Search

Pancreatic adenocarcinoma is an aggressive disease marked by high rates of both local and distant failure. In the minority of patients with potentially resectable disease, multimodal treatment paradigms have allowed for prolonged survival in an increasingly larger pool of well-selected patients. Therefore, it is critical for surgical oncologists to be abreast of current guideline recommendations for both surgical management and multimodal therapy for pancreas cancer. We discuss these guidelines, as well as the underlying data supporting these positions, to offer surgical oncologists a framework for managing patients with pancreatic adenocarcinoma., (© 2023. Society of Surgical Oncology.)

Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC., (© 2023. The Author(s).)

Background: Whether formal regional lymph node (LN) evaluation is necessary for patients with appendiceal adenocarcinoma (AA) who have peritoneal metastases is unclear. The aim of this study was to evaluate the prognostic value of LN metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC)., Methods: A retrospective analysis of the US HIPEC collaborative, a multi-institutional consortium comprising 12 high-volume centers, was performed to identify patients with AA who underwent CRS-HIPEC with adequate LN sampling (≥ 12 LNs)., Results: Two hundred-fifty patients with AA who underwent CRS-HIPEC were included. Outcomes were compared between LN - and LN + disease. Baseline patient characteristics between groups were similar, with most patients undergoing complete cytoreduction (0/1: 86.0% vs. 76.8%, p = 0.08), respectively. More adverse tumor factors were found in patients with LN + disease, including poor differentiation, signet ring cells, and lymphovascular invasion. Multivariate analysis of overall survival (OS) found LN + disease was independently associated with worse OS (HR: 2.82 95%CI: 1.25-6.34, p = 0.01), even after correction for receipt of systemic therapy. On Kaplan-Meier analysis, median OS was lower in patients with LN + disease (25.9 months vs. 91.4 months, p < 0.01). LN + disease remained associated with poor OS following propensity score matching (HR: 4.98 95%CI: 1.72-14.40, p < 0.01) and in patients with PCI ≥ 20 (HR: 3.68 95%CI: 1.54-8.80, p < 0.01)., Conclusions: In this large multi-institutional study of patients with AA undergoing CRS-HIPEC, LN status remained associated with worse OS even in the setting of advanced peritoneal carcinomatosis. Formal LN evaluation should be performed for most patients with AA undergoing CRS-HIPEC., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Systemic therapy is an essential part of treatment for pancreatic ductal adenocarcinoma (PDAC). However, not all patients receive every cycle of chemotherapy and even if they do, the impact of reduced dose density (DD) on survival is not known., Patients and Methods: A single institutional prospective database was queried for patients with PDAC who underwent curative resection between 2009 and 2018. The primary outcome was DD, defined as the percentage of total planned chemotherapy actually received and associated survival., Results: Of the 126 patients included, 38.9% underwent a neoadjuvant approach, which was associated with a greater median number of completed chemotherapy cycles (5 cycles versus 4 cycles, p < 0.01) and a higher median total DD (93.0% versus 65.0%, p < 0.01), compared with an adjuvant treatment approach. In both groups, adjuvant chemotherapy completion rates were low, with only 55 patients completing all adjuvant cycles. After sequential survival analysis, patients who received a DD ≥ 80% had improved median overall survival (OS) (27.1 months versus 18.6 months, p = 0.01), compared with patients who achieved a DD < 80%. On multivariate Cox proportional-hazards modeling, only the presence of lymphovascular invasion (HR: 1.77, 95% CI: 1.04-2.99, p = 0.04) and DD < 80% (HR: 1.91, 95% CI: 1.23-3.00, p = 0.01) were associated with decreased OS., Conclusions: In this cohort study, patients who received ≥ 80% DD had significantly better OS. DD should be considered an important prognostic metric in pancreatic cancer, and strategies are needed to improve chemotherapy tolerance to improve patient outcomes., (© 2022. Society of Surgical Oncology.)

Background: Prognostication based on preoperative clinical factors is lacking in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). This study aims to determine the value of preoperative tumor markers as predictors of progression-free survival (PFS) and overall survival (OS) for patients with peritoneal carcinomatosis from a primary mucinous adenocarcinoma of the appendix (MACA)., Methods: We queried the United States HIPEC Collaborative, a database of patients with peritoneal carcinomatosis treated with CRS/HIPEC at twelve institutions between 2000 and 2017, identifying 409 patients with MACA. Multivariate analysis was used to identify independent predictors of disease progression. Subgroup analysis was conducted to evaluate the impact of tumor grade on the predictive value of tumor markers., Results: CA19-9 [HR 2.44, CI 1.2-3.4] emerged as an independent predictor of PFS while CEA [HR 4.98, CI 1.06-23.46] was independently predictive of OS (p <0.01). Tumor differentiation was the most potent predictor of both PFS (poorly differentiated vs well, [HR 4.5 CI 2.01-9.94]) and OS ([poorly differentiated vs well-differentiated: [HR 13.5, CI 3.16-57.78]), p <0.05. Among patients with combined CA19-9 elevation and poorly differentiated histology, 86% recurred within a year of CRS/HIPEC (p < 0.01). Similarly, the coexistence of CEA elevation and unfavorable histology led to the lowest survival rate at two years [36%, p < 0.01]. CA-125 was not predictive of PFS or OS., Conclusion: Elevated preoperative CA19-9 portends worse PFS, while elevated CEA predicts worse OS after CRS/HIPEC in patients with MACA. This study provides additional evidence that CA19-9 and CEA levels should be collected during standard preoperative bloodwork, while CA-125 can likely be omitted. Tumor differentiation, when added to preoperative tumor marker levels, provides powerful prognostic information. Prospective studies are required to confirm this association., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: Level 1 evidence for multimodal treatment of resectable gastric adenocarcinoma from the Intergroup 0116 (2001) and MAGIC (2006) trials demonstrated survival benefit of adjuvant chemoradiation (CRT) and perioperative chemotherapy, respectively. We evaluated the adoption of evidence-based treatment in the post-MAGIC era and its impact on survival., Methods: A total of 7058 patients with resectable gastric adenocarcinoma undergoing definitive surgical resection between 2004 and 2015 were analyzed using the National Cancer Database., Results: Over the study period, the proportion of patients receiving adjuvant CRT decreased from 19.1% to 9.1%, while perioperative chemotherapy increased from 1.9% to 28.6%. Utilization of perioperative chemotherapy surpassed adjuvant CRT in 2011. Evidence-based treatment (either perioperative chemotherapy or adjuvant CRT) had better overall survival (OS) than other treatments for clinical stage II-III patients (p < 0.05). On multivariate analysis of the whole study period, evidence-based treatments were associated with better OS (HR 0.67 [0.60-0.74], p < 0.05). Only 360/1262 (28.5%) patients in the perioperative chemotherapy group completed postoperative therapy, which was associated with improved OS (p < 0.05). For clinical stage III patients (n = 2402), only 806 (33.6%) received evidence-based treatment, while 487 (22.2%) underwent surgery alone. On multivariate analysis of these patients between 2010 and 2015, both perioperative chemotherapy (HR 0.49 [0.35-0.68]) and adjuvant CRT (HR 0.31 [0.21-0.44]) were associated with better OS than surgery alone (p < 0.05)., Conclusions: Since the INT-0116 and MAGIC trials, utilization of evidence-based treatments for resectable gastric adenocarcinoma has increased, with perioperative chemotherapy surpassing adjuvant CRT as the preferred practice. However, overall utilization of these regimens remains quite low nationally despite association with improved OS.

Background: Proximal (duodenal) small bowel adenocarcinomas have a worse prognosis than distal (jejuno-ileal) tumors, but differences in patient, tumor, and treatment factors between locations remain unclear., Methods: Patients in the National Cancer Database with surgically resected pathologic stage I-IV small bowel adenocarcinomas between 2004 and 2015 were analyzed. Clinical stage IV patients were excluded., Results: Proximal tumors (n = 3767) were more likely to be higher grade (OR 1.52, CI 1.22-1.85 for moderately; OR 1.83, CI 1.49-2.33 for poorly differentiated, P < 0.01 for both) and have positive lymph nodes (OR 2.04, CI 1.30-3.23, P < 0.01), while distal tumors (n = 3252) were likely to be larger (OR 1.31, CI 1.07-1.60 for size > 5 cm, P < 0.01). Proximal tumors were associated with worse overall survival (OS) and stage-specific survival compared with distal tumors (all P < 0.01). Cox regression analysis of the entire cohort showed worse survival with community versus academic cancer programs, higher comorbidity scores, pathologic stage IV, poorly differentiated histology, positive nodal or margin status, and proximal location, while female gender, larger tumor size, and chemotherapy predicted better survival. On separate Cox regression analyses of each location, neoadjuvant chemotherapy was associated with better OS in the proximal cohort (HR 0.70, CI 0.55-0.88, P < 0.01), while adjuvant chemotherapy was associated with better OS for both proximal (HR 0.49, CI 0.42-0.57, P < 0.01) and distal tumors (HR 0.68, CI 0.57-0.81, P < 0.01)., Conclusions: Proximal small bowel adenocarcinomas are associated with worse overall and stage-specific survival. This may be due to tumor biologic differences as proximal tumors were more likely to have higher grade. Future studies should further investigate differences between proximal and distal tumors to guide targeted treatment algorithms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Circumferential resection margin (CRM) status is an important predictor of outcomes after rectal cancer operation, and is influenced not only by operative technique, but also by incorporation of a multidisciplinary treatment strategy. This study sought to develop a risk-adjusted quality metric based on CRM status to assess hospital-level performance for rectal cancer operation., Study Design: We conducted a retrospective observational cohort study of 58,374 patients with resected stage I to III rectal cancer within 1,303 hospitals who were identified from the National Cancer Database (2010 to 2015). The number of observed cases with a positive CRM (≤ 1 mm) was divided by the risk-adjusted expected number of cases with positive CRM to form the observed-to-expected (O/E) ratio. Secondary endpoint was overall survival., Results: The overall rate of CRM positivity was 15.9%. Based on the O/E ratio for 1,139 hospitals, 147 (12.9%) and 103 (9.0%) were significantly worse and better performers, respectively. The majority of hospitals (n = 570) performed as expected. Positive CRMs using criteria of 0 mm and 0.1 to 1 mm were associated with a significantly shorter 5-year overall survival of 49% and 63.5% (hazard ratio 1.67; 95% CI, 1.57 to 1.76 and hazard ratio 1.19; 95% CI, 1.12 to 1.26) than negative CRM > 1 mm of 74.1% (all p < 0.001)., Conclusions: CRM-based O/E ratio is a robust hospital-based quality measure for rectal cancer operation. It allows facilities to compare their performance with that of centers of similar characteristics and helps identify underperforming, at-risk, and high-performing centers. National quality-improvement initiatives for rectal cancer should focus on ensuring high-quality data collection and providing ready access to risk-adjusted comparative metrics., (Copyright © 2020. Published by Elsevier Inc.)

Background and Objectives: The role of HER2 in patients with early stage/resected gastric cancer is controversial. This study investigates the prevalence and prognostic value of HER2 in patients undergoing curative intent resection for gastric adenocarcinoma., Methods: HER2 status was evaluated in 111 patients with gastric adenocarcinoma treated surgically between 1/00 and 6/11 with tissue available for analysis. Immunohistochemistry (IHC) for HER2 was graded by two blinded pathologists. IHC was scored as 0+/1+: negative, 2+: equivocal, and 3+: positive. Fluorescence in situ hybridization (FISH) for HER2 was performed on equivocal (2+) samples, and in cases of pathologist disagreement., Results: HER2 expression as measured by IHC was negative in 61 (55%), equivocal in 37 (33.3%), and positive in 13 (11.7%) cases. FISH was positive in 8 of 37 samples tested, for a total of 21 HER2-positive cases (18.9%, 95% CI 11.6-26.2%). Patients with HER2-positive tumors were less likely to have signet ring cell features (23.8% vs. 53.9%, P = 0.008). HER2 status was not associated with tumor size, location, perineural or lymphovascular invasion, margin status, nodal metastasis, or stage (P > 0.05). HER2 status was not associated with OS (P = 0.385)., Conclusions: HER2 amplification/over-expression is present in patients with resected gastric adenocarcinoma, but is not associated with the presence of adverse prognostic factors. Our results suggest HER2 is not prognostic for patients with resected gastric adenocarcinoma., (© 2013 Wiley Periodicals, Inc.)

Background: Excision repair cross-complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are associated with overall survival (OS) in several malignancies. Their expression patterns and prognostic value in resected gastric adenocarcinoma (GAC) are not known., Methods: In total, 109 patients who underwent resection for GAC between January 2000 and June 2011 had tissue available for analysis. The primary objective was to assess for the differential expression of ERCC1 and TS using immunohistochemistry. The secondary objective was to assess for the association between OS and the expression of ERCC1 and TS., Results: The median follow-up was 21.2 months, and the median OS was 28.8 months. Resected GAC exhibited differential expression of ERCC1 (high expression, 23%; n = 25) and TS (high expression, 43%; n = 47). ERCC1 and TS expression were not associated with OS. In a subset analysis of patients who received chemotherapy (n = 73), high ERCC1 expression was associated with decreased OS (16.7 months vs 53.8 months; P = 0.03). After controlling for known adverse pathologic features, high ERCC1 expression persisted as a negative prognostic factor in multivariate Cox regression analysis (hazard ratio, 2.5; 95% confidence interval, 1.03-6.0; P = .04). Conversely, in patients who underwent resection only (n = 35), high ERCC1 expression demonstrated a trend toward improved OS (40.4 months vs 12.7 months; P = .10); a positive prognostic influence also was present on multivariate analysis (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .03)., Conclusions: Resected GAC exhibited differential expression of TS and ERCC1. Among all patients, ERCC1 and TS expression levels were not associated with OS. High ERCC1 tumor expression was associated with decreased OS in the patients who received chemotherapy but was associated with increased OS in those who underwent surgery alone. ERCC1 expression had prognostic value in resected gastric cancer, and further investigation is warranted., (Copyright © 2013 American Cancer Society.)

Background: Feeding jejunostomy tubes (J-tube) are often placed during gastrectomy for cancer to decrease malnutrition and promote delivery of adjuvant therapy. We hypothesized that J-tubes actually are associated with increased complications and do not improve nutritional status nor increase rates of adjuvant therapy., Methods: One hundred thirty-two patients were identified from a prospectively maintained database that underwent gastric resection for gastric adenocarcinoma between 1/00 and 3/11 at one institution. Pre- and postoperative nutritional status and relevant intraoperative and postoperative parameters were examined., Results: Median age was 64 years (range 23-85). Forty-six (35%) underwent a total and 86 (65%) a subtotal gastrectomy. J-tubes were placed in 66 (50%) patients, 34 of whom underwent a subtotal and 32 a total gastrectomy. Preoperative nutritional status was similar between J-tube and no J-tube groups as measured by serum albumin (3.5 vs. 3.4 g/dL). Tumor grade, T, N, and overall stage were similar between groups. J-tube placement was associated with increased postop complications (59% vs. 41%, P = 0.04) and infectious complications (36% vs. 17%, P = 0.01), of which majority were surgical site infections. J-tubes were associated with prolonged length of stay (13 vs. 11 days; P = 0.05). There was no difference in postoperative nutritional status as measured by 30, 60, and 90-day albumin levels and the rate of receiving adjuvant therapy was similar between groups (J-tube: 61%, no J-tube: 53%, P = 0.38). Multivariate analyses revealed J-tubes to be associated with increased postop complications (HR: 4.8; 95% CI: 1.3-17.7; P = 0.02), even when accounting for tumor stage and operative difficulty and extent. Subset analysis revealed J-tubes to have less associated morbidity after total gastrectomy., Conclusion: J-tube placement after gastrectomy for gastric cancer may be associated with increased postoperative complications with no demonstrable advantage in receiving adjuvant therapy. Routine use of J-tubes after subtotal gastrectomy may not be justified, but may be selectively indicated in patients undergoing total gastrectomy. A prospective trial is needed to validate these results., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Tumor overexpression of excision repair cross-complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined., Methods: A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS)., Results: The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS., Conclusions: High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy., (Copyright © 2012 American Cancer Society.)

Objective and Background: Morbidity, mortality, and length of hospital stay after pancreaticoduodenectomy (PD) have significantly decreased over recent decades. Despite this progress, early readmission rates after PD have been reported as high as 50%. Few reports have delineated factors associated with readmission after PD., Methods: The medical records of 6 high-volume institutions were reviewed for patients who underwent PD between 2005 and 2010. Data collection included patient characteristics, medical comorbidities, and perioperative factors. Analysis included readmissions up to 90 days after PD., Results: A total of 1302 patients underwent PD across all institutions. The 30-day and 90-day readmission rates were 15% and 19%, respectively. The most common reasons for 30-day readmission included infectious complications (n = 65) and delayed gastric emptying (n = 29). The most common reasons for readmission after 90 days included wound infections and intra-abdominal abscess (n = 75) and failure to thrive (n = 38). On multivariate analysis, factors associated with higher readmission rates included a preoperative diagnosis of chronic pancreatitis, higher transfusion requirements, and postoperative complications including intra-abdominal abscess and pancreatic fistula (all P < 0.02). Factors not associated with higher readmission rates included advanced age, body mass index, cardiovascular/pulmonary comorbidities, diabetes, steroid use, Whipple type (standard vs pylorus preserving PD), preoperative endobiliary stenting, and vascular reconstruction., Conclusions: These multi-institutional data represent a large experience of PD without the biases typically of single center studies. Factors related to infection, nutritional status, and delayed gastric emptying were the most common reasons for readmission after PD. Postoperative complications including pancreatic fistula predicted higher rates of readmission.

Gastric adenocarcinoma is one of the most common causes of death worldwide. Surgical resection remains the mainstay of therapy, offering the only chance for complete cure. Resection is based on the principles of obtaining adequate margins, with the extent of lymphadenectomy remaining controversial. Neoadjuvant and adjuvant therapies are used to reduce local recurrence and improve long-term survival. This article reviews the literature and provides a summary of surgical management options and neoadjuvant/adjuvant therapies for gastric adenocarcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The premise that allogeneic red blood cell transfusion (RBCT) contributes to adverse oncologic outcomes after surgery remains controversial. We examined the effects of RBCT during and after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) on disease recurrence and survival., Methods: A prospective database of 220 patients undergoing PD for PDAC from 2000 to 2008 was reviewed and transfusion data collected. Univariate and multivariate analyses were performed for factors influencing RBCT, recurrence-free survival (RFS), and overall survival (OS). The effect of amount and timing (intraoperative vs. postoperative) of RBCT was analyzed., Results: One hundred forty-seven patients (67%) received RBCT: 70 (32%) received 1 to 2 units, and 77 (35%) received >2 units. Median RFS and OS for the entire cohort was 12 and 16 months, respectively. RBCT of >2 units was associated with reduced RFS (9 vs. 15 months; P = 0.033) and OS (14 vs. 20 months; P = 0.003). Stratified by timing of transfusion, postoperative RBCT was associated with shortened RFS and OS. Controlling for age, body mass index, comorbidities, tumor factors, and major complications, each incremental unit of postoperative RBCT was associated with reduced RFS (hazard ratio 1.10, 95% confidence interval 1.02-1.18) and OS (hazard ratio 1.08, 95% confidence interval 1.03-1.12). Low hemoglobin and presence of comorbidities were the only preoperative factors independently associated with RBCT., Conclusions: Allogeneic red blood cell transfusion after PD for PDAC is independently associated with earlier cancer recurrence and reduced survival, in particular when administered postoperatively and in larger quantities. Blood-conservation methods are especially indicated for patients with preoperative anemia and medical comorbidities.

Simple Summary: Treatment of pancreas ductal adenocarcinoma (PDAC) remains challenging due to the late stage of presentation, limited efficacy of cytotoxic chemotherapies, and aggressive tumor biology. Novel therapeutic targets are desperately needed. The voltage-gated potassium channel, Kv1.3, is one such unique target. It has been extensively studied in many cancers but less is known in pancreas cancer. In this study, we evaluated the tissue expression of Kv1.3 in resected PDAC and tumor inhibition using novel Kv1.3 inhibitors developed by our group (PCARBTP and PAPTP) with cytotoxic chemotherapies. We found that Kv1.3 is expressed in early stage, non-metastatic, resectable pancreas cancer specimens. Treatment with novel mitochondrial Kv1.3 inhibitors resulted in 95% reduced tumor growth when combined with cytotoxic chemotherapies. This near complete eradication of tumors using this treatment strategy shows that Kv1.3 represents an innovative therapeutic target for pancreas cancer therapy. Pancreas ductal adenocarcinoma (PDAC) is one the most aggressive cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in tumor reductions of 87% and 70%, respectively. When combined with clinically used Gemcitabine plus Abraxane (albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the antioxidant system. In contrast, tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be a novel, effective treatment for PDAC. [ABSTRACT FROM AUTHOR]

Differences in clinical staging and survival among pancreatic head, body, and tail cancers are not well defined. We aim to identify the prognostic relevance of primary tumor location in patients undergoing treatment for pancreatic ductal adenocarcinoma (PDAC). The National Cancer Database was used to identify patients with PDAC from 1998 to 2011 (n = 175,556). Patients were categorized by primary tumor site into head (67.5%, n = 118,343), body (15.5%, n = 27,218), and tail (17.0%, n = 29,885) groups. Univariate and Cox regression analyses were used to determine covariates associated with overall survival (OS). Patients with head PDAC presented with earlier stage disease (39.2% Stage I/II versus 19.7% versus 16.0%, P < 0.001) and underwent resection more often (27.9% versus 10.7% versus 17.0%, P < 0.001) than those with body or tail tumors. Of surgically resected PDAC, those localized to the head had advanced pathologic stage (84.8% stage II/III versus 66.6% versus 65.6%, P < 0.001), higher nodal positivity (64.9% versus 45.8% versus 45%, P < 0.001), and worse tumor grade (35.9% poorly differentiated versus 29.5% versus 27.8%, P < 0.001). Despite increased utilization of adjuvant therapies (54.4% versus 45.6% versus 42.0%, P < 0.001), patients with head PDAC had inferior OS compared with those with body and tail tumors (P < 0.001). When examining patients with PDAC undergoing resection, tumor localization to the head is associated with improved resectability because they present earlier. Of resected PDACs, however, those localized to the head have worse OS compared with body and tail tumors. This discrepancy may represent a combination of lead time and selection biases and biologic differences between tumor sites. [ABSTRACT FROM AUTHOR]