Bradley Krasnick

Assessing the impact of common bile duct resection in the surgical management of gallbladder cancer.

Although radical re‐resection for gallbladder cancer (GBC) has been advocated, the optimal extent of re‐resection remains unknown. The current study aimed to assess the impact of common bile duct (CBD) resection on survival among patients undergoing surgery for GBC.

Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium

Curative‐intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection.

Nomogram predicting the risk of recurrence after curative-intent resection of primary non-metastatic gastrointestinal neuroendocrine tumors: An analysis of the U.S. Neuroendocrine Tumor Study Group

The risk of recurrence after resection of non‐metastatic gastro‐entero‐pancreatic neuroendocrine tumors (GEP‐NET) is poorly defined. We developed/validated a nomogram to predict risk of recurrence after curative‐intent resection.

Routine port‐site excision in incidentally discovered gallbladder cancer is not associated with improved survival: A multi‐institution analysis from the US Extrahepatic Biliary Malignancy Consortium

Current data on the utility of port‐site excision (PSE) during re‐resection for incidentally discovered gallbladder cancer (IGBC) in the US are conflicting and limited to single‐institution series.

Gallbladder cancer presenting with jaundice: Uniformly fatal or still potentially curable?

336 Background: The prognosis of patients with gallbladder cancer (GBC) who present with jaundice has historically been considered dismal, however recent Eastern literature has demonstrated that surgical resection can be associated with long-term survival. The objective of this study was to utilize a contemporary, Western, multi-institutional dataset to examine the prognostic significance of preoperative jaundice on short- and long-term outcomes after GBC resection. Methods: Patients with GBC managed surgically from 2000 to 2015 in 10 academic institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium were stratified based on the presence of preoperative jaundice (bilirubin > 3 mg/ml or requiring preoperative biliary drainage). Postoperative morbidity, mortality, and overall survival were compared. Results: Of 449 patients with GBC evaluated for resection, 301 (67%) eventually underwent curative-intent resection. Resectability for cure was much lower in patients with preoperative ja...

Influence of carcinoid syndrome on the clinical characteristics and outcomes of patients with gastroenteropancreatic neuroendocrine tumors undergoing operative resection

Background: The incidence, clinical characteristics, and long‐term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized. Methods: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8‐institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease‐free survival were compared among patients with and without carcinoid syndrome. Results: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative‐intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease‐free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64–1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis. Conclusion: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease‐free survival or overall survival.

Margin status and long-term prognosis of primary pancreatic neuroendocrine tumor after curative resection: Results from the US Neuroendocrine Tumor Study Group

Background: The impact of margin status on resection of primary pancreatic neuroendocrine tumors has been poorly defined. The objectives of the present study were to determine the impact of margin status on long‐term survival of patients with pancreatic neuroendocrine tumors after curative resection and evaluate the impact of reresection to obtain a microscopically negative margin. Methods: Patients who underwent curative‐intent resection for pancreatic neuroendocrine tumors between 2000 and 2016 were identified at 8 hepatobiliary centers. Overall and recurrence‐free survival were analyzed relative to surgical margin status using univariable and multivariable analyses. Results: Among 1,020 patients, 866 (84.9%) had an R0 (>1 mm margin) resection, whereas 154 (15.1%) had an R1 (≤1 mm margin) resection. R1 resection was associated with a worse recurrence‐free survival (10‐year recurrence‐free survival, R1 47.3% vs R0 62.8%, hazard ratio 1.8, 95% confidence interval 1.2–2.7, P = .002); residual tumor at either the transection margin (R1t) or the mobilization margin (R1m) was associated with increased recurrence versus R0 (R1t versus R0: hazard ratio 1.8, 95% confidence interval 1.0–3.0, P = .033; R1m versus R0: hazard ratio 1.3, 95% confidence interval 1.0–1.7, P = .060). In contrast, margin status was not associated with overall survival (10‐year overall survival, R1 71.1% vs R0 71.8%, P = .392). Intraoperatively, 539 (53.6%) patients had frozen section evaluation of the surgical margin; 49 (9.1%) patients had a positive margin on frozen section analysis; 38 of the 49 patients (77.6%) had reresection, and a final R0 (secondary R0) margin was achieved in 30 patients (78.9%). Extending resection to achieve an R0 status remained associated with worse overall survival (hazard ratio 3.1, 95% confidence interval 1.6–6.2, P = .001) and recurrence‐free survival (hazard ratio 2.6, 95% confidence interval 1.4–5.0, P = .004) compared with primary R0 resection. On multivariable analyses, tumor‐specific factors, such as cellular differentiation, perineural invasion, Ki‐67 index, and major vascular invasion, rather than surgical margin, were associated with long‐term outcomes. Conclusion: Margin status was not associated with long‐term survival. The reresection of an initially positive surgical margin to achieve a negative margin did not improve the outcome of patients with pancreatic neuroendocrine tumors. Parenchymal‐sparing pancreatic procedures for pancreatic neuroendocrine tumors may be appropriate when feasible.

IL23 and TGF-ß diminish macrophage associated metastasis in pancreatic carcinoma

The precise role of tumor associated macrophages remains unclear in pancreatic ductal adenocarcinoma (PDAC) while TGF-ß has an unclear role in metastases formation. In order to understand the role of IL23, an interleukin associated with macrophage polarization, we investigated IL23 in the context of TGF-ß expression in PDAC. We hypothesized that IL23 expression is associated with metastatic development and survival in PDAC. We investigated IL23 and TGF-ß protein expression on resected PDAC patient tumor sections who were divided into short-term (<12 months) survivors and long-term (>30 months) survivors. Panc-1 cells treated with IL23, TGF-ß, macrophages, or combinations thereof, were orthotopically implanted into NSG mice. Patients in the long-term survivor group had higher IL23 protein expression (P = 0.01). IL23 expression was linearly correlated with TGF-ß expression in patients in the short-term survivor group (P = 0.038). Macrophages induce a higher rate of PDAC metastasis in the mouse model (P = 0.02), which is abrogated by IL23 and TGF-ß treatment (P < 0.001). Macrophages serve a critical role in PDAC tumor growth and metastasis. TGF-ß contributes to a less tumorigenic TME through regulation of macrophages. Macrophages increases PDAC primary tumor growth and metastases formation while combined IL23 and TGF-ß pre-treatment diminishes these processes.

Recruitment of CCR2+ tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer

ABSTRACT The tumor microenvironment (TME) represents a significant barrier to creating effective therapies for metastatic colorectal cancer (mCRC). In several malignancies, bone marrow derived CCR2+ inflammatory monocytes (IM) are recruited to the TME by neoplastic cells, where they become immunosuppressive tumor associated macrophages (TAM). Here we report that mCRC expression of the chemokine CCL2 facilitates recruitment of CCR2+ IM from the bone marrow to the peripheral blood. Immune monitoring of circulating monocytes in patients with mCRC found this influx was a prognostic biomarker and correlated with worse clinical outcomes. At the metastatic site, mCRC liver tumors were heavily infiltrated by TAM, which displayed a robust ability to dampen endogenous anti-tumor lymphocyte activity. Using a murine model of mCRC that recapitulates these findings from human disease, we show that targeting CCR2 reduces TAM accumulation in liver metastasis and restores anti-tumor immunity. Additional quantitative analysis of hepatic metastatic tumor burden and treatment efficacy found that administration of a small molecule CCR2 inhibitor (CCR2i) improves chemotherapeutic responses and increases overall survival in mice with mCRC liver tumors. Our study suggests that targeting the CCL2/CCR2 chemokine axis decreases TAM at the metastatic site, disrupting the immunosuppressive TME and rendering mCRC susceptible to anti-tumor T-cell responses.

Association of perioperative transfusion with survival and recurrence after resection of gallbladder cancer: A 10-institution study from the US Extrahepatic Biliary Malignancy Consortium

Perioperative blood transfusion is associated with poor outcomes in several malignancies. Its effect in gallbladder cancer (GBC) is unknown.