Kabir Mody

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

BACKGROUND Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing

Cholangiocarcinoma is a heterogeneous malignant process, which is further classified into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The poor prognosis of the disease is partly due to the lack of understanding of the disease mechanism. Multiple gene alterations identified by various molecular techniques have been described recently. As a result, multiple targeted therapies for ICC and ECC are being developed. In this study, we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing (NGS) (Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips). Eleven of 16 samples passed internal quality control established for NGS testing. ICC cases (n=3) showed IDH1 (33.3%) and NRAS (33.3%) mutations. Meanwhile, TP53 (75%), KRAS (50%), and BRAF (12.5%) mutations were identified in ECC cases (n=8). Our study confirmed the molecular heterogeneity of ICC and ECC using NGS. This information will be important for individual patients as targeted therapies for ICC and ECC become available in the future.

Drug eluting biliary stents to decrease stent failure rates: A review of the literature.

Biliary stenting is clinically effective in relieving both malignant and non-malignant obstructions. However, there are high failure rates associated with tumor ingrowth and epithelial overgrowth as well as internally from biofilm development and subsequent clogging. Within the last decade, the use of prophylactic drug eluting stents as a means to reduce stent failure has been investigated. In this review we provide an overview of the current research on drug eluting biliary stents. While there is limited human trial data regarding the clinical benefit of drug eluting biliary stents in preventing stent obstruction, recent research suggests promise regarding their safety and potential efficacy.

The effect of neoadjuvant chemoradiation on pancreatic cancer-associated diabetes mellitus.

Objectives Pancreatic cancer-associated diabetes mellitus (PaCDM) occurs in approximately 50% of patients. In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy before surgical resection, we hypothesized that pancreatic tumor destruction would lead to improvement in fasting glucose levels. Methods A retrospective chart review was performed on patients with newly diagnosed pancreatic adenocarcinoma without a history of DM treated with neoadjuvant therapy at our center. All patients underwent combined modality neoadjuvant chemoradiation therapy, followed by surgical excision of the primary tumor. Results Sixty-nine patients (31 with PaCDM) met inclusion criteria for the study; 18 had Evans grade II tumor kill response, 10 had grade III response, and 3 had grade IV response. In patients with grade IV response, the odds ratio (OR) for achieving a normal preoperative glucose was 5.0 (95% confidence interval [CI], 0.4–63.2), compared with grade III (OR, 0.5; 95% CI, 0.1–3.0) and grade II (OR, 1.1; 95% CI, 0.2–5.2). When adjusted for percent kilogram weight loss and tumor size in a multivariable regression model, the grade IV response became significant to an OR of 6.5 (95% CI, 1.2–77.3). Conclusions In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy, fasting glucose response may mirror the extent of tumor destruction.