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Pancreatic Neoplasms: HELP
Articles by G. Varadhachary
Based on 6 articles published since 2010
(Why 6 articles?)
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Between 2010 and 2020, G. Varadhachary wrote the following 6 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients. 2018

Castillo, J / Bernard, V / San Lucas, F A / Allenson, K / Capello, M / Kim, D U / Gascoyne, P / Mulu, F C / Stephens, B M / Huang, J / Wang, H / Momin, A A / Jacamo, R O / Katz, M / Wolff, R / Javle, M / Varadhachary, G / Wistuba, I I / Hanash, S / Maitra, A / Alvarez, H. ·Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · The University of Texas MD Anderson Cancer UTHealth Graduate School of Biomedical Sciences, Houston, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. · ContinuumDx, Houston, USA. · McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #29045505.

ABSTRACT: Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

2 Article A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients. 2017

Fogelman, David R / Morris, J / Xiao, L / Hassan, M / Vadhan, S / Overman, M / Javle, S / Shroff, R / Varadhachary, G / Wolff, R / Vence, L / Maitra, A / Cleeland, C / Wang, X S. ·Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd Unit 426, Houston, TX, 77030, USA. dfogelman@mdanderson.org. · Department of Biostatistics, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd Unit 426, Houston, TX, 77030, USA. · Department of Sarcoma Research, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Department of Immunology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Department of Pathology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Department of Symptom Research, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. ·Support Care Cancer · Pubmed #28111717.

ABSTRACT: BACKGROUND: Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. METHODS: Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. RESULTS: Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker. CONCLUSIONS: Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

3 Article High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. 2017

Allenson, K / Castillo, J / San Lucas, F A / Scelo, G / Kim, D U / Bernard, V / Davis, G / Kumar, T / Katz, M / Overman, M J / Foretova, L / Fabianova, E / Holcatova, I / Janout, V / Meric-Bernstam, F / Gascoyne, P / Wistuba, I / Varadhachary, G / Brennan, P / Hanash, S / Li, D / Maitra, A / Alvarez, H. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA. · Genetic Epidemiology Group International Agency for Research on Cancer, Lyon, France. · Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia. · Institute of Public Health and Preventive Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. · Department of Preventive Medicine, Palacky University of Medicine, Olomouc, Czech Republic. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. · Department of Investigational Cancer Therapeutics and the Institute for Personalized Cancer Therapy, Houston, USA. · Section of Experimental Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28104621.

ABSTRACT: Background: Exosomes arise from viable cancer cells and may reflect a different biology than circulating cell-free DNA (cfDNA) shed from dying tissues. We compare exosome-derived DNA (exoDNA) to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methods: Patient samples were obtained between 2003 and 2010, with clinically annotated follow up to 2015. Droplet digital PCR was performed on exoDNA and cfDNA for sensitive detection of KRAS mutants at codons 12/13. A cumulative series of 263 individuals were studied, including a discovery cohort of 142 individuals: 68 PDAC patients of all stages; 20 PDAC patients initially staged with localized disease, with blood drawn after resection for curative intent; and 54 age-matched healthy controls. A validation cohort of 121 individuals (39 cancer patients and 82 healthy controls) was studied to validate KRAS detection rates in early-stage PDAC patients. Primary outcome was circulating KRAS status as detected by droplet digital PCR. Secondary outcomes were disease-free and overall survival. Results: KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Higher exoKRAS MAFs were associated with decreased disease-free survival in patients with localized disease. In the validation cohort, mutant KRAS exoDNA was detected in 43.6% of early-stage PDAC patients and 20% of healthy controls. Conclusions: Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.

4 Article Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. 2016

San Lucas, F A / Allenson, K / Bernard, V / Castillo, J / Kim, D U / Ellis, K / Ehli, E A / Davies, G E / Petersen, J L / Li, D / Wolff, R / Katz, M / Varadhachary, G / Wistuba, I / Maitra, A / Alvarez, H. ·Department of Translational Molecular Pathology Department of Pathology. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston. · Department of Pathology The University of Texas Graduate School of Biomedical Sciences at Houston, Houston. · Department of Pathology. · Avera Institute for Human Genetics, Sioux Falls. · Department of Gastrointestinal (GI) Medical Oncology. · Department of Translational Molecular Pathology. · Department of Translational Molecular Pathology Department of Pathology Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA amaitra@mdanderson.org. ·Ann Oncol · Pubmed #26681674.

ABSTRACT: BACKGROUND: The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies. PATIENTS AND METHODS: We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data. RESULTS: Whole-exome sequencing resulted in 95%-99% of the target regions covered at a mean depth of 133-490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens. CONCLUSIONS: We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.

5 Article A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy. 2013

Jiang, Z-Q / Varadhachary, G / Wang, X / Kopetz, S / Lee, J E / Wang, H / Shroff, R / Katz, M / Wolff, R A / Fleming, J / Overman, M J. ·Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515Holcombe Blvd. Houston, TX 77030, USA. ·Ann Oncol · Pubmed #23704197.

ABSTRACT: BACKGROUND: Whether carcinomas of the ampulla of Vater should be classified with biliary tract tumors and treated in a similar manner remains unknown. We sought to compare the outcomes of similarly staged periampullary adenocarcinomas (AAs) and analyze the chemotherapy responsiveness of AAs. PATIENTS AND METHODS: A total of 905 patients with resected periampullary adenocarcinomas were identified from a prospective surgical registry from 1988 to 2010. A second cohort of 64 metastatic AA patients from 1992 to 2009 who received either front-line fluoropyrimidine-based or gemcitabine-based chemotherapy was also identified. RESULTS: Overall survival (OS) for AAs was similar to survival with duodenal adenocarcinomas, but was significantly different from both extrahepatic biliary and pancreatic adenocarcinomas (P < 0.001 for each comparison). In multivariate analysis, AAs had a significantly improved OS in comparison with extrahepatic biliary adenocarcinomas (HR = 1.97, P = 0.006). Fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy for metastatic AAs resulted in a significant improvement in time to progression (P = 0.001) but only a trend toward benefit for OS (P = 0.07) in multivariate analysis. CONCLUSIONS: Differences in the natural history of ampullary and extrahepatic biliary adenocarcinomas exist. Analyses of metastatic ampullary adenocarcinomas suggest that fluoropyrimidine-based chemotherapy may represent a more appropriate front-line chemotherapy approach.

6 Article CT imaging features of acinar cell carcinoma and its hepatic metastases. 2013

Bhosale, P / Balachandran, A / Wang, H / Wei, W / Hwang, R F / Fleming, J B / Varadhachary, G / Charnsangavej, C / Tamm, E. ·Department of Diagnostic Radiology, UT MD Anderson Cancer Center, 1400 Pressler Street, Unit 1473, Houston, TX, 77030, USA, priya.bhosale@mdanderson.org. ·Abdom Imaging · Pubmed #23232580.

ABSTRACT: OBJECTIVE: To evaluate and describe the computed tomography features of pure acinar cell carcinoma (ACC) and its liver metastases. METHODS: Thirty patients were evaluated. Two radiologists evaluated imaging findings for each tumor for size, location, internal density, enhancement, tumor calcifications, pancreatic, and common biliary ductal obstructions and metastases. RESULTS: 70 % were male. Fourteen tumors were located in the pancreatic head, 14 in the tail, one in the neck, and one in the uncinate process. Abdominal pain was the most common presenting symptom (93 %), 20 % had pancreatitis and 17 % had obstructive jaundice. The average tumor size was 7 cm, 97 % of tumors were solid, well circumscribed (73 %); isodense to normal pancreatic parenchyma (40 %) on the non-contrast study, hypodense on the arterial (47 %), and hypodense on the portal venous (37 %) phase. 30 % patients had pancreatic ductal dilation, 10 % had pancreatic ductal ingrowth, 6 % had calcifications, and 20 % had central necrosis, and 31 % (5/16) showed biliary ductal dilation. At presentation, 50 % had metastatic adenopathy and 40 % patients had liver metastases, which typically were well circumscribed, hypoattenuating to the hepatic parenchyma on all the phases of contrast enhancement and had a lobulated margin. CONCLUSION: ACCs of the pancreas often present as large, well circumscribed, solid masses commonly in males. Despite their large size, they may not cause CBD obstruction.