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Background Resectability rates for extrahepatic cholangiocarcinoma have increased over time, but long-term survival after resection alone with curative intent remains poor. Recent series suggest improved survival with adjuvant therapy. Patient subsets benefiting most from adjuvant therapy have not been clearly defined. Methods Patients with extrahepatic cholangiocarcinoma who underwent resection with curative intent and received adjuvant therapy (chemotherapy ± radiotherapy) or surgery alone (SA) were identified in the U.S. National Cancer Data Base (2004–2014). Cox regression identified covariates associated with overall survival (OS). Adjuvant therapy and SA cohorts were matched (1:1) by propensity scores based on the survival hazard in Cox modeling. Overall survival was compared by Kaplan–Meier estimates. Results Of 4872 patients, adjuvant chemotherapy was used frequently for 2416 (49.6%), often in conjunction with radiotherapy (RT) ( n  = 1555, 64.4%). Adjuvant chemotherapy with or without RT was used increasingly for cases with higher T classification [reference: T1–2; T3: 1.36; 95% confidence interval (CI), 1.19–1.55; T4: 1.77; 95% CI 1.38–2.26], nodal positivity [odds ratio (OR), 1.26; 95% CI 1.01–1.56], lymphovascular invasion (OR 1.21; 95% CI 1.01–1.46), or margin-positive resection (OR 1.85; 95% CI 1.61–2.12), and was associated with significant improvements in OS for each high-risk subset in the propensity score-matched cohort. Adjuvant therapy was associated with improved median OS for hilar tumors (40.0 vs 30.6 months; p  = 0.025) but not distal tumors (33.0 vs 30.3 months; p  = 0.123). Chemoradiotherapy was associated with superior outcomes compared with chemotherapy alone in the subset of margin-positive resection [hazard ratio (HR), 0.63; 95% CI 0.42–0.94]. Conclusions Adjuvant multimodality therapy is associated with improved survival for patients with resected extrahepatic cholangiocarcinoma and high-risk features.

Background Recent data illustrates improved outcomes when adhering to early drain removal following pancreatoduodenectomy (PD). This study aims to explore the potential benefits of expanding the timeframe for early drain removal. Methods Six hundred forty PDs were originally managed by selective drain placement and early removal. Outcomes were reappraised in the framework of a novel proposal; intraoperative drains were omitted based on a low-risk profile (Fistula Risk Score 0–2), followed by drain removal at PODs 1, 3, and 5 if drain fluid amylase (DFA) fell below specific cutoffs based on optimized negative predictive values (NPV) for clinically relevant postoperative pancreatic fistula (CR-POPF). Characteristics of the remaining cohort with drains in situ on POD5 were examined using multivariable analysis (MVA). Results Intraoperative FRS would preclude drains from 230 (35.9%) negligible/low-risk cases with a cohort CR-POPF rate of 1.7%. Of the remaining patients, 30.5% would have drains removed on POD1 based on a DFA threshold of 300 IU/L (NPV = 98.4%), demonstrating a 1.6% CR-POPF rate. On POD3, drains could be removed in the residual cohort from 21.1% of patients with DFA ≤ 150 IU/L (NPV = 96.6%), reflecting a 3.4% CR-POPF rate. On POD5, a DFA threshold of 50 IU/L (NPV = 84%) identified 16.3% more patients whose drains could be removed. The remaining cohort (POD5 DFA > 50 IU/L), “enriched” for fistula development and reflecting just 18.4% of the original patients, displays a 61% CR-POPF rate. Among these patients on POD5, a DFA threshold > 2000 IU/L best predicted subsequent CR-POPF (PPV = 89.5%), and MVA revealed a positive association between pancreatic cancer/pancreatitis (OR = 4.37, p  = 0.022) and longer operations (OR = 3.74, p  = 0.014) with CR-POPF development. Conclusion Early drain removal is a dynamic concept and can be employed throughout the postoperative time course using conditional thresholds to better identify patients at risk for CR-POPF.

Despite the success of vaccines against some microbial pathogens, their utility in the prevention and treatment of cancer has thus far been limited. We have previously demonstrated that vaccination with dendritic cells activated with the TLR-4 ligand LPS and IFN-γ promotes an antigen-specific anti-tumor response that prevents tumor recurrence. To evaluate this mechanistically, we here studied the effects of this TLR-activated DC on regulatory T cell activity. Dendritic cells activated with LPS and IFN- γ negated the effects of regulatory T cells on responder cell proliferation. Restoration of responder cell proliferation was noted when TLR-activated dendritic cells were separated from both regulators and responders by a semi-permeable membrane. The effect is therefore mediated by a soluble factor but was independent of both IL-6 and IL-12. Furthermore, the soluble mediator appeared to act at least in part on the regulators themselves rather than responder cells exclusively. Because recent studies have demonstrated conversion of T regulatory cells into IL-17-producing effectors, we further questioned whether the TLR-activated dendritic cell would induce cytokine production and effector function in our system. We found that regulators produced a substantial amount of IFN- γ in the presence of TLR-activated dendritic cells but not immature dendritic cells. IFN-γ production was associated with upregulation of the Th1 transcriptional regulator T-bet, and a significant fraction of IFN-γ-producing regulators coexpressed T-bet and FoxP3. While the effects of the LPS-activated dendritic cell on responder cell proliferation were IL-12 independent, upregulation of T-bet was inhibited by a neutralizing anti-IL-12 antibody. Collectively, these and prior data suggest that varying innate immune signals may direct the phenotype of the immune response in part by inhibiting suppressor T cells and promoting differentiation of these regulators into particular subsets of effectors.

BackgroundHyperbilirubinemia is commonly observed in patients requiring pancreatoduodenectomy (PD). Thus far, literature regarding the danger of operating in the setting of hyperbilirubinemia is equivocal. What remains undefined is at what specific level of bilirubin there is an adverse safety profile for undergoing PD. The aim of this study is to identify the optimal safety profile of patients with hyperbilirubinemia undergoing PD.Patients and MethodsThe present work analyzed 803 PDs from 2004 to 2018. A generalized additive model was used to determine cutoff values of total serum bilirubin (TB) that were associated with increases in adverse outcomes, including 90-day mortality. Subgroup comparisons and biliary stent-specific analyses were performed for patients with TB below and above the cutoff.ResultsTB of 13 mg/dL was associated with an increase in 90-day mortality (P = 0.043) and was the dominant risk factor on multivariate logistic regression [odds ratio (OR) 8.193, P = 0.001]. Increased TB levels were also associated with reoperations, number of complications per patient, and length of stay. Patients with TB greater than or equal to 13 mg/dL (TB ≥ 13) who received successful biliary decompression through stenting had less combined death and serious morbidity (P = 0.048).ConclusionsPreoperative TB ≥ 13 mg/dL was associated with increased 90-day mortality after PD. Reducing a TB ≥ 13 is generally recommended before proceeding to surgery.

Background While contemporary studies demonstrate decreasing complication rates following total pancreatectomy (TP), none have quantified the impact of post-TP complications. The Postoperative Morbidity Index (PMI)—a quantitative measure of postoperative morbidity—combines ACS-NSQIP complication data with severity weighting derived from Modified Accordion Grading System. We establish the PMI for TP in a multi-institutional cohort. Methods Nine institutions contributed ACS-NSQIP data for 64 TPs (2005–2011). Each complication was assigned an Accordion severity weight ranging from 0.110 (grade 1/mild) to 1.00 (grade 6/death). PMI equals the sum of complication severity weights (“Total Burden”) divided by total number of patients. Results Overall, 29 patients (45.3 %) suffered 55 ACS-NSQIP complications; 15 (23.4 %) had >1 complication. Thirteen patients (20.3 %) were readmitted and one death (1.6 %) occurred within 30 days. Non-risk adjusted PMI was 0.151, while PMI for complication-bearing cases rose to 0.333. Bleeding/Transfusion and Sepsis were the most common complications. Discordance between frequency and burden of complications was observed. While grades 4–6 comprised only 18.5 % of complications, they contributed 37.1 % to the series’ total burden. Conclusion This multi-institutional series is the first to quantify the complication burden following TP using the rigor of ACS-NSQIP. A PMI of 0.151 indicates that, collectively, patients undergoing TP have an average burden of complications in the mild to moderate severity range, although complication-bearing patients have a considerable reduction in health utility.

Background Evidence suggests externalized trans-anastomotic stents may be beneficial as a fistula mitigation strategy for pancreatoduodenectomy (PD); however, previous studies have not been rigorously risk-adjusted. Methods From 2001 to 2015, PDs were performed at three institutions, with externalized stents placed at the surgeon’s discretion. The Fistula Risk Score (FRS) and the Modified Accordion Severity Grading System were used to analyze occurrence and severity of clinically relevant postoperative pancreatic fistula (CR-POPF) across various risk scenarios. Results Of 729 PDs, externalized stents were placed during 129 (17.7 %). Overall, CR-POPFs occurred in 77 (10.6 %) patients. The median FRS of patients who received externalized stents was significantly higher compared with patients who did not (6 vs. 3, p  < 0.0001). Patients with negligible, low, or moderate CR-POPF risk (FRS 0–6) did not demonstrate improved outcomes with externalized stents; however, among high-risk patients (FRS 7–10), stents were associated with significantly reduced rates of CR-POPF (14.0 vs. 36.4 %, p  = 0.031), severe complications ( p  = 0.039), and hospital stay ( p  = 0.014) compared with no stents. The average complication burden of CR-POPF was significantly lower for patients with externalized stents ( p  = 0.035). Conclusion This multicenter study, the largest comparative analysis of externalized trans-anastomotic stents versus no stent for PD, demonstrates a risk-stratified benefit to externalized stents.

Introduction: The relative contributions of CD4⁺ and CD8⁺ T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4⁺ and CD8⁺ lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. Materials and Methods: Clone 4 and TS1 mice possess MHC class I- and II-restricted CD8⁺ and CD4⁺ T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8⁺ and CD4⁺ T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. Results: As in the authors' CD4⁺ model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5×10⁵ Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA⁺ grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4⁺ and CD8⁺ cells acquired effector function and proliferated with similar kinetics. Conclusions: These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.

Long-term survival of transplanted organs currently requires chronic immunosuppressive treatment of recipients. While the efficacy of these therapies is satisfactory, their toxicity to host tissues and non-specific inhibition of the immune response are disadvantageous. The ideal in transplantation is induction of donor-specific tolerance, but this has been achieved reliably only in experimental models. Accumulating evidence suggests that immunoregulatory CD4+CD25+ T cells (T-regs) are a critical component in many strategies used to effect tolerance. These cells therefore represent a potentially invaluable tool for prolonging survival of allografts. However, many aspects of T-reg function in vivo have yet to be elucidated including the mechanism of T-reg-mediated allograft prolongation. In Chapter III, we establish a model for investigation of the mechanism of regulatory T cell-mediated allograft prolongation. This model correlates T cell proliferation in the draining lymph node with the biologically relevant readout of graft rejection in an immunocompetent host. In Chapter IV, we extend this model to characterize the mechanism by which T-regs prolong graft survival. We demonstrate that T-reg-mediated allograft prolongation is correlated with inhibition of naïve T cell proliferation in the draining lymph node. These findings establish the lymph node as a potentially critical site of regulation of the allograft response. In Chapter V, we further this premise by illustrating that the lymph node is an independent site of suppression. Regulatory cells that do not encounter the allograft are capable of restricting T cell responses to alloantigen in the draining lymph node. Finally, in Chapter VI, we investigate how regulatory cells are themselves controlled in vivo. Our data indicate that innate signals transiently inhibit T-regs to allow development of the immune response, and that the interaction of GITR with the GITR ligand may be the mechanistic basis of this regulation. Studies here not only advance our understanding of T-reg-mediated allograft prolongation, but can also be generalized to model how T-regs are integrated into the immune system allowing initiation of productive immune responses yet controlling them to prevent autoimmune attack.

Despite the success of vaccines against some microbial pathogens, their utility in the prevention and treatment of cancer has thus far been limited. We have previously demonstrated that vaccination with dendritic cells activated with the TLR-4 ligand LPS and IFN- gamma promotes an antigen-specific anti-tumor response that prevents tumor recurrence. To evaluate this mechanistically, we here studied the effects of this TLR-activated DC on regulatory T cell activity. Dendritic cells activated with LPS and IFN- gamma negated the effects of regulatory T cells on responder cell proliferation. Restoration of responder cell proliferation was noted when TLR-activated dendritic cells were separated from both regulators and responders by a semi-permeable membrane. The effect is therefore mediated by a soluble factor but was independent of both IL-6 and IL-12. Furthermore, the soluble mediator appeared to act at least in part on the regulators themselves rather than responder cells exclusively. Because recent studies have demonstrated conversion of T regulatory cells into IL-17-producing effectors, we further questioned whether the TLR-activated dendritic cell would induce cytokine production and effector function in our system. We found that regulators produced a substantial amount of IFN- gamma in the presence of TLR-activated dendritic cells but not immature dendritic cells. IFN- gamma production was associated with upregulation of the Th1 transcriptional regulator T-bet, and a significant fraction of IFN- gamma -producing regulators coexpressed T-bet and FoxP3. While the effects of the LPS-activated dendritic cell on responder cell proliferation were IL-12 independent, upregulation of T-bet was inhibited by a neutralizing anti-IL-12 antibody. Collectively, these and prior data suggest that varying innate immune signals may direct the phenotype of the immune response in part by inhibiting suppressor T cells and promoting differentiation of these regulators into particular subsets of effectors.

Significance: Surgery is often paramount in the management of many solid organ malignancies because optimal resection is a major factor in disease-specific survival. Cancer surgery has multiple challenges including localizing small lesions, ensuring negative surgical margins around a tumor, adequately staging patients by discriminating positive lymph nodes, and identifying potential synchronous cancers. Intraoperative molecular imaging (IMI) is an emerging potential tool proposed to address these issues. IMI is the process of injecting patients with fluorescent-targeted contrast agents that highlight cancer cells prior to surgery. Over the last 5 to 7 years, enormous progress has been achieved in tracer development, near-infrared camera approvals, and clinical trials. Therefore, a second biennial conference was organized at the University of Pennsylvania to gather surgical oncologists, scientists, and experts to discuss new investigative findings in the field. Our review summarizes the discussions from the conference and highlights findings in various clinical and scientific trials. Aim: Recent advances in IMI were presented, and the importance of each clinical trial for surgical oncology was critically assessed. A major focus was to elaborate on the clinical endpoints that were being utilized in IMI trials to advance the respective surgical subspecialties. Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center’s second clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Results: Multiple phase III, II, and I trials were discussed during the conference. Since the approval of 5-ALA for commercial use in neurosurgical malignancies, multiple tracers and devices have been developed to address common challenges faced by cancer surgeons across numerous specialties. Discussants also presented tracers that are being developed for delineation of normal anatomic structures that can serve as an adjunct during surgical procedures. Conclusions: IMI is increasingly being recognized as an improvement to standard oncologic surgical resections and will likely advance the art of cancer surgery in the coming years. The endpoints in each individual surgical subspecialty are varied depending on how IMI helps each specialty solve their clinical challenges.