Hitendra Patel

Gemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with collateral hypersensitivity to histone deacetylase inhibitors

Gemcitabine based treatment is currently a standard first line treatment for patients with advanced pancreatic cancer, however overall survival remains poor, and few options are available for patients that fail gemcitabine based therapy. To identify potential molecular targets in gemcitabine refractory pancreatic cancer, we developed a series of gemcitabine resistant (GR) cell lines. Initial drug exposure selected for an early resistant phenotype that was independent of drug metabolic pathways. Prolonged drug selection pressure after 16 weeks, led to an induction of cytidine deaminase (CDA) and enhanced drug detoxification. Cross resistance profiles demonstrate approximately 100-fold cross resistance to the pyrimidine nucleoside cytarabine, but no resistance to the same in class agents, azacytidine and decitabine. GR cell lines demonstrated a dose dependent collateral hypersensitivity to class I and II histone deacetylase (HDAC) inhibitors and decreased expression of 3 different global heterochromatin marks, as detected by H4K20me3, H3K9me3 and H3K27me3. Cell morphology of the drug resistant cell lines demonstrated a fibroblastic type appearance with loss of cell-cell junctions and an altered microarray expression pattern, using Gene Ontology (GO) annotation, consistent with progression to an invasive phenotype. Of particular note, the gemcitabine resistant cell lines displayed up to a 15 fold increase in invasive potential that directly correlates with the level of gemcitabine resistance. These findings suggest a mechanistic relationship between chemoresistance and metastatic potential in pancreatic carcinoma and provide evidence for molecular pathways that may be exploited to develop therapeutic strategies for refractory pancreatic cancer.

Economic evaluation for the US of nab-paclitaxel plus gemcitabine versus FOLFIRINOX versus gemcitabine in the treatment of metastatic pancreas cancer.

Abstract Background: Nab-paclitaxel plus gemcitabine (NAB-P + GEM) and FOLFIRINOX have shown superior efficacy over gemcitabine (GEM) in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDA). Although the incremental clinical benefits are modest, both treatments represent significant advances in the treatment of a high-mortality cancer. In this independent economic evaluation for the US, the aim was to estimate the comparative cost-utility and cost-effectiveness of these three regimens from the payer perspective. Methods: In the absence of a direct treatment comparison in a single clinical trial, the Bucher indirect comparison method was used to estimate the comparative efficacy of each regimen. A Markov model evaluated life years (LY) and quality-adjusted life years (QALY) gained with NAB-P + GEM and FOLFIRINOX over GEM, expressed as incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR). All costs and outcomes were discounted at 3%/year. The impact of parameter uncertainty on the model was assessed by probabilistic sensitivity analyses. Results: NAB-P + GEM was associated with differentials of +0.180 LY and +0.127 QALY gained over GEM at an incremental total cost of

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

25,965; yielding an ICER of

Intrabiliary Hepatic Metastasis of Colorectal Carcinoma Mimicking Primary Cholangiocarcinoma: A Case Report and Review of the Literature

144,096/LY and ICUR of

Metformin and Pancreatic Cancer Metabolism

204,369/QALY gained. FOLFIRINOX was associated with differentials of +0.368 LY and +0.249 QALY gained over GEM at an incremental total cost of

Phase I Study of Concomitant Pemetrexed and Cisplatin Plus External Beam Radiation Therapy in Patients with Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Carcinomas.

93,045; yielding an ICER of

Abstract 1434: Metformin-induced metabolic changes are k-ras-dependent in animal models of pancreatic cancer

253,162/LY and ICUR of

A SU2C catalyst randomized phase II trial of pembrolizumab with or without paricalcitol in patients with stage IV pancreatic cancer who have been placed in best possible response.

372,813/QALY gained. In indirect comparison, the overall survival hazard ratio (OS HR) for NAB-P + GEM vs FOLFIRINOX was 0.79 (95%CI = 0.59–1.05), indicating no superiority in OS of either regimen. FOLFIRINOX had an ICER of

Optimized economic evaluation for the United States (US) of nab-paclitaxel plus gemcitabine (NAB-P+GEM), FOLFIRINOX (FFX), and gemcitabine (GEM) as first-line treatment for metastatic pancreatic cancer (mPDA).

358,067/LY and an ICUR of

Epidemiology and survival of small cell carcinoma of gastrointestional tract: A Surveillance, Epidemiology, and End Results (SEER) database review.

547,480/QALY gained over NAB-P + GEM. Tornado diagrams identified variation in the OS HR, but no other parameters, to impact the NAB-P + GEM and FOLFIRINOX ICURs. Conclusions: In the absence of a statistically significant difference in OS between NAB-P + GEM and FOLFIRINOX, this US analysis indicates that the greater economic benefit in terms of cost-savings and incremental cost-effectiveness and cost-utility ratios favors NAB-P + GEM over FOLFIRINOX.