Mathew M. Augustine

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance.

T-cell tolerance is the central program that prevents harmful immune responses against self-antigens, in which inhibitory PD-1 signal given by B7-H1 interaction plays an important role. Recent studies demonstrated that B7-H1 binds CD80 besides PD-1, and B7-H1/CD80 interaction also delivers inhibitory signals in T cells. However, a role of B7-H1/CD80 signals in regulation of T-cell tolerance has yet to be explored. We report here that attenuation of B7-H1/CD80 signals by treatment with anti-B7-H1 monoclonal antibody, which specifically blocks B7-H1/CD80 but not B7-H1/PD-1, enhanced T-cell expansion and prevented T-cell anergy induction. In addition, B7-H1/CD80 blockade restored Ag responsiveness in the previously anergized T cells. Experiments using B7-H1 or CD80-deficient T cells indicated that an inhibitory signal through CD80, but not B7-H1, on T cells is responsible in part for these effects. Consistently, CD80 expression was detected on anergic T cells and further up-regulated when they were re-exposed to the antigen (Ag). Finally, blockade of B7-H1/CD80 interaction prevented oral tolerance induction and restored T-cell responsiveness to Ag previously tolerized by oral administration. Taken together, our findings demonstrate that the B7-H1/CD80 pathway is a crucial regulator in the induction and maintenance of T-cell tolerance.

B7-H4 deficient mice display augmented neutrophil-mediated innate immunity

B7-H4 is an immunoglobulin superfamily molecule and shown to be inhibitory for T-cell responses. To explore physiologic roles of B7-H4, we created B7-H4-deficient (KO) mice by genetic targeting. B7-H4KO mice are healthy and their T- and B-cell responses to polyclonal antigens are in normal range. However, B7-H4KO mice are more resistant to infection by Listeria monocytogenes than their littermates. Within 3 days after infection, bacterial colonies in livers and spleens are significantly lower than the controls, suggesting a role of B7-H4 in enhancing innate immunity. Further studies demonstrate that neutrophils increase in peripheral organs of B7-H4KO mice more so than their littermates but their bactericidal functions remain unchanged. Augmented innate resistance is completely dependent on neutrophils, even in the absence of adaptive immunity. In vitro B7-H4 inhibits the growth of bone marrow-derived neutrophil progenitors, suggesting an inhibitory function of B7-H4 in neutrophil expansion. Our results identify B7-H4 as a negative regulator of the neutrophil response to infection and provide a new target for manipulation of innate immunity.

Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis

Purpose To compare overall survival between patients who received neoadjuvant therapy (NAT) followed by resection and those who received upfront resection (UR)-as well as a subgroup of UR patients who also received adjuvant therapy-for early-stage resectable pancreatic adenocarcinoma. Patients and Methods Adult patients with resected, clinical stage I or II adenocarcinoma of the head of the pancreas were identified in the National Cancer Database from 2006 to 2012. Patients who underwent NAT followed by curative-intent resection were matched by propensity score with patients whose tumors were resected upfront. Overall survival was compared by using a Cox proportional hazards regression model. Early postoperative and oncologic outcomes were evaluated. Results We identified 15,237 patients with clinical stage I or II resected pancreatic head adenocarcinoma. From the NAT group, 2,005 patients (95%) were matched with 6,015 patients who underwent UR. The NAT group was associated with improved survival compared with UR (median survival, 26 months v 21 months, respectively; stratified log-rank P < .01; hazard ratio, 0.72; 95% CI, 0.68 to 0.78). Patients in the UR group had higher pathologic T stage (pT3 and T4: 86% v 73%; P < .01), higher positive lymph nodes (73% v 48%; P < .01), and higher positive resection margin (24% v 17%; P < .01). Compared with a subset of UR patients who received adjuvant therapy, NAT patients had a better survival (adjusted hazard ratio, 0.83; 95% CI, 0.73 to 0.89). Conclusion NAT followed by resection has a significant survival benefit compared with UR in early-stage, resected pancreatic head adenocarcinoma. These findings support the use of NAT, particularly as a patient selection tool, in the management of resectable pancreatic adenocarcinoma.

B7-H5 costimulates human T cells via CD28H.

The B7/CD28 family has profound modulatory effects in immune responses and constitutes important targets for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homolog (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H-negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homolog 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction co-stimulates human T cell growth and cytokine production, selectively via an AKT-dependent signaling cascade. Our study identifies a novel co-stimulatory pathway regulating human T cell responses.

Hilar cholangiocarcinoma: tumor depth as a predictor of outcome.

BACKGROUND The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries. OBJECTIVES To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth. DESIGN, SETTING, AND PATIENTS From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review. MAIN OUTCOME MEASURES Tumor depth and overall survival. RESULTS Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P > .05 for all). Median survival was associated with the invasion depth of the tumor (≥5 mm vs <5 mm): 18 months vs 30 months (P = .01). On multivariate analysis, tumor depth remained predictive of disease-specific death (hazard ratio, 1.70; P = .03). CONCLUSIONS The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome.

Surgical treatment of primary hyperparathyroidism.

OBJECTIVE To review the surgical treatment options for primary hyperparathyroidism with a focus on recent refinements in minimally invasive techniques and endoscopic and video- or robot-assisted parathyroidectomy. METHODS We review the relevant surgical treatment options for primary hyperparathyroidism. RESULTS Parathyroidectomy is the standard therapy for patients with primary hyperparathyroidism. Advancements in imaging, including technetium Tc 99m-sestamibi single-photon emission computed tomography and ultrasonography, have improved preoperative localization, while intraoperative parathyroid hormone measurement provides a rapid test to confirm operative success. These adjuncts have enabled surgeons to perform an operation that is both safe and minimally invasive. CONCLUSIONS The minimally invasive approach to parathyroidectomy provides comparable cure rates to conventional bilateral neck exploration with reduced operative time and improved cosmetic results. The durability, safety, and success of these procedures make them valuable options in the current and future care of patients with primary hyperparathyroidism.

Epidemiology and Risk Factors of Biliary Tract and Primary Liver Tumors

Primary liver and biliary tract tumors encompass a range of benign and malignant neoplasms. They consist of histologically distinct types of tumors that arise from and are influenced by hepatocytes, biliary epithelial cells, and mesenchymal cells. Improvements in imaging have allowed the detection and diagnosis of these neoplasms to be refined. Investigation at the histologic, molecular, and genetic levels has allowed neoplasms to be categorized and treated. Epidemiology has improved understanding of geographic, ethnic, gender, and cultural differences that link exposures with cancer risk. This article focuses on the epidemiology of major primary adult liver and biliary tract tumors.

Minimally Invasive Versus Open Pancreaticoduodenectomy: A Propensity-matched Study From a National Cohort of Patients

Objective: To compare the perioperative outcomes of minimally invasive pancreaticoduodenectomy (MIPD) in comparison with open pancreaticoduodenectomy (OPD) in a national cohort of patients. Background: Limited well-controlled studies exist comparing perioperative outcomes between MIPD and OPD. Methods: Patients who underwent MIPD and OPD were abstracted from the 2014 to 2015 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program. OPD and MIPD patients were matched 3:1 using propensity score, and perioperative outcomes were compared. Results: A total of 4484 patients were identified with 334 (7.4%) undergoing MIPD. MIPD patients were younger, more likely to be White, and had a lower rate of weight loss. They were more likely to undergo classic Whipple and to have a drain placed. After 3:1 matching, 1002 OPD patients were compared with 334 MIPD patients. MIPD was associated with longer mean operative time (426.6 vs 359.6 minutes; P < 0.01), higher readmission rate (19.2% vs 14.3%; P = 0.04) and lower rate of prolonged length of stay >14 days (16.5% vs 21.6%; P = 0.047). The 2 groups had a similar rate of 30-day mortality (MIPD 1.8% vs OPD 1.3%; P = 0.51), overall complications, postoperative pancreatic fistula, and delayed gastric emptying. A secondary analysis comparing MIPD without conversion or open assist with OPD showed that MIPD patients had lower rates of overall surgical site infection (13.4% vs 19.6%; P = 0.04) and transfusion (7.9% vs 14.4%; P = 0.02). Conclusions: MIPD had an equivalent morbidity and mortality rate to OPD, with the benefit of a decreased rate of prolonged length of stay, though this is partially offset by an increased readmission rate.

Robotic Versus Laparoscopic Pancreaticoduodenectomy: a NSQIP Analysis

BackgroundAn increasing body of literature is supporting the safety of minimally invasive pancreaticoduodenectomy compared to open pancreaticoduodenectomy, but there are limited comparative studies between laparoscopic and robotic pancreaticoduodenectomy.The aim of this study was to compare the rate of postoperative 30-day overall complications between laparoscopic and robotic pancreaticoduodenectomy.MethodsPatients who underwent laparoscopic and robotic pancreaticoduodenectomy were abstracted from the 2014–2015 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program. A multivariable logistic regression model was developed to determine if the type of minimally invasive approach was associated with 30-day overall complications.ResultsWe identified 428 minimally invasive pancreaticoduodenectomy cases, of which 235 (55%) were performed laparoscopically and 193 (45%) robotically. Patients who underwent the robotic approach were more likely to be white compared to those who underwent the laparoscopic approach and were less likely to have pulmonary disease, undergo preoperative radiotherapy, and have vascular and multivisceral resection. On multivariable analysis, we found that the type of minimally invasive approach, whether laparoscopic or robotic, was not associated with overall complications. The predictors of 30-day overall complications were higher body mass index (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02–1.09), vascular resection (OR, 2.10; 95% CI, 1.23–3.58), and longer operative time (OR, 1.002; 95% CI, 1.001–1.004).ConclusionsRobotic pancreaticoduodenectomy was associated with a similar 30-day overall complication rate to laparoscopic pancreaticoduodenectomy. Further studies are needed to corroborate these findings and to establish the best approach to perform this complex operation.

Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM

The SALM5-HVEM interaction limits inflammation and contributes to immune privilege in the CNS. The central nervous system (CNS) is an immune-privileged organ with the capacity to prevent excessive inflammation. Aside from the blood-brain barrier, active immunosuppressive mechanisms remain largely unknown. We report that a neuron-specific molecule, synaptic adhesion-like molecule 5 (SALM5), is a crucial contributor to CNS immune privilege. We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. In addition, we identified herpes virus entry mediator as a functional receptor that mediates SALM5’s suppressive function. Our findings reveal a molecular link between the neuronal system and the immune system, and provide potential therapeutic targets for the control of CNS diseases.