-Meier estimates of disease-free survival (p = 0.226) and overall survival (p = 0.308) were similar. In a comprehensive analysis of wound complications including infection, skin necrosis, and seroma, patients undergoing VIL had markedly less morbidity (VIL, 47.5%; open, 80.0%; p = 0.002). CONCLUSIONS Videoscopic inguinal lymphadenectomy is associated with similar oncologic outcomes and markedly reduced wound complications when compared with open inguinal lymphadenectomy. The minimally invasive procedure may be the preferred method for inguinal lymphadenectomy in melanoma.

Hypophosphataemia after major hepatectomy and the risk of post-operative hepatic insufficiency and mortality: an analysis of 719 patients.

BACKGROUND Hypophosphataemia after a hepatectomy suggests hepatic regeneration. It was hypothesized that the absence of hypophosphataemia is associated with post-operative hepatic insufficiency (PHI) and complications. METHODS Patients who underwent a major hepatectomy from 2000-2012 at a single institution were identified. Post-operative serum phosphorus levels were assessed. Primary outcomes were PHI (peak bilirubin >7 mg/dl), major complications, and 30- and 90-day mortality. RESULTS Seven hundred and nineteen out of 749 patients had post-operative phosphorus levels available. PHI and major complications occurred in 63 (8.8%) and 169 (23.5%) patients, respectively. Thirty- and 90-day mortality were 4.0% and 5.4%, respectively. The median phosphorus level on post-operative-day (POD) 2 was 2.2 mg/dl; 231 patients (32.1%) had phosphorus >2.4 on POD2. Patients with POD2 phosphorus >2.4 had a significantly higher incidence of PHI, major complications and mortality. On multivariate analysis, POD2 phosphorus >2.4 remained a significant risk factor for PHI [(hazard ratio HR):1.78; 95% confidence interval (CI):1.02-3.17; P = 0.048], major complications (HR:1.57; 95%CI:1.02-2.47; P = 0.049), 30-day mortality (HR:2.70; 95%CI:1.08-6.76; P = 0.034) and 90-day mortality (HR:2.51; 95%CI:1.03-6.15; P = 0.044). Similarly, patients whose phosphorus level reached nadir after POD3 had higher PHI, major complications and mortality. CONCLUSION Elevated POD2 phosphorus levels >2.4 mg/dl and a delayed nadir in phosphorus beyond POD3 are associated with increased post-operative hepatic insufficiency, major complications and early mortality. Failure to develop hypophosphataemia within 72 h after a major hepatectomy may reflect insufficient liver remnant regeneration.

Designing an ethics curriculum to support global health experiences in surgery.

BACKGROUND The field of global health is rapidly expanding in many medical centers across the US. As a result, medical students have increasing opportunities to incorporate global health experiences (GHEs) into their medical education. Ethics is a critical component of global health curricula, yet little literature exists to direct the further development of didactic training. Therefore, we sought to define ethical encounters experienced by medical students participating in short-term surgical GHEs and create a framework for the design of ethics curriculum specific to global surgery. MATERIALS AND METHODS Emory University Departments of Surgery, Urology, and Anesthesia, in partnership with the non-profit organization Project Medishare, have taken annual humanitarian surgical trips to Hinche, Haiti. All medical students returning from the trips in 2011 and 2012 received a 35-question survey to assess demographic data, extent of prior ethics education, frequency of exposure and situational confidence to ethical subject matter, as well as ethical conflicts involved in surgical GHEs. The same comparative data were also collected for domestic clinical clerkships. RESULTS Seventeen out of 21 medical students completed the survey. Nearly all (88.3%) students had previous formal ethics training as an undergraduate or in medical school. Ethical issues were commonly encountered during domestic clinical encounters and volunteerism. However, students reported enhanced exposure to the professional obligation of surgeons (P = 0.025) and truth-telling/surgeon-patient relationships (P = 0.044) during surgical volunteerism. Despite increased exposure, situational confidence did not change. CONCLUSIONS Ethical issues are commonly confronted during GHEs in surgery and differ from domestic clinical encounters. Healthcare ethics curriculum should be designed to meet the needs of medical students involved in global health.

Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood‐mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig‐to‐primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof‐of‐concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3‐galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

Early identification of patients at increased risk for hepatic insufficiency, complications and mortality after major hepatectomy.

OBJECTIVE Total bilirubin (TB) of >7 mg/dl is an accepted definition of postoperative hepatic insufficiency (PHI) given its association with the occurrence of complications and mortality after hepatectomy. The aim of this study was to identify a surrogate marker for PHI early in the postoperative course. METHODS A single-institution database of patients undergoing major hepatectomy (three or more segments) during 2000-2012 was retrospectively reviewed. Demographic, clinicopathologic and perioperative factors were assessed for their association with PHI, defined as postoperative TB of >7 mg/dl or new ascites. Secondary outcomes included complications, major complications (Clavien-Dindo Grades III-V) and 90-day mortality. RESULTS A total of 607 patients undergoing major hepatectomy without bile duct reconstruction were identified. Postoperative hepatic insufficiency occurred in 60 (9.9%) patients. A postoperative day 3 (PoD 3) TB level of ≥3 mg/dl was the only early perioperative factor associated with the development of PHI on multivariate analysis [hazard ratio (HR) = 7.81, 95% confidence interval (CI) 3.74-16.31; P < 0.001]. A PoD 3 TB of ≥3 mg/dl was associated with increased risk for postoperative complications (75.7% versus 53.9%), major complications (45.6% versus 17.6%), and 90-day mortality (15.5% versus 2.3%). This association persisted on multivariate analysis for any complications (HR = 1.98, 95% CI 1.10-3.54; P = 0.022), major complications (HR = 3.18, 95% CI 1.90-5.32; P < 0.001), and 90-day mortality (HR = 8.11, 95% CI 3.00-21.92; P < 0.001). CONCLUSIONS Total bilirubin of ≥3 mg/dl on PoD 3 after major hepatectomy is associated with PHI, increased complications, major complications and 90-day mortality. This marker may serve as an early postoperative predictor of hepatic insufficiency.

Videoscopic inguinal lymphadenectomy for metastatic melanoma.

BACKGROUND The standard treatment of care for melanoma metastatic to the inguinal lymph node basin is lymphadenectomy. However, up to 50% of patients forgo the operation partly due to concerns about morbidity. Videoscopic inguinal lymphadenectomy (VIL) is a minimally invasive technique designed to minimize wound complications while achieving comparable oncological control. METHODS We reviewed pertinent literature related to open inguinal lymphadenectomy and VIL specific to melanoma, offering personal experience where appropriate. RESULTS Despite efforts to minimize the complications of open inguinal lymphadenectomy, approximately 50% of patients experience a wound-related complication. However, performing minimally invasive VIL has led to a significant decrease in length of hospital stay, a decrease in complications, and equivalent or superior lymph node retrieval in patients with metastatic melanoma to the inguinal basin. CONCLUSIONS VIL is an alternative to open inguinal lymphadenectomy for patients with melanoma and regional metastases.

Lymph Node Dissection for Stage III Melanoma

Locoregional spread of melanoma to its draining lymph node basin is the strongest negative prognostic factor for patients. Exclusive of clinical trials, patients with sentinel lymph node-positive (microscopic) or clinically palpable (macroscopic) nodal disease should undergo lymphadenectomy. This article reviews the management and technical aspects of surgical care for regional metastases. Adjunct therapies (immunotherapy, targeted therapy, and radiation) may supplement lymphadenectomy in certain patient populations. Surgical morbidity after lymphadenectomy can be substantial, creating opportunities for improvement via minimally invasive techniques or refined patient selection.

Emory global surgery program: learning to serve the underserved well.

Over the past 25 years, there has been a surge in interest andactivity surrounding surgery in public health, the globalsurgical workforce, and the availability and quality ofsurgical services in low-resource settings. Significant researchand encouraging progress has been made on numerousfronts, from studies quantifying various aspects of theburden of surgical disease to innovative projects buildingand strengthening surgical capacity.