Background and aim: To compare cancer-specific survival (CSS) between patients who received neoadjuvant radiation followed by resection (NRR) and those who received upfront resection (UR) for locally advanced pancreatic cancer (LAPC). Methods: A total of 772 LAPC patients who underwent curative-intent surgical resection with or without neoadjuvant radiation from 2004 to 2013 were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Propensity score matching (PSM) was conducted to eliminate possible bias. Kaplan-Meier method was used to analyze long-term outcome. Independent risk factors of CSS were predicted by Cox proportional hazards model. Subgroup analyses were done according to 5 variables. Results: The propensity score model matched 196 patients from the whole cohort. Neoadjuvant radiation was an independent predictor of CSS no matter before or after PSM. After PSM, the 1-, 3-, 5-year CSS rates of NRR group were 82.7%, 39.2% and 17.1%, while 64.3%, 19.9% and 12.4% for UR group. The median CSS for NRR group was 25 months, while 17 months for UR group. In subgroup analyses, CSS rates or median CSS of NRR group were still superior to those of UR group in married, unmarried, pancreatic adenocarcinoma, G1+G2, G3+G4, N0 stage, N1 stage and M0 stage subgroups, but no differences were found in other histological types and M1 stage subgroups. Other predictors of CSS included histological type, tumor grade and marital status. Conclusions: Neoadjuvant radiation followed by resection has a significant survival benefit compared with upfront resection in LAPC patients. Therapeutic strategy for LAPC patients should be further explored.

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.

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 reexposed 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. (Blood. 2010;116(8): 1291-1298) Introduction B7-H1 (CD274, PD-L1), a transmembrane glycoprotein belonging to immunoglobulin (Ig) superfamily molecule, plays an integral role in the regulation of immune tolerance and homeostasis. 1 Mice deficient of B7-H1 gene or wild-type mice treated with anti-B7-H1 blocking monoclonal antibody (mAb) exhibit exacerbated autoimmune phenotypes associated with an activation of self-reactive CD4 ϩ and CD8 ϩ T cells. [2][3][4][5] Tolerogenic functions of B7-H1 are dependent on its expression on hematopoietic or parenchymal cells, and mediated by its interaction with PD-1 receptor. 6-8 PD-1 is inducibly expressed on T cells after activation and delivers coinhibitory signals via immunoreceptor tyrosine-based switch motif in the cytoplasmic domain. 9,10 PD-1 signal interferes with phosphatidylinositol-3-kinase (PI3K) activity and subsequently inhibits interleukin-2 (IL-2) production, which eventually renders T cells anergic. 11 The mice deficient of PD-1 gene spontaneously develop autoimmune phenotypes, and single nucleotide polymorphisms of human PD-1 gene are associated with an increased risk of autoimmune diseases. [12][13][14][15][16] Recent studies by Butte et al discovered that B7-H1 interacts with CD80 (B7-1) in addition to PD-1. 17,18 In vitro studies using CD4ϩ T cells deficient of PD-1, CD28, and/or CTLA-4 indicated that B7-H1/CD80 interaction delivers bidirectional inhibitory signals to T cells. 17 These findings are consistent with previous observations implicating the presence of non-PD-1 receptor(s) of B7-H1. For instance, when the B7-H1/PD-1 interaction is blocked in models of T-cell tolerance, the effects of anti-B7-H1 antagonistic mAb in rest...

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SUMMARY CD28 and CTLA-4 are cell surface cosignaling molecules essential for the control of T cell activation upon the engagement of their ligands, B7-1 and B7-2 from antigen-presenting cells. By employing a newly developed receptor array, we have demonstrated that B7-H2, best known as the ligand of Inducible Costimulator, was a ligand for CD28 and CTLA-4 in human, whereas these interactions were not conserved in mouse. B7-H2 interacted with CD28 in a non-overlapping domain as B7-1 and B7-2, and was essential for the costimulation of human T cells’ primary responses to allogeneic antigens and memory recall responses. Similar to B7-1 and B7-2, B7-H2 costimulation via CD28 induced survival factor Bcl-xL, downregulated cell cycle inhibitor p27kip1 and triggered signaling cascade of ERK and AKT kinases-dependent pathways. Our findings warrant re-evaluation of CD28 and CTLA-4’s functions previously attributed exclusively to B7-1 and B7-2, and has important implications in therapeutic interventions against human diseases.

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Although patients with ASCP and PDAC tumors have similar survival when non-surgical and surgical patients are combined, ASCP is associated with worse survival in stage I/II resected patients.

Background An 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. Methods Patients 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. Results We 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 laparoscopic, and 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). Conclusions Robotic 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.