Nipun B Merchant

Vanderbilt University, Нашвилл, Michigan, United States

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Publications (130)647.06 Total impact

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    ABSTRACT: Objectives: Three-dimensional organoids derived from primary pancreatic ductal adenocarcinomas are an attractive platform for testing potential anticancer drugs on patient-specific tissue. Optical metabolic imaging (OMI) is a novel tool used to assess drug-induced changes in cellular metabolism, and its quantitative end point, the OMI index, is evaluated as a biomarker of drug response in pancreatic cancer organoids. Methods: Optical metabolic imaging is used to assess both malignant cell and fibroblast drug response within primary murine and human pancreatic cancer organoids. Results: Anticancer drugs induce significant reductions in the OMI index of murine and human pancreatic cancer organoids. Subpopulation analysis of OMI data revealed heterogeneous drug response and elucidated responding and nonresponding cell populations for a 7-day time course. Optical metabolic imaging index significantly correlates with immunofluorescence detection of cell proliferation and cell death. Conclusions: Optical metabolic imaging of primary pancreatic ductal adenocarcinoma organoids is highly sensitive to drug-induced metabolic changes, provides a nondestructive method for monitoring dynamic drug response, and presents a novel platform for patient-specific drug testing and drug development.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    No preview · Article · Oct 2015 · Pancreas
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    ABSTRACT: Purpose: Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and is thought to contribute to cancer cell metabolic reprogramming. The aim of this study was to evaluate PKM2 immunohistochemical expression as a potential prognostic biomarker in pancreatic ductal adenocarcinoma (PDAC). Methods: A tissue microarray was constructed using surgical specimens for 115 patients who underwent resections for PDAC, stained with PKM2 antibody, and scored for expression level. Statistical analyses were performed to investigate the association between PKM2 and patient survival, tumor stage, tumor grade, surgical margin status, lymph node ratio, perineural invasion status, or the use of adjuvant chemotherapy. Results: Fifty-three percent of tumors had positive PKM2 expression, and 47 % of tumors had negative PKM2 expression. PKM2 expression was associated with overall survival (HR 0.56, p = 0.007) and CA 19-9 levels (p = 0.035), but was not associated with tumor stage, tumor grade, surgical margin status, lymph node ratio, perineural invasion, or adjuvant chemotherapy use. Conclusions: PKM2 expression is associated with overall survival in PDAC. Further studies are warranted to validate the value of PKM2 as a prognostic biomarker and to examine the potential utility of PKM2 in predicting treatment response, as well as a potential therapeutic target in PDAC.
    No preview · Article · Sep 2015 · Journal of Gastrointestinal Cancer
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    ABSTRACT: A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified STAT3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by MALDI-imaging mass spectrometry. Collagen second harmonic generation (SHG) imaging quantified tumor collagen alignment and density. STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma and downregulation of cytidine deaminase (Cda). Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and downregulation of Cda without depletion of tumor stromal content. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Gastroenterology

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Jul 2015 · Cancer Research

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: Background Delayed gastric emptying (DGE) is a frequent cause of morbidity, prolonged hospital stay and readmission after a pancreaticoduodenectomy (PD). We sought to evaluate predictive peri-operative factors for DGE after a PD.Methods Four hundred and sixteen consecutive patients who underwent a PD at our tertiary referral centre were identified. Univariate and multivariate (MV) logistic regression models were used to assess peri-operative factors associated with the development of clinically significant DGE and a post-operative pancreatic fistula (POPF).ResultsDGE occurred in 24% of patients (n = 98) with Grades B and C occurring at 13.5% (n = 55) and 10.5% (n = 43), respectively. Using MV regression, a body mass index (BMI) ≥35 [odds ratio (OR) = 3.19], operating room (OR) length >5.5 h (OR = 2.72) and prophylactic octreotide use (OR = 2.04) were independently associated with an increased risk of DGE. DGE patients had a significantly longer median hospital stay (12 versus 7 days), higher 90-day readmission rates (32% versus 18%) and an increased incidence of a pancreatic fistula (59% versus 27%). When controlling for POPF, only OR length >5.5 h (OR 2.73) remained significantly associated with DGE.ConclusionsDGE remains a significant cause of morbidity, increased hospital stay and readmission after PD. Our findings suggest patients with a BMI ≥35 or longer OR times have a higher risk of DGE either independently or through the development of POPF. These patients should be considered for possible enteral feeding tube placement along with limited octreotide use to decrease the potential risk and consequences of DGE.
    No preview · Article · Feb 2015 · HPB
  • Lesly A. Dossett · Nipun B. Merchant
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    ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the GI tract and account for 1–3 % of all GI malignancies. GISTs arise from the interstitial cells of Cajal, an intestinal pacemaker cell located in and around the myenteric plexus. They typically arise in the stomach (65–70 %) or small intestine (25–45 %). An important immunohistochemical marker is KIT, a membrane receptor with tyrosine kinase activity that is present in most GISTs (80–95 %). Some GISTs (5–7 %) have a mutation in platelet-derived growth factor receptor alpha (PDGFRA) instead. Several factors including tumor site, size greater than 5 cm, and greater than 5 mitoses per 50 high-power field predict aggressive behavior and recurrence. The treatment for localized GISTs is resection. Systemic chemotherapy and radiation are ineffective. The tyrosine kinase inhibitor imatinib improves progression-free survival in patients with metastatic disease, and its use in the adjuvant and neoadjuvant settings is increasingly common. Many patients ultimately develop imatinib resistance, and for these patients, dose escalation or the use of another tyrosine kinase inhibitor is recommended.
    No preview · Article · Jan 2015
  • J. Castellanos · N. Nagathihalli · Y. Xiong · N. Merchant

    No preview · Article · Nov 2014 · Pancreas
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    ABSTRACT: AimsRecently, we described a series of pancreatic neuroendocrine tumours (PanNETs) featuring prominent stromal fibrosis, which we called sclerosing PanNETs. The aim of this study was to examine the pathological, immunophenotypic and clinical differences between sclerosing and non-sclerosing PanNETs.Methods and resultsOne hundred and six PanNETs were identified, of which 15 (14%) were sclerosing NETs. Tissue microarrays containing 44 non-sclerosing and five sclerosing panNETs, as well as sections from 10 additional sclerosing tumours, were immunohistochemically labelled for serotonin, CDX2, CDH17, and islet 1. Sclerosing PanNETs were smaller (P = 0.045) and more likely to show an infiltrative growth pattern (P < 0.001) than non-sclerosing PanNETs. They were frequently associated with a large pancreatic duct, causing duct stenosis. Additionally, we found significantly increased expression of the small intestinal NET markers serotonin, CDX2 and CDH17 in sclerosing PanNETs (P < 0.001) as compared with non-sclerosing PanNETs. No difference in clinical outcome was found; however, more sclerosing PanNETs were stage IIB or above (P = 0.035), with lymph node metastasis being seen in three of nine sclerosing PanNETs with a tumour size of <20 mm.Conclusions Sclerosing PanNETs have distinct pathological features and biomarker expression profiles. In addition, lymph node metastasis can be present even with small sclerosing PanNETs.This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2014 · Histopathology
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    ABSTRACT: Introduction: During pancreaticoduodenectomy (PD) for ductal adenocarcinoma, a frozen section (FS) neck margin is typically assessed, and if positive, additional pancreas is removed to achieve an R0 margin. We analyzed the association of this practice with improved overall survival (OS). Methods: Patients who underwent PD for pancreatic ductal adenocarcinoma from January 2000 to August 2012 at 8 academic centers were classified by neck margin status as negative (R0) or microscopically positive (R1) on the basis of FS and permanent section (PS). Impact on OS of converting an FS-R1-neck margin to a PS-R0-neck margin by additional resection was assessed. Results: A total of 1399 patients had FS neck margins analyzed. Median OS was 19.7 months. On FS, 152 patients (10.9%) were R1, and an additional 51 patients (3.6%) had false-negative FS-R0 margins. PS-R0-neck was achieved in 1196 patients (85.5%), 131 patients (9.3%) remained PS-R1, and 72 patients (5.1%) were converted from FS-R1-to-PS-R0 by additional resection. Median OS for PS-R0-neck patients was 21.1 months versus 13.7 months for PS-R1-neck patients (P < 0.001) and 11.9 months for FS-R1-to-PS-R0 patients (P < 0.001). Both FS-R1-to-PS-R0 and PS-R1-neck patients had larger tumors (P = 0.001), more perineural invasion (P = 0.02), and more node positivity (P = 0.08) than PS-R0-neck patients. On multivariate analysis controlling for adverse pathologic factors, FS-R1-to-PS-R0 conversion remained associated with significantly worse OS compared with PS-R0-neck patients (hazard ratio: 1.55; P = 0.009). Conclusions: For patients who undergo pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, additional resection to achieve a negative neck margin after positive frozen section is not associated with improved OS.
    No preview · Article · Sep 2014 · Annals of Surgery
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    ABSTRACT: Background and Objectives Two pivotal randomized controlled trials (RCTs), the Intergroup (INT-0116) and Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trials, demonstrated a survival benefit of multimodality therapy in patients with resectable gastric cancer. The purpose of this study was to determine utilization rates of these treatment regimens in the United States and to identify factors associated with receipt of evidence-based care.Methods We performed a retrospective cohort study of patients with Stage IB–IV (M0) gastric adenocarcinoma who underwent resection from 1991 to 2009 using the linked SEER–Medicare database.ResultsOnly 19.1% of patients received post-operative chemoradiation therapy (CRT), and 1.9% received peri-operative chemotherapy; most patients underwent surgery alone (60.9%). Patients with more advanced stage, younger age, and fewer comorbidities were more likely to receive evidence-based care. We found no association between National Cancer Institute (NCI) designation and delivery of multimodality therapy. However, patients who underwent medical oncology consultation were much more likely to receive evidence-based treatment (OR 3.10, 95% CI 2.35–4.09).Conclusions Rates of peri-operative chemotherapy and post-operative CRT in patients with resected gastric cancer remain remarkably low, despite high-quality RCT evidence demonstrating their benefit. Furthermore, NCI designation does not appear to be associated with administration of evidence-based treatment. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Sep 2014 · Journal of Surgical Oncology
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    ABSTRACT: The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCN Pancreatic Adenocarcinoma Panel meeting. The panel discussion focused mainly on the management of borderline resectable and locally advanced disease. In particular, the panel discussed the definition of borderline resectable disease, role of neoadjuvant therapy in borderline disease, role of chemoradiation in locally advanced disease, and potential role of newer, more active chemotherapy regimens in both settings.
    Full-text · Article · Aug 2014 · Journal of the National Comprehensive Cancer Network: JNCCN
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    ABSTRACT: Background: The incidence of secondary malignancies is increased in patients with malignant and premalignant conditions. Although neuroendocrine tumors (NET) are uncommon, their incidence is increasing. We evaluated the rate of additional malignancies in patients with NET. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified a cohort of patients with pancreatic NET (PNET) or gastrointestinal NET (GINET). We determined the incidence of additional cancers diagnosed either before or after the diagnosis of PNET or GINET, by comparing these rates with the general population. Using multivariable regression, we evaluated factors that increased the risk of an additional malignancy. Results: A cohort of 9,727 NET patients was identified. A total of 3,086 additional cancers occurred in 2,508 patients (25.8 %). The most common sites of additional malignancies included colorectal (21.1 %), prostate (14.5 %), breast (13.3 %), and lung (11.6 %). Among patients with PNET, the incidence of breast, lung, uterine, lymph, and pancreatic cancers was less than expected in the general population, whereas in patients with GINET, the observed incidence of nearly all malignancies exceeded that expected. Increasing age, marital status, and localized NET were associated with increased risk. Conclusion: Our study shows that the incidence of additional malignancies in patients with PNET and GINET is 25.8 %. Patients with GINET are at increased risk of additional malignancies, whereas patients with PNET have a decreased risk compared with the general population. More vigilant surveillance for secondary malignancies should be performed in patients with GINET. Studies investigating potential etiologic oncogenic pathways are warranted.
    Full-text · Article · Jul 2014 · Annals of Surgical Oncology
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    ABSTRACT: Introduction In this multi-institutional study of patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, we sought to identify factors associated with perioperative transfusion requirement as well as the association between blood transfusion and perioperative and oncologic outcomes. Methods The surgical databases across six high-volume institutions were analyzed to identify patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 2005 to 2010. For statistical analyses, patients were then stratified by transfusion volume according to whether they received 0, 1–2, or >2 units of packed red blood cells. Results Among 697 patients identified, 42 % required blood transfusion. Twenty-three percent received 1–2 units, and 19 % received >2 units. Factors associated with an increased transfusion requirement included older age, heart disease, diabetes, longer operative time, higher blood loss, tumor size, and non-R0 margin status (all p
    Full-text · Article · Jun 2014 · Journal of Gastrointestinal Surgery
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    ABSTRACT: The Papanicolaou Society of Cytopathology (PSC) has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature for pancreatobiliary cytology, ancillary testing and post-procedure management. All documents are based on the expertise of the authors, a review of the literature and discussions of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the PSC web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on the follow-up and treatment options for patients after procedures performed for obtaining cytology samples for the evaluation of biliary strictures and solid and cystic masses in the pancreas. These recommendations follow the six-tiered terminology and nomenclature scheme proposed by committee III.
    No preview · Article · Jun 2014 · CytoJournal
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    ABSTRACT: The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing and postbiopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed.
    No preview · Article · Jun 2014 · CytoJournal
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    Jason A Castellanos · Nipun B Merchant
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    ABSTRACT: The management of synchronous presentation of colorectal cancer and liver metastases has long been a topic of debate and discussion for surgeons due to the unique dilemma of balancing operative timing along with treatment strategy. Operative strategies for resection include staged resection with colon first approach, "reverse" staged resection with liver metastases resected first, and one-stage, or simultaneous, resection of both the primary tumor and liver metastases approach. These operative strategies can be further augmented with perioperative chemotherapy and other novel approaches that may improve resectability and patient survival. The decision on operative timing and approach, however, remains largely dependent on the surgeon's determination of disease resectability, patient fitness, and the need for neoadjuvant chemotherapy.
    Preview · Article · Jun 2014
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    ABSTRACT: Background: Hepatic endometriosis/uterus-like mass is rare and may be overlooked during hepatic cyst workups. We report a case of uterus-like mass, misdiagnosed as hepatic abscess. Case report: A 47-year-old woman developed abdominal pain and vomiting. Infectious colitis with hepatic abscess was diagnosed, and remained antibiotic-refractory. Fine-needle aspiration and core biopsies showed benign contents. The patient presented to our institution with symptoms and normal blood work. Laparoscopic excision demonstrated a 1.4-cm cyst composed of endometrial glands (estrogen receptor+ and progesterone receptor+) and stroma (CD10+) with smooth muscle actin (SMA+), arranged in an organoid fashion. The patient, status-post hysterectomy, had no history or symptoms of endometriosis. Conclusion: This rare case illustrates the merit of considering uterus-like mass/endometriosis in the differential diagnosis of antibiotic-refractory hepatic cysts. Cyst heterogeneity may confound needle biopsy. We report the first instance of a hepatic uterus-like mass, with a review of related entities, postulated histogenesis, and important clinical associations.
    No preview · Article · May 2014 · International Journal of Surgical Pathology

Publication Stats

2k Citations
647.06 Total Impact Points

Institutions

  • 2005-2015
    • Vanderbilt University
      • • Department of Surgery
      • • Division of Surgical Oncology
      Нашвилл, Michigan, United States
  • 2012
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
  • 2006
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2004
    • VU University Medical Center
      • Department of Surgery
      Amsterdamo, North Holland, Netherlands