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Pancreatic Neoplasms: HELP
Articles by Richard A. Burkhart
Based on 24 articles published since 2010
(Why 24 articles?)
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Between 2010 and 2020, Richard Burkhart wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature. 2018

Groot, Vincent P / Thakker, Sameer S / Gemenetzis, Georgios / Noë, Michaël / Javed, Ammar A / Burkhart, Richard A / Noveiry, Behnoud B / Cameron, John L / Weiss, Matthew J / VandenBussche, Christopher J / Fishman, Elliot K / Hruban, Ralph H / Wolfgang, Christopher L / Lennon, Anne Marie / He, Jin. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jhe11@jhmi.edu. ·HPB (Oxford) · Pubmed #29530477.

ABSTRACT: BACKGROUND: Lymphoepithelial cysts (LECs) are rare pancreatic cystic lesions. Since LECs are benign, preoperative diagnosis is important to differentiate from a cystic neoplasm and avoid unnecessary surgery. The aim of this study was to identify clinical, radiographic and cytopathologic features associated with LECs. METHODS: A retrospective review was performed of patients diagnosed with LEC between 1995 and 2017 at our hospital. Clinicopathologic and radiographic imaging features were documented. RESULTS: Of 29 patients with pancreatic LEC, 22 underwent surgical resection. The majority were male (n = 24) with a median age of 55 years (range, 21-74). During the evaluation, all patients underwent a CT, with endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) biopsy (n = 22) and/or MRI/MRCP (n = 11) performed in a smaller number of patients. A combination of exophytic tumor growth on imaging and the presence of specific cytomorphologic features on the EUS-FNA cytology biopsy led to the correct diagnosis of LEC and prevention of unnecessary surgery in 7 patients. DISCUSSION: Differentiating LECs from premalignant pancreatic cystic neoplasms remains difficult. Findings of an exophytic growth pattern of the lesion on abdominal imaging and the presence of specific cytomorphologic features in the EUS-FNA biopsy could help clinicians diagnose LEC preoperatively.

2 Review Geographical variation and trends in outcomes of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessel preservation: A meta-analysis. 2017

Yongfei, Hua / Javed, Ammar A / Burkhart, Richard / Peters, Niek A / Hasanain, Alina / Weiss, Matthew J / Wolfgang, Christopher L / He, Jin. ·Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA; Department of Surgery, Lihuili Eastern Hospital, Ningbo, China. · Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. · Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA; University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. · Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address: jhe11@jhmi.edu. ·Int J Surg · Pubmed #28735894.

ABSTRACT: BACKGROUND: Distal pancreatectomy (DP) is performed to treat tumors of the pancreatic body and tail. Traditionally, splenectomy is performed with a DP, however, laparoscopic spleen-preserving DP (SPDP) using Warshaw's (splenic vessels ligation) or Kimura's (splenic vessels preservation) techniques have been reported. The clinical benefits of using either technique remain unclear. In this study, we conducted a meta-analysis to compare the clinical outcomes of patients undergoing Warshaw's and Kimura SPDP. This is the first study to evaluate the geographical variation in outcomes of Warshaw's and Kimura SPDP. METHODS: Databases of PubMed, Embase, and Cochrane library were used to identify studies reporting Warshaw's and Kimura SPDP. Clinical outcomes were compared. Pooled odds risk and weighted mean difference with 95% confidence interval were calculated using random effect models. RESULTS: Fourteen non-randomized controlled studies involving 945 patients met our selection criteria. 301 (31.9%) patients underwent Warshaw's SPDP; 644 (68.1%) underwent Kimura SPDP. Compared to Warshaw's SPDP, patients undergoing Kimura SPDP had a lower incidence of post-operative complications including spleen infarction (OR = 9.64, 95% CI = 5.79 to 16.05, P < 0.001) and gastric varices (OR = 11.88, 95% CI = 5.11 to 27.66, P < 0.001). The length of surgery was significantly shorter for Warshaw's SPDP (WMD = -18.12, 95%CI = -26.52 to -9.72, p < 0.001). Decreased blood loss was reported for patients undergoing Warshaw's SPDP (WMD = -59.72, 95%CI = -102.01 to -17.43, p = 0.006). There were no differences between the two groups' rates of conversion to an open procedure (P = 0.35), postoperative pancreatic fistula (P = 0.71), need for reoperation (P = 0.25), and length of hospital stay (P = 0.38). CONCLUSION: Both Warshaw's and Kimura are safe SPDP techniques. These data suggest Kimura SPDP is the preferred technique due to less risk of splenic infarct and gastric varices. Despite evidence of regional variation in volume performed (between Kimura and Warshaw's), there are no statistically significant differences in outcomes between these techniques.

3 Article Disparities in the Use of Chemotherapy in Patients with Resected Pancreatic Ductal Adenocarcinoma. 2019

Wright, Michael J / Overton, Heidi N / Teinor, Jonathan A / Ding, Ding / Burkhart, Richard A / Cameron, John L / He, Jin / Wolfgang, Christopher L / Weiss, Matthew J / Javed, Ammar A. ·The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, 600 N. Wolfe St. / Blalock 1222A, Baltimore, MD, 2I287, USA. · The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, 600 N. Wolfe St. / Blalock 1222A, Baltimore, MD, 2I287, USA. ajaved1@jhmi.edu. ·J Gastrointest Surg · Pubmed #31270718.

ABSTRACT: BACKGROUND: Introduction of effective systemic therapies for pancreatic ductal adenocarcinoma (PDAC) has demonstrated survival benefit. However, chemotherapy remains underutilized in these patients. We sought to investigate the implications of disparities on the trends in utilization of chemotherapy. METHODS: A retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database identified patients who underwent surgical resection for PDAC from 1998 to 2014. Clinicopathologic, demographic, racial, and geographical factors were analyzed to assess associations with receipt of chemotherapy and disease-specific survival. RESULTS: A total of 15,585 patients were included in the study. A majority (N = 9953, 63.9%) received chemotherapy. Factors associated with poorer odds of receiving chemotherapy included older age (p < 0.001), African-American race (p = 0.003), and living in the Southwest region of the USA (p < 0.001). Married patients were at higher odds of receiving chemotherapy (all p < 0.001). Receipt of chemotherapy was independently associated with improved disease-specific survival (p < 0.001). CONCLUSIONS: Receipt of chemotherapy results in an improved survival in patients with resected PDAC. Demographic, racial, and geographic factors influence the rate of receipt of chemotherapy. Despite prior reports, these trends have not changed over the recent decades.

4 Article Surgical Outcomes After Pancreatic Resection of Screening-Detected Lesions in Individuals at High Risk for Developing Pancreatic Cancer. 2019

Canto, Marcia Irene / Kerdsirichairat, Tossapol / Yeo, Charles J / Hruban, Ralph H / Shin, Eun Ji / Almario, Jose Alejandro / Blackford, Amanda / Ford, Madeline / Klein, Alison P / Javed, Ammar A / Lennon, Anne Marie / Zaheer, Atif / Kamel, Ihab R / Fishman, Elliot K / Burkhart, Richard / He, Jin / Makary, Martin / Weiss, Matthew J / Schulick, Richard D / Goggins, Michael G / Wolfgang, Christopher L. ·Division of Gastroenterology and Hepatology, Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Blalock 407, Baltimore, MD, 21287, USA. mcanto1@jhmi.edu. · Division of Gastroenterology and Hepatology, Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Blalock 407, Baltimore, MD, 21287, USA. · Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Surgery, University of Colorado School of Medicine, Denver, CO, USA. ·J Gastrointest Surg · Pubmed #31197699.

ABSTRACT: BACKGROUND: Screening high-risk individuals (HRI) can detect potentially curable pancreatic ductal adenocarcinoma (PDAC) and its precursors. We describe the outcomes of high-risk individuals (HRI) after pancreatic resection of screen-detected neoplasms. METHODS: Asymptomatic HRI enrolled in the prospective Cancer of the Pancreas Screening (CAPS) studies from 1998 to 2014 based on family history or germline mutations undergoing surveillance for at least 6 months were included. Pathologic diagnoses, hospital length of stay, incidence of diabetes mellitus, operative morbidity, need for repeat operation, and disease-specific mortality were determined. RESULTS: Among 354 HRI, 48 (13.6%) had 57 operations (distal pancreatectomy (31), Whipple (20), and total pancreatectomy (6)) for suspected pancreatic neoplasms presenting as a solid mass (22), cystic lesion(s) (25), or duct stricture (1). The median length of stay was 7 days (IQR 5-11). Nine of the 42 HRI underwent completion pancreatectomy for a new lesion after a median of 3.8 years (IQR 2.5-7.6). Postoperative complications developed in 17 HRI (35%); there were no perioperative deaths. New-onset diabetes mellitus after partial resection developed in 20% of HRI. Fourteen PDACs were diagnosed, 11 were screen-detected, 10 were resectable, and 9 had an R0 resection. Metachronous PDAC developed in remnant pancreata of 2 HRI. PDAC-related mortality was 4/10 (40%), with 90% 1-year survival and 60% 5-year survival, respectively. CONCLUSIONS: Screening HRI can detect PDAC with a high resectability rate. Surgical treatment is associated with a relatively short length of stay and low readmission rate, acceptable morbidity, zero 90-day mortality, and significant long-term survival. CLINICAL TRIAL REGISTRATION NUMBER: NCT2000089.

5 Article Surgical Resection of 78 Pancreatic Solid Pseudopapillary Tumors: a 30-Year Single Institutional Experience. 2019

Wright, Michael J / Javed, Ammar A / Saunders, Tyler / Zhu, Yayun / Burkhart, Richard A / Yu, Jun / He, Jin / Cameron, John L / Makary, Martin A / Wolfgang, Christopher L / Weiss, Matthew J. ·The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. · The John L. Cameron Division of Hepatobiliary and Pancreatic Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. mweiss5@jhmi.edu. · Pancreas Cancer Multidisciplinary Clinic, Liver Cancer Multidisciplinary Clinic, Surgical Oncology Fellowship, Miller Coulson Academy of Clinical Excellence, Johns Hopkins University, 600 N. Wolfe St. / Blalock 685, Baltimore, MD, 21287, USA. mweiss5@jhmi.edu. ·J Gastrointest Surg · Pubmed #31073801.

ABSTRACT: BACKGROUND: Solid pseudopapillary tumors (SPTs) are rare, benign tumors of the pancreas that present as heterogeneous masses. We sought to evaluate the short- and long-term outcomes of surgical resected SPTs. Patients managed via initial surveillance were compared to those who underwent upfront resection. METHODS: A prospectively maintained institutional database was used to identify patients who underwent surgical resection for a SPT between 1988 and 2018. Data on clinicopathological features and outcomes were collected and analyzed. RESULTS: Seventy-eight patients underwent surgical resection for SPT during the study period. The mean age was 34.0 ± 14.6 years and a majority were female (N = 67, 85.9%) and white (N = 46, 58.9%). Thirty patients (37.9%) were diagnosed incidentally. Imaging-based presumed diagnosis was SPT in 49 patients (62.8%). A majority were located in the body or tail of the pancreas (N = 47, 60.3%), and 48 patients (61.5%) underwent a distal pancreatectomy. The median tumor size was 4.0 cm (IQR, 3.0-6.0), nodal disease was present in three patients (3.9%), and R0 resection was performed in all patients. No difference was observed in clinicopathological features and outcomes between patients who were initially managed via surveillance and those who underwent upfront resection. None of the patients under surveillance had nodal disease or metastasis at the time of resection; however, one of them developed recurrence of disease 95.1 months after resection. At a median follow-up of 36.1 months (IQR, 8.1-62.1), 77 (%) patients were alive and one patient (1.3%) had a recurrence of disease at 95.1 months after resection and subsequently died due to disease. CONCLUSIONS: SPTs are rare pancreatic tumors that are diagnosed most frequently in young females. While a majority are benign and have an indolent course, malignant behavior has been observed. Surgical resection can result in exceptional outcomes.

6 Article Recurrence after neoadjuvant therapy and resection of borderline resectable and locally advanced pancreatic cancer. 2019

Groot, Vincent P / Blair, Alex B / Gemenetzis, Georgios / Ding, Ding / Burkhart, Richard A / Yu, Jun / Borel Rinkes, Inne H M / Molenaar, I Quintus / Cameron, John L / Weiss, Matthew J / Wolfgang, Christopher L / He, Jin. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jhe11@jhmi.edu. ·Eur J Surg Oncol · Pubmed #31023560.

ABSTRACT: INTRODUCTION: The incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. MATERIALS AND METHODS: Patients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. RESULTS: For 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). CONCLUSION: Despite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

7 Article Pancreatic Nerve Sheath Tumors: a Single Institutional Series and Systematic Review of the Literature. 2019

Javed, Ammar A / Wright, Michael J / Hasanain, Alina / Chang, Kevin / Burkhart, Richard A / Hruban, Ralph H / Thompson, Elizabeth / Fishman, Elliot K / Cameron, John L / He, Jin / Wolfgang, Christopher L / Weiss, Matthew J. ·Departments of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. · Departments of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. · Departments of Radiology, Johns Hopkins Hospital, Baltimore, MD, USA. · Departments of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. mweiss5@jhmi.edu. · , Baltimore, USA. mweiss5@jhmi.edu. ·J Gastrointest Surg · Pubmed #30941687.

ABSTRACT: INTRODUCTION: Improvement in imaging has resulted in frequent diagnosis of benign and premalignant pancreatic tumors. Pancreatic nerve sheath (PNS) tumors are one of the rarest pancreatic tumors. Literature on PNS is limited and their biology is poorly understood. Here, we report the largest series of PNS tumors to date and review the literature to evaluate the current data available on PNS tumors. METHODS: An institutional database was used to identify patients who underwent resection for PNS tumors. Clinicopathological characteristics and outcomes of these patients were reported. Furthermore, a review of literature was performed. RESULTS: From January 1994 through December 2016, seven patients underwent resection for PNS tumors. The median age was 57.7 years (IQR, 44.9-61.9) and the sex was approximately equally distributed (male = 4; 57.1%). Three (42.9%) patients were diagnosed incidentally and six (85.7%) were misdiagnosed as having other pancreatic tumors. The median tumor size was 2.1 (IQR 1.8-3.0) cm and six (85.7%) had no nodal disease. At a median follow-up of 15.5 (IQR 13.7-49.3) months, six patients were alive without evidence of disease and one patient was lost to follow-up. The literature review identified 49 studies reporting 54 patients with PNS tumors. Forty-six were misdiagnosed as having other pancreatic tumors. The median tumor size was 3.6 (range 1-20) cm, nodal disease was present in six patients (22.2%), and no patient had distant metastatic disease. At the time of last follow-up, all patients were free of disease. CONCLUSION: This is the largest single institution series on PNS tumors reported to date. These tumors are rare and are often misdiagnosed, given their radiological characteristics. PNS tumors have a benign course of disease and surgical resection results in favorable long-term outcomes.

8 Article Outcome of Patients with Borderline Resectable Pancreatic Cancer in the Contemporary Era of Neoadjuvant Chemotherapy. 2019

Javed, Ammar A / Wright, Michael J / Siddique, Ayat / Blair, Alex B / Ding, Ding / Burkhart, Richard A / Makary, Martin / Cameron, John L / Narang, Amol / Herman, Joseph / Zheng, Lei / Laheru, Daniel / Weiss, Matthew J / Wolfgang, Christopher / He, Jin. ·Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 614, Baltimore, MD, 21287, USA. · The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 614, Baltimore, MD, 21287, USA. jhe11@jhmi.edu. · The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jhe11@jhmi.edu. ·J Gastrointest Surg · Pubmed #30242644.

ABSTRACT: INTRODUCTION: Approximately, 20% of patients with pancreatic ductal adenocarcinoma have resectable disease at diagnosis. Given improvements in locoregional and systemic therapies, some patients with borderline resectable pancreatic cancer (BRPC) can now undergo successful resection. The outcomes of patients with BRPC after neoadjuvant therapy remain unclear. METHODS: A prospectively maintained single-institution database was utilized to identify patients with BRPC who were managed at the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC) between 2013 and 2016. BRPC was defined as any tumor that presented with radiographic evidence of the involvement of the portal vein (PV) or superior mesenteric vein (SMV) that was deemed to be technically resectable (with or without the need for reconstruction), or the abutment (< 180° involvement) of the common hepatic artery (CHA) or superior mesenteric artery (SMA), in the absence of involvement of the celiac axis (CA). We collected data on treatment, the course of the disease, resection rate, and survival. RESULTS: Of the 866 patients evaluated at the PMDC during the study period, 151 (17.5%) were staged as BRPC. Ninety-six patients (63.6%) underwent resection. Neoadjuvant chemotherapy was administered to 142 patients (94.0%), while 78 patients (51.7%) received radiation therapy in the neoadjuvant setting. The median overall survival from the date of diagnosis, of resected BRPC patients, was 28.8 months compared to 14.5 months in those who did not (p < 0.001). Factors associated with increased chance of surgical resection included lower ECOG performance status (p = 0.011) and neck location of the tumor (p = 0.001). Forty-seven patients with BRPC (31.1%) demonstrated progression of disease; surgical resection was attempted and aborted in 12 patients (7.9%). Eight patients (5.3%) were unable to tolerate chemotherapy; six had disease progression and two did not want to pursue surgery. Lastly, four patients (3.3%) were conditionally unresectable due to medical comorbidities at the time of diagnosis due to comorbidities and failed to improve their status and subsequently had progression of the disease. CONCLUSION: After initial management, 31.1% of patients with BRPC have progression of disease, while 63.6% of all patients successfully undergo resection, which was associated with improved survival. Factors associated with increased likelihood of surgical resection include lower ECOG performance status and tumor location in the neck.

9 Article Circulating Tumor Cells Dynamics in Pancreatic Adenocarcinoma Correlate With Disease Status: Results of the Prospective CLUSTER Study. 2018

Gemenetzis, Georgios / Groot, Vincent P / Yu, Jun / Ding, Ding / Teinor, Jonathan A / Javed, Ammar A / Wood, Laura D / Burkhart, Richard A / Cameron, John L / Makary, Martin A / Weiss, Matthew J / He, Jin / Wolfgang, Christopher L. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. · The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Surgery, UMC Utrecht Cancer Center, Utrecht, The Netherlands. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #30080739.

ABSTRACT: OBJECTIVES: Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes correlate with overall survival in patients with pancreatic ductal adenocarcinoma (PDAC). Herein, we report results of a prospective observational study on CTCs dynamics to assess their clinical significance. METHODS: The CLUSTER study is a prospective longitudinal study on PDAC CTCs dynamics (NCT02974764). Multiple peripheral blood samples were collected from 200 consecutively enrolled patients with presumed PDAC diagnosis. CTCs were isolated and characterized by immunofluorescence. RESULTS: Two major CTCs subtypes were identified in PDAC patients: epithelial CTCs (eCTCs) and epithelial/mesenchymal CTCs (mCTCs). Patients who received neoadjuvant chemotherapy had significantly lower total CTCs (tCTCs, P = 0.007), eCTCs (P = 0.007), and mCTCs (P = 0.034), compared with untreated patients eligible for upfront resection. Surgical resection of the primary tumor resulted in significant reduction, but not disappearance, of CTCs burden across all cell subtypes (P < 0.001). In multivariable logistic regression analysis, preoperative numbers of all CTCs subpopulations were the only predictors of early recurrence within 12 months from surgery in both chemo-naive and post-neoadjuvant patients (odds ratio 5.9 to 11.0). Alterations in CTCs were also observed longitudinally, before disease recurrence. A risk assessment score based on the difference of tCTCs increase accurately identified disease recurrence within the next 2 months, with an accuracy of 75% and 84% for chemo-naive and post-neoadjuvant patients, respectively. CONCLUSION: We report novel findings regarding CTCs from a large prospective cohort of PDAC patients. CTCs dynamics reflect progression of disease and response to treatment, providing important information on clinical outcomes, not available by current tumor markers and imaging.

10 Article Implications of the Pattern of Disease Recurrence on Survival Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. 2018

Groot, Vincent P / Gemenetzis, Georgios / Blair, Alex B / Ding, Ding / Javed, Ammar A / Burkhart, Richard A / Yu, Jun / Borel Rinkes, Inne H / Molenaar, I Quintus / Cameron, John L / Fishman, Elliot K / Hruban, Ralph H / Weiss, Matthew J / Wolfgang, Christopher L / He, Jin. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. · Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. jhe11@jhmi.edu. ·Ann Surg Oncol · Pubmed #29948425.

ABSTRACT: BACKGROUND: After radical resection of pancreatic ductal adenocarcinoma (PDAC), approximately 80% of patients will develop disease recurrence. It remains unclear to what extent the location of recurrence carries prognostic significance. Additionally, stratifying the pattern of recurrence may lead to a deeper understanding of the heterogeneous biological behavior of PDAC. OBJECTIVE: The aim of this study was to characterize the relationship of recurrence patterns with survival in patients with resected PDAC. METHODS: This single-center cohort study included patients undergoing pancreatectomy at the Johns Hopkins Hospital between 2000 and 2013. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. Sites of first recurrence were stratified into five groups and survival outcomes were estimated using Kaplan-Meier curves. The association of specific recurrence locations with overall survival (OS) was analyzed using Cox proportional-hazards models with and without landmark analysis. RESULTS: Accurate follow-up data were available for 877 patients, 662 (75.5%) of whom had documented recurrence at last follow-up. Patients with multiple-site (n = 227, 4.7 months) or liver-only recurrence (n = 166, 7.2 months) had significantly worse median survival after recurrence when compared with lung- (n = 93) or local-only (n = 158) recurrence (15.4 and 9.7 months, respectively). On multivariable analysis, the unique recurrence patterns had variable predictive values for OS. Landmark analyses, with landmarks set at 12, 18, and 24 months, confirmed these findings. CONCLUSIONS: This study demonstrates that specific patterns of PDAC recurrence result in different survival outcomes. Furthermore, distinct first recurrence locations have unique independent predictive values for OS, which could help with prognostic stratification and decisions regarding treatment after the diagnosis of recurrence.

11 Article Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. 2018

Tiriac, Hervé / Belleau, Pascal / Engle, Dannielle D / Plenker, Dennis / Deschênes, Astrid / Somerville, Tim D D / Froeling, Fieke E M / Burkhart, Richard A / Denroche, Robert E / Jang, Gun-Ho / Miyabayashi, Koji / Young, C Megan / Patel, Hardik / Ma, Michelle / LaComb, Joseph F / Palmaira, Randze Lerie D / Javed, Ammar A / Huynh, Jasmine C / Johnson, Molly / Arora, Kanika / Robine, Nicolas / Shah, Minita / Sanghvi, Rashesh / Goetz, Austin B / Lowder, Cinthya Y / Martello, Laura / Driehuis, Else / LeComte, Nicolas / Askan, Gokce / Iacobuzio-Donahue, Christine A / Clevers, Hans / Wood, Laura D / Hruban, Ralph H / Thompson, Elizabeth / Aguirre, Andrew J / Wolpin, Brian M / Sasson, Aaron / Kim, Joseph / Wu, Maoxin / Bucobo, Juan Carlos / Allen, Peter / Sejpal, Divyesh V / Nealon, William / Sullivan, James D / Winter, Jordan M / Gimotty, Phyllis A / Grem, Jean L / DiMaio, Dominick J / Buscaglia, Jonathan M / Grandgenett, Paul M / Brody, Jonathan R / Hollingsworth, Michael A / O'Kane, Grainne M / Notta, Faiyaz / Kim, Edward / Crawford, James M / Devoe, Craig / Ocean, Allyson / Wolfgang, Christopher L / Yu, Kenneth H / Li, Ellen / Vakoc, Christopher R / Hubert, Benjamin / Fischer, Sandra E / Wilson, Julie M / Moffitt, Richard / Knox, Jennifer / Krasnitz, Alexander / Gallinger, Steven / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. · Department of Medicine, Stony Brook University, Stony Brook, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California. · New York Genome Center, New York, New York. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · SUNY Downstate Medical Center, Department of Medicine, New York, New York. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. · University Medical Center (UMC), Utrecht, the Netherlands. · Princess Maxime Center (PMC), Utrecht, the Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland. · Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts. · Department of Surgery, Stony Brook University, Stony Brook, New York. · Department of Pathology, Stony Brook University, Stony Brook, New York. · Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York. · Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. · University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Weill Cornell Medical College, New York, New York. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca. ·Cancer Discov · Pubmed #29853643.

ABSTRACT: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

12 Article Is a Pathological Complete Response Following Neoadjuvant Chemoradiation Associated With Prolonged Survival in Patients With Pancreatic Cancer? 2018

He, Jin / Blair, Alex B / Groot, Vincent P / Javed, Ammar A / Burkhart, Richard A / Gemenetzis, Georgios / Hruban, Ralph H / Waters, Kevin M / Poling, Justin / Zheng, Lei / Laheru, Daniel / Herman, Joseph M / Makary, Martin A / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Medical Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #29334562.

ABSTRACT: OBJECTIVES: To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) following neoadjuvant chemoradiation. BACKGROUND: Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result. METHODS: A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported. RESULTS: One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22-0.93, P = 0.030) and OS (HR=0.41; 0.17-0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26-0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36-0.90, P = 0.018) were also associated with improved survival. CONCLUSIONS: Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.

13 Article Long-term survival after resection of sarcomatoid carcinoma of the pancreas: an updated experience. 2017

Blair, Alex B / Burkhart, Richard A / Griffin, James F / Miller, James A / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / He, Jin. ·Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland; The Sidney Kimmel Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland. · The Sidney Kimmel Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland; Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland. · Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland; The Sidney Kimmel Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: jhe11@jhmi.edu. ·J Surg Res · Pubmed #29078888.

ABSTRACT: BACKGROUND: Sarcomatoid carcinoma of the pancreas (SCP) is a rare histologic subtype of undifferentiated pancreatic carcinoma. Historically, this has been associated with a worse overall prognosis than adenocarcinoma. However, the clinical course and surgical outcomes of SCP remain poorly characterized owing to its rarity. METHODS: A single-institution, prospectively maintained database was queried for patients who underwent pancreatic resection with a final diagnosis of SCP. We describe their histology, clinicopathologic features, and perioperative outcomes. Survival data are highlighted, and common traits of long-term survivors are examined. RESULTS: Over a 25-year period, 7009 patents underwent pancreatic resection at our institution. Eight (0.11%) were diagnosed with SCP on final histopathology. R0 resection was achieved in six patients (75%). Four patients had early recurrence leading to death (<3 months). Two (25%) experienced long-term survival (>5 years), with the longest surviving nearly 16 years despite the presence of lymph node metastasis. There were no deaths attributed to perioperative complications. Both long-term survivors had disease in the body/tail of the pancreas and received adjuvant radiotherapy. One also received adjuvant gemcitabine-based chemotherapy. CONCLUSIONS: SCP is a rarely appreciated subset of pancreatic malignancy that does not necessarily portend to a uniformly dismal prognosis. Although some have rapid recurrence and an early demise, long-term survival may be possible. Future studies are needed to better define the cohort with potential for long-term survival so that aggressive therapies may be tailored appropriately in this patient subset.

14 Article Preoperative risk factors for conversion and learning curve of minimally invasive distal pancreatectomy. 2017

Hua, Yongfei / Javed, Ammar A / Burkhart, Richard A / Makary, Martin A / Weiss, Matthew J / Wolfgang, Christopher L / He, Jin. ·Department of Surgery, Johns Hopkins Hospital, Baltimore, MD; Department of Surgery, Lihuili Eastern Hospital, Ningbo, China. · Department of Surgery, Johns Hopkins Hospital, Baltimore, MD. · Department of Surgery, Johns Hopkins Hospital, Baltimore, MD. Electronic address: jhe11@jhmi.edu. ·Surgery · Pubmed #28866314.

ABSTRACT: BACKGROUND: Although laparoscopic distal pancreatectomy is considered a standard approach, 10% to 40% of these are converted. The preoperative risk factors for conversion are not well described. The aim of this study was to identify risk factors associated with conversion. METHODS: Clinicopathological variables of 211 consecutive patients who underwent laparoscopic distal pancreatectomy between January 2007 and December 2015 at Johns Hopkins were analyzed to identify factors associated with conversion. Furthermore, the learning curve for laparoscopic distal pancreatectomy was studied. RESULTS: On univariate analysis of diabetes mellitus, preoperative diagnosis of malignant disease, multiorgan resection, surgeons' years and case experience were significantly associated with conversion (all P < .05). Risk factors independently associated with conversion included diagnosis of malignant disease (odds ratio = 5.40; 95% confidence interval, 1.93-15.12, P = .001), multiorgan resection (odds ratio = 7.10; 95% confidence interval, 1.60-31.53, P = .01), and surgeons' case experience (odds ratio = 0.32; 95% confidence interval, 0.12-0.85, P = .023). Intraoperative reasons for conversion included presence of excessive intraabdominal and retroperitoneal fat (N = 10, 32.3%), adhesions (N = 10, 32.3%), extent of tumor invasion (N = 8, 25.8%), anatomy of vessels (N = 6, 19.4%), and intraoperative bleeding (N = 2, 6.5%). CONCLUSION: Patients undergoing laparoscopic distal pancreatectomy with a preoperative diagnosis of malignant disease or possible multiorgan resection are at a higher risk of conversion. Surgeon experience of performing >15 procedures significantly reduces the risk of conversion.

15 Article Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. 2017

Roe, Jae-Seok / Hwang, Chang-Il / Somerville, Tim D D / Milazzo, Joseph P / Lee, Eun Jung / Da Silva, Brandon / Maiorino, Laura / Tiriac, Hervé / Young, C Megan / Miyabayashi, Koji / Filippini, Dea / Creighton, Brianna / Burkhart, Richard A / Buscaglia, Jonathan M / Kim, Edward J / Grem, Jean L / Lazenby, Audrey J / Grunkemeyer, James A / Hollingsworth, Michael A / Grandgenett, Paul M / Egeblad, Mikala / Park, Youngkyu / Tuveson, David A / Vakoc, Christopher R. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. · Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Division of Gastroenterology & Hepatology, Stony Brook University School of Medicine, Stony Brook, NY 11790, USA. · Division of Hematology/Oncology, UC Davis Medical Center, Sacramento, CA 95817, USA. · Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu. ·Cell · Pubmed #28757253.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.

16 Article Management of Type 9 Hepatic Arterial Anatomy at the time of Pancreaticoduodenectomy: Considerations for Preservation and Reconstruction of a Completely Replaced Common Hepatic Artery. 2016

Hicks, Caitlin W / Burkhart, Richard A / Weiss, Matthew J / Wolfgang, Christopher L / Cameron, Andrew M / Pawlik, Timothy M. ·Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. · Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 688, Baltimore, MD, 21287, USA. · Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 688, Baltimore, MD, 21287, USA. tpawlik1@jhmi.edu. ·J Gastrointest Surg · Pubmed #27138326.

ABSTRACT: Recognition and management of aberrant hepatic arterial anatomy for patients undergoing pancreaticoduodenectomy (PD) are critical to ensure safe completion of the operation. When the common hepatic artery (CHA) is noted to emanate from the superior mesenteric artery (Michels' type 9 variant), it is vulnerable to injury during the dissection required for PD. While this anatomy does not preclude an operation, care must be taken to avoid injury, often by identifying the CHA throughout its entire course before beginning the dissection of the portal venous structures. The oncologic principle that cautions against resection of a pancreatic cancer when it involves the CHA in its standard position may not universally apply to tumors that focally involve the CHA in the type 9 anatomic variant. In highly selected patients, surgical resection may be entertained as disease biology may be analogous to local involvement of the gastroduodenal artery in a patient with standard anatomy. Here, we review the indications, techniques, and outcomes associated with arterial resection and reconstruction during pancreatectomy among patients with a pancreatic tumor involving a common hepatic artery arising from the superior mesenteric artery.

17 Article MUC1 Promoter-Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer. 2015

Tholey, Renee M / Lal, Shruti / Jimbo, Masaya / Burkhart, Richard A / Blanco, Fernando F / Cozzitorto, Joseph A / Eisenberg, Josh D / Jiang, Wei / Iacobuzio-Donahue, Christine A / Witkiewicz, Agnieszka K / Glbert, Melissa / Yeo, Charles J / Brody, Jonathan R / Sawicki, Janet A / Winter, Jordan M. ·Department of Surgery and the Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology and the David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, UT Southwestern Medical Center; Dallas, Texas. · Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. jordan.winter@jefferson.edu SawickiJ@MLHS.org. · Department of Surgery and the Jefferson Pancreas, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. jordan.winter@jefferson.edu SawickiJ@MLHS.org. ·Mol Cancer Res · Pubmed #25336517.

ABSTRACT: IMPLICATIONS: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs.

18 Article dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial. 2014

McAllister, Florencia / Pineda, Danielle M / Jimbo, Masaya / Lal, Shruti / Burkhart, Richard A / Moughan, Jennifer / Winter, Kathryn A / Abdelmohsen, Kotb / Gorospe, Myriam / Acosta, Ana de Jesus / Lankapalli, Rachana H / Winter, Jordan M / Yeo, Charles J / Witkiewicz, Agnieska K / Iacobuzio-Donahue, Christine A / Laheru, Daniel / Brody, Jonathan R. ·Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA; Department of Medicine; Division of Clinical Pharmacology; Johns Hopkins University; Baltimore, MD USA. · Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA. · RTOG Statistical Center; Philadelphia, PA USA. · Laboratory of Genetics; National Institute on Aging Intramural Research Program; National Institutes of Health; Baltimore, MD USA. · Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA. · Department of Pathology; The University of Texas Southwestern Medical Center; Dallas, TX USA. ·Cancer Biol Ther · Pubmed #24618665.

ABSTRACT: Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.

19 Article HuR posttranscriptionally regulates WEE1: implications for the DNA damage response in pancreatic cancer cells. 2014

Lal, Shruti / Burkhart, Richard A / Beeharry, Neil / Bhattacharjee, Vikram / Londin, Eric R / Cozzitorto, Joseph A / Romeo, Carmella / Jimbo, Masaya / Norris, Zoë A / Yeo, Charles J / Sawicki, Janet A / Winter, Jordan M / Rigoutsos, Isidore / Yen, Timothy J / Brody, Jonathan R. ·Authors' Affiliations: Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Medical College; Computational Medicine Center; Kimmel Cancer Center, Thomas Jefferson University; Fox Chase Cancer Center, Philadelphia; and Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. ·Cancer Res · Pubmed #24536047.

ABSTRACT: HuR (ELAV1), an RNA-binding protein abundant in cancer cells, primarily resides in the nucleus, but under specific stress (e.g., gemcitabine), HuR translocates to the cytoplasm in which it tightly modulates the expression of mRNA survival cargo. Here, we demonstrate for the first time that stressing pancreatic ductal adenocarcinoma (PDA) cells by treatment with DNA-damaging anticancer agents (mitomycin C, oxaliplatin, cisplatin, carboplatin, and a PARP inhibitor) results in HuR's translocation from the nucleus to the cytoplasm. Importantly, silencing HuR in PDA cells sensitized the cells to these agents, whereas overexpressing HuR caused resistance. HuR's role in the efficacy of DNA-damaging agents in PDA cells was, in part, attributed to the acute upregulation of WEE1 by HuR. WEE1, a mitotic inhibitor kinase, regulates the DNA damage repair pathway, and therapeutic inhibition of WEE1 in combination with chemotherapy is currently in early phase trials for the treatment of cancer. We validate WEE1 as a HuR target in vitro and in vivo by demonstrating (i) direct binding of HuR to WEE1's mRNA (a discrete 56-bp region residing in the 3' untranslated region) and (ii) HuR siRNA silencing and overexpression directly affects the protein levels of WEE1, especially after DNA damage. HuR's positive regulation of WEE1 increases γ-H2AX levels, induces Cdk1 phosphorylation, and promotes cell-cycle arrest at the G2-M transition. We describe a novel mechanism that PDA cells use to protect against DNA damage in which HuR posttranscriptionally regulates the expression and downstream function of WEE1 upon exposure to DNA-damaging agents.

20 Article HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer. 2013

Burkhart, Richard A / Pineda, Danielle M / Chand, Saswati N / Romeo, Carmella / Londin, Eric R / Karoly, Edward D / Cozzitorto, Joseph A / Rigoutsos, Isidore / Yeo, Charles J / Brody, Jonathan R / Winter, Jordan M. ·Department of Surgery; Jefferson Pancreas, Biliary and Related Cancer Center; Philadelphia, PA USA. ·RNA Biol · Pubmed #23807417.

ABSTRACT: Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein-immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment.

21 Article Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. 2013

Burkhart, Richard A / Peng, Yu / Norris, Zoë A / Tholey, Renée M / Talbott, Vanessa A / Liang, Qin / Ai, Yongxing / Miller, Kathy / Lal, Shruti / Cozzitorto, Joseph A / Witkiewicz, Agnieska K / Yeo, Charles J / Gehrmann, Matthew / Napper, Andrew / Winter, Jordan M / Sawicki, Janet A / Zhuang, Zhihao / Brody, Jonathan R. ·Thomas Jefferson University, 1015 Walnut Street, Curtis 611A, Philadelphia, PA 19107, USA. ·Mol Cancer Res · Pubmed #23696131.

ABSTRACT: IMPLICATIONS: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA.

22 Article Defining treatment and outcomes of hepaticojejunostomy failure following pancreaticoduodenectomy. 2013

Burkhart, Richard A / Relles, Daniel / Pineda, Danielle M / Gabale, Salil / Sauter, Patricia K / Rosato, Ernest L / Koniaris, Leonidas G / Lavu, Harish / Kennedy, Eugene P / Yeo, Charles J / Winter, Jordan M. ·Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. ·J Gastrointest Surg · Pubmed #23292459.

ABSTRACT: BACKGROUND: The overall complication rate after pancreaticoduodenectomy (PD) approaches 50 %, with anastomotic failure being the most frequent cause of serious postoperative morbidity. Hepaticojejunostomy leaks (also called bile leaks) are the second most common type of leak, behind pancreaticojejunostomy leaks, yet have been the focus of only a single study as reported by Suzuki et al. (Hepatogastroenterology 50:254-257, 12). METHODS: We reviewed the recent experience with bile leaks at a single, high-volume pancreatic surgery center over a six-year time period. RESULTS: Bile leaks were identified in 16 out of 715 patients (2.2 %). Low preoperative albumin was associated with an increased risk. Bile leaks typically manifested within the first week after surgery as bilious drainage in a surgically placed drain. Associated warning signs included fever and leukocytosis. Patients with a bile leak frequently developed other complications, including a pancreatic fistula, wound infection, delayed gastric emptying, and sepsis. The impact on perioperative outcomes was comparable to patients with a pancreatic leak. A grading system is proposed based on the International Study Group on Pancreatic Fistula model. Grade A bile leaks were classified as those managed with prolonged drainage by operatively placed drains, grade B bile leaks with percutaneous abdominal drainage, and grade C bile leaks with insertion of a percutaneous transhepatic biliary drainage. CONCLUSIONS: Hepaticojejunostomy leaks are rare after PD. The complication severity ranges from trivial to life threatening and is comparable overall to pancreaticojejunostomy leaks. Surgical intervention is rarely, if ever, required. With prompt and aggressive management, a full recovery can be expected.

23 Article HuR's post-transcriptional regulation of Death Receptor 5 in pancreatic cancer cells. 2012

Pineda, Danielle M / Rittenhouse, David W / Valley, Christopher C / Cozzitorto, Joseph A / Burkhart, Richard A / Leiby, Benjamin / Winter, Jordan M / Weber, Matthew C / Londin, Eric R / Rigoutsos, Isidore / Yeo, Charles J / Gorospe, Myriam / Witkiewicz, Agnieska K / Sachs, Jonathan N / Brody, Jonathan R. ·Department of Surgery, Division of Surgical Research, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. ·Cancer Biol Ther · Pubmed #22785201.

ABSTRACT: Apoptosis is one of the core signaling pathways disrupted in pancreatic ductal adenocarcinoma (PDA). Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF)-receptor superfamily that is expressed in cancer cells. Binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR5 is a potent trigger of the extrinsic apoptotic pathway, and numerous clinical trials are based on DR5-targeted therapies for cancer, including PDA. Human antigen R (HuR), an RNA-binding protein, regulates a select number of transcripts under stress conditions. Here we report that HuR translocates from the nucleus to the cytoplasm of PDA cells upon treatment with a DR5 agonist. High doses of DR5 agonist induce cleavage of both HuR and caspase 8. HuR binds to DR5 mRNA at the 5'-untranslated region (UTR) in PDA cells in response to different cancer-associated stressors and subsequently represses DR5 protein expression; silencing HuR augments DR5 protein production by enabling its translation and thus enhances apoptosis. In PDA specimens (n = 53), negative HuR cytoplasmic expression correlated with elevated DR5 expression (odds ratio 16.1, p < 0.0001). Together, these data demonstrate a feedback mechanism elicited by HuR-mediated repression of the key apoptotic membrane protein DR5.

24 Minor Surgical Site Infections Following Pancreaticoduodenectomy. 2017

Burkhart, Richard A / Weiss, Matthew J. ·Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, USA. Electronic address: mweiss5@jhmi.edu. ·HPB (Oxford) · Pubmed #28935454.

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