Faculty Bibliography

Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.

We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.

Irreversible Electroporation (IRE) is used to treat locally advanced cancers, commonly of the pancreas, liver, kidney, and other soft tissues. Precise eligibility for IRE should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of IRE technique and protocols is expected to improve safety, lead to reproducible outcomes, and facilitate further research into IRE. The present article provides a set of technical recommendations for the use of IRE in the treatment of locally advanced pancreatic cancer. J. Surg. Oncol. 2016;114:865-871. © 2016 2016 Wiley Periodicals, Inc.

BACKGROUND:Delta hemoglobin (ΔHb) is defined as the difference between the preoperative Hb and the lowest post-operative Hb level. We sought to define the impact of ΔHb relative to nadir Hb levels on the likelihood of transfusion, as well as characterize the impact of ΔHb and nadir Hb on morbidity among a large cohort of patients undergoing complex hepatopancreatobiliary (HPB) surgery. METHODS:Patients who underwent pancreatic or hepatic resection between January 1, 2009 and June 30, 2015 at Johns Hopkins Hospital were identified. Data on the perioperative ΔHb, nadir Hb, as well as blood utilization were obtained and analyzed. Multivariable logistic regression models were used to identify the factors associated with ΔHb and the impact of ΔHb on perioperative morbidity. A Bayesian model was used to evaluate the correlation of ΔHb and nadir Hb with the likelihood of transfusion, as well as the impact on morbidity. RESULTS:A total of 4363 patients who underwent hepatobiliary (n = 2200, 50.4 %) or pancreatic (n = 2163, 49.6 %) surgery were identified. More than one quarter of patients received at least one unit of packed red blood cells (PRBC) (n = 1187, 27.2 %). The median nadir Hb was 9.2 (IQR 7.9-10.5) g/dL resulting in an average ΔHb of 3.4 mg/dL (IQR 2.2-4.7) corresponding to 26.3 %. Both ΔHb and nadir Hb strongly influenced provider behavior with regards to use of transfusion. Among patients with the same nadir Hb, ΔHb was strongly associated with use of transfusion; among patients who had a nadir Hb ≤6 g/dL, the use of transfusion was only 17.9 % when the ΔHb = 10 % versus 49.1 and 80.9 % when the ΔHb was 30 or 50 %, respectively. Perioperative complications occurred in 584 patients (13.4 %) and were more common among patients with a higher value of ΔHb, as well as patients who received PRBC (both P < 0.001). CONCLUSIONS:The combination of the Hb trigger with ΔHb was associated with transfusion practices among providers. Larger ΔHb values, as well as receipt of transfusion, were strongly associated with risk of perioperative complication following HPB surgery.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The prognostic impact of primary colorectal cancer (CRC) location following resection of colorectal liver metastasis (CRLM) remains largely unknown. We sought to characterize the prognostic implications of primary tumor location among patients who underwent curative-intent hepatectomy for CRLM. METHODS:Tumors of the cecum, ascending, and transverse colon were defined as right-sided; tumors of the sigmoid flexure, descending, and sigmoid colon were defined as left-sided. Clinicopathologic and long-term survival data were collected and assessed using univariable and multivariable analyses. RESULTS:About 475 patients who underwent CRLM resection at a single institution were included; most patients had left-sided tumors (n = 284). Median and 5-year RFS was 20.2 months and 28.0%, respectively. Patients who had a left-sided primary tumor had a shorter RFS compared with patients who had a right-sided tumor (P = 0.01). Although site of and time to recurrence did not differ between the two groups (P > 0.05), patients with right-sided primary tumors were more likely to recur with advanced disease (i.e., ≥4 recurrent lesions) (P < 0.01). In turn, patients with right-sided tumors had both worse OS (P = 0.03) and worse survival after recurrence (P = 0.01). CONCLUSION/CONCLUSIONS:While patients with right-sided tumors experienced longer RFS, when these patients did recur following CRLM resection, disease extent was more advanced. In turn, OS following recurrence was shorter among patients with right-sided CRC. J. Surg. Oncol. 2016;114:803-809. © 2016 2016 Wiley Periodicals, Inc.

OBJECTIVE:We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). BACKGROUND:PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. METHODS:Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. RESULTS:Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). CONCLUSIONS:CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.

BACKGROUND:Retroperitoneal sarcomas are rare tumors that can be locally aggressive with high rates of recurrence. Given that data on survival in patients with retroperitoneal sarcomas are conflicting, we sought to use a nationwide cancer database to identify factors associated with survival in patients with retroperitoneal sarcomas. METHODS:The Surveillance, Epidemiology, and End Results database was utilized to identify patients with retroperitoneal sarcomas from 2002 to 2012. Univariable and multivariable survival analysis was performed using a generalized gamma parametric survival function. RESULTS:A total of 2,920 patients were included; overall 5- and 10-year survivals were 58.4% and 45.3%, respectively. On multivariable survival analysis, age, histologic type, grade, size, local extension, lymph node, and distant metastasis were associated with decreased survival (all P < .05). Patients undergoing operative resection survived 2.5 times longer (95% confidence interval: 2.0-3.0, P < .001) and those receiving radiation therapy 1.3 times longer (95% confidence interval: 1.1-1.6, P = .001), respectively. CONCLUSION:During the past decade, retroperitoneal sarcoma patients treated with radiation demonstrate longer survival compared with patients who did not receive radiation. Further study is needed to fully elucidate the mechanisms that underlie the radiation-related survival benefit observed in this study.