Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.

The Impact of Age in the Treatment of Non-comorbid Patients with Rectal Cancer: Survival Outcomes from the National Cancer Database.

BACKGROUND: Multimodal therapy has improved survival outcomes for rectal cancer (RC) significantly with an exemption for older patients. We sought to assess whether older non-comorbid patients receive substandard oncological treatment for localized RC referring to the National Comprehensive Cancer Network (NCCN) guidelines and whether it affects survival outcomes. METHODS: This is a retrospective study using patient data from the National Cancer Data Base (NCDB) for histologically confirmed RC from 2002 to 2014. Non-comorbid patients between ≥50 and ≤85 years and defined treatment for localized RC were included and assigned to a younger (<75 years) and an older group (≥75 years). Treatment approaches and their impact on relative survival (RS) were analyzed using loess regression models and compared between both groups. Furthermore, mediation analysis was performed to measure the independent relative effect on age and other variables on RS. Data were assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist. RESULTS: Of 59,769 included patients, 48,389 (81.0%) were assigned to the younger group (<75 years). Oncologic resection was performed in 79.6% of the younger patients compared to 67.2% of the older patients (p < 0.001). Chemotherapy (74.3% vs. 56.1%) and radiotherapy (72.0% vs. 58.1%) were provided less often in older patients, respectively (p < 0.001). Increasing age was associated with enhanced 30- and 90-day mortality with 0.6% and 1.1% in the younger and 2.0% and 4.1% in the elderly group (p < 0.001) and worse RS rates [multivariable adjusted HR: 1.93 (95% CI 1.87-2.00), p < 0.001]. Adherence to standard oncological therapy resulted in a significant increase in 5-year RS (multivariable adjusted HR: 0.80 (95% CI 0.74-0.86), p < 0.001). Mediation analysis revealed that RS was mainly affected by age itself (84%) rather than the choice of therapy. CONCLUSIONS: The likelihood to receive substandard oncological therapy increases in the older population and negatively affects RS. Since age itself has a major impact on RS, better patient selection should be performed to identify those that are potentially eligible for standard oncological care regardless of their age.

Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model.

BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). METHODS: KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. RESULTS: The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4-6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. CONCLUSIONS: IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.

Oxaliplatin-induced peripheral neuropathy can be minimized by pressurized regional intravascular delivery in an orthotopic murine pancreatic cancer model.

PURPOSE: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. METHODS: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. RESULTS: Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. CONCLUSION: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

Role of lymphadenectomy in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%. PURPOSE: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS. CONCLUSIONS: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model.

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.

Role of lymphadenectomy, adjuvant chemotherapy, and treatment at high-volume centers in patients with resected pancreatic cancer-a distinct view on lymph node yield.

PURPOSE: While the importance of lymphadenectomy is well-established for patients with resectable pancreatic cancer, its direct impact on survival in relation to other predictive factors is still ill-defined. METHODS: The National Cancer Data Base 2006-2015 was queried for patients with resected pancreatic adenocarcinoma (stage IA-IIB). Patients were dichotomized into the following two groups, those with 1-14 resected lymph nodes and those with ≥ 15. Optimal number of resected lymph nodes and the effect of lymphadenectomy on survival were assessed using various statistical modeling techniques. Mediation analysis was performed to differentiate the direct and indirect effect of lymph node resection on survival. RESULTS: A total of 21,912 patients were included; median age was 66 years (IQR 59-73), 48.9% were female. Median number of resected lymph nodes was 15 (IQR 10-22), 10,163 (46.4%) had 1-14 and 11,749 (53.6%) had ≥ 15 lymph nodes retrieved. Lymph node positivity increased by 4.1% per lymph node up to eight examined lymph nodes, and by 0.6% per lymph node above eight. Five-year overall survival was 17.9%. Overall survival was better in the ≥ 15 lymph node group (adjusted HR 0.91, CI 0.88-0.95, p < 0.001). On a continuous scale, survival improved with increasing LNs collected. Patients who underwent adjuvant chemotherapy and were treated at high-volume centers had improved overall survival compared with their counterparts (adjusted HR 0.59, CI 0.57-0.62, p < 0.001; adjusted HR 0.86, CI 0.83-0.89, p < 0.001, respectively). Mediation analysis revealed that lymphadenectomy had only 18% direct effect on improved overall survival, while 82% of its effect were mediated by other factors like treatment at high-volume hospitals and adjuvant chemotherapy. DISCUSSION: While higher number of resected lymph nodes increases lymph node positivity and is associated with better overall survival, most of the observed survival benefit is mediated by chemotherapy and treatment at high-volume centers.

Is There a Role for Surgery in Patients with Neuroendocrine Tumors of the Esophagus? A Contemporary View from the NCDB.

BACKGROUND: Esophageal neuroendocrine tumors (eNETs) are exceedingly rare, aggressive and have a poor prognosis. Treatment guidelines are ill-defined and mainly based on evidence from case reports and analogous experiences drawn from similar disease sites. METHODS: The NCDB was reviewed for histologically confirmed stage I-III, primary eNETs from 2006 to 2014. Patients were grouped into whether or not they underwent primary tumor resection. Univariate, multivariable, and full bipartite propensity score (PS) adjusted Cox regression analyses were used to assess overall and relative survival differences. RESULTS: A total of 250 patients were identified. Mean age was 65.0 (standard deviation [SD] 11.9) years, and 174 (69.6%) patients were male. Most patients had stage III disease (n = 136, 54.4%), and the most common type of NET was small cell eNET (n = 111, 44.4%). Chemotherapy was used in 186 (74.4%), radiation therapy in 178 (71.2%), and oncological resection was performed in 69 (27.6%) patients. Crude 2-year survival rates were higher in the operated (57.3%) compared with the nonoperated group (35.2%; p < 0.001). The survival benefit held true after multivariable adjustment (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.32-0.69, p < 0.001). After full bipartite PS adjustment analysis, survival was longer for patients who received a surgical resection compared with those who did not (HR 0.48, 95% CI 0.31-0.75, p = 0.003) with a corresponding 2-year overall survival rate of 63.3% (95% CI 52.0-77.2) versus 38.8% (95% CI 30.9-48.8), respectively. CONCLUSIONS: Multimodal treatment that includes surgery is associated with better overall survival for eNETs. Additional research is needed to more definitively identify patients who benefit from esophagectomy and to establish an appropriate treatment algorithm.

C-Reactive Protein on Postoperative Day 1: a Predictor of Early Intra-abdominal Infections After Bariatric Surgery.

BACKGROUND: Early intra-abdominal infections (IAI) compromise short-term outcomes in bariatric surgery. The timely detection of IAI is challenging but essential to prevent major sequelae of such complications. C-reactive protein (CRP) is a reliable marker for detecting IAI after colorectal surgery. In bariatric surgery, data on CRP as a marker for IAI are limited, particularly for postoperative day one (POD1). OBJECTIVE: The objective of this study was to assess CRP on POD1 as a predictor for early IAI (within 7 days following surgery) in patients after laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (LRYGB). METHODS: Patients with bariatric surgery between 08/2010 and 06/2017 were included. The predictive capacity of CRP for early IAI was determined using a receiver operating characteristics (ROC) analysis. RESULTS: In 523 patients (68.5% female, LSG = 358, LRYGB = 165), 16 (3%) early IAI were observed. ROC analysis revealed a significant predictive capacity of POD1 CRP for early IAI, with a sensitivity and a specificity of 81.2 and 94.3%, respectively, at a CRP cut-off value of 70 mg/L. In patients with confirmed early IAI, 81.3% had a CRP level ≥ 70 mg/L (LSG 85.7%, LRYGB 77.8%). The negative predictive value for a CRP level < 70 mg/L was 99.4% overall and was 100 and 98% for LSG and LRYGB, respectively. CONCLUSION: In patients with a CRP level < 70 mg/L on POD1, early IAI can be excluded with high accuracy in bariatric patients. Thus, early postoperative CRP may be used to assess the risk of early IAI in enhanced recovery programs.

Functional Outcomes After Rectal Resection for Deep Infiltrating Pelvic Endometriosis: Long-term Results.

BACKGROUND: Curative management of deep infiltrating endometriosis requires complete removal of all endometriotic implants. Surgical approach to rectal involvement has become a topic of debate given potential postoperative bowel dysfunction and complications. OBJECTIVE: This study aims to assess long-term postoperative evacuation and incontinence outcomes after laparoscopic segmental rectal resection for deep infiltrating endometriosis involving the rectal wall. DESIGN: This is a retrospective study of prospectively collected data. SETTINGS: This single-center study was conducted at the University Hospital of Bern, Switzerland. PATIENTS: Patients with deep infiltrating endometriosis involving the rectum undergoing rectal resection from June 2002 to May 2011 with at least 24 months follow-up were included. MAIN OUTCOME MEASURES: Aside from endometriosis-related symptoms, detailed symptoms on evacuation (points: 0 (best) to 21 (worst)) and incontinence (0-24) were evaluated by using a standardized questionnaire before and at least 24 months after surgery. RESULTS: Of 66 women who underwent rectal resection, 51 were available for analyses with a median follow-up period of 86 months (range: 26-168). Forty-eight patients (94%) underwent laparoscopic resection (4% converted, 2% primary open), with end-to-end anastomosis in 41 patients (82%). Two patients (4%) had an anastomotic insufficiency; 1 case was complicated by rectovaginal fistula. Dysmenorrhea, nonmenstrual pain, and dyspareunia substantially improved (p < 0.001 for all comparisons). Overall evacuation score increased from a median of 0 (range: 0-11) to 2 points (0-15), p = 0.002. Overall incontinence also increased from 0 (range: 0-9) to 2 points (0-9), p = 0.003. LIMITATIONS: This study was limited by its retrospective nature and moderate number of patients. CONCLUSIONS: Laparoscopic segmental rectal resection for the treatment of deep infiltrating endometriosis including the rectal wall is associated with good results in endometriotic-related symptoms, although patients should be informed about possible postoperative impairments in evacuation and incontinence. However, its clinical impact does not outweigh the benefit that can be achieved through this approach. See Video Abstract at http://links.lww.com/DCR/A547.

Application of the 8th edition of the AJCC yTNM staging system shows improved prognostication in a single center cohort of esophageal carcinomas.

BACKGROUND: The 8th edition of the AJCC TNM staging system presents for the first time a specific classification for esophageal carcinomas treated with neoadjuvant therapy (yTNM8). In this single center study, we applied the novel staging system in a "real life" case series and compared the prognostic value of yTNM8 with the preceding 7th edition (TNM7). METHODS: Out of 272 consecutive esophageal carcinomas that were treated during a 15-year period in one surgical center, all 198 cases that had undergone neoadjuvant therapy were reviewed and classified according to TNM7 and yTNM8. RESULTS: 50 ypT0 cases that had no specific staging in TNM7 were included into stages I (ypT0N0M0; n = 42), IIIA (ypT0N1M0; n = 6), IVA (ypT0N3M0; n = 1) and IVB (ypT0N0M1; n = 1) in yTNM8. Both systems showed significant prognostic impact (p < 0.0001 each). yTNM8 was superior regarding prognostication with lower values for goodness-of-fit criteria (Akaike Information Criterion 1589.331 vs 1593.239; and Schwarz Bayesian Criterion 1605.487 vs.1619.088). However, in TNM7, stage IIB tumors had better prognosis than stage IIA tumors, and likewise, stage IIIA tumors better compared to stage II in yTNM8. CONCLUSIONS: yTNM8 allows accurate staging of esophageal carcinomas treated by neoadjuvant therapy, with slightly improved prognostication compared to TNM7. Additional data acquisition will be necessary for further improvement of staging for esophageal carcinomas after neoadjuvant treatment.