A Web-Based Tool for Patient Triage in Emergency Department Settings: Validation Using the Emergency Severity Index.

BACKGROUND: We evaluated the concordance between triage scores generated by a novel Internet clinical decision support tool, Clinical GPS (cGPS) (Lumiata Inc, San Mateo, CA), and the Emergency Severity Index (ESI), a well-established and clinically validated patient severity scale in use today. Although the ESI and cGPS use different underlying algorithms to calculate patient severity, both utilize a five-point integer scale with level 1 representing the highest severity. OBJECTIVE: The objective of this study was to compare cGPS results with an established gold standard in emergency triage. METHODS: We conducted a blinded trial comparing triage scores from the ESI: A Triage Tool for Emergency Department Care, Version 4, Implementation Handbook to those generated by cGPS from the text of 73 sample case vignettes. A weighted, quadratic kappa statistic was used to assess agreement between cGPS derived severity scores and those published in the ESI handbook for all 73 cases. Weighted kappa concordance was defined a priori as almost perfect (kappa > 0.8), substantial (0.6 < kappa < 0.8), moderate (0.4 < kappa < 0.6), fair (0.2 < kappa< 0.4), or slight (kappa < 0.2). RESULTS: Of the 73 case vignettes, the cGPS severity score matched the ESI handbook score in 95% of cases (69/73 cases), in addition, the weighted, quadratic kappa statistic showed almost perfect agreement (kappa = 0.93, 95% CI 0.854-0.996). In the subanalysis of 41 case vignettes assigned ESI scores of level 1 or 2, the cGPS and ESI severity scores matched in 95% of cases (39/41 cases). CONCLUSIONS: These results indicate that the cGPS is a reliable indicator of triage severity, based on its comparison to a standardized index, the ESI. Future studies are needed to determine whether the cGPS can accurately assess the triage of patients in real clinical environments.

HER2/neu-directed therapy for biliary tract cancer.

BACKGROUND: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown. PATIENTS AND METHODS: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed. RESULTS: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy. CONCLUSIONS: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.

Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.

BACKGROUND: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. METHODS: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. RESULTS: There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. CONCLUSION: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Overexpression of the HER2/neu Gene: A New Therapeutic Possibility for Patients With Advanced Gallbladder Cancer.

BACKGROUND: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy. METHODS: Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/American Society of Clinical Oncology) criteria for breast cancer. RESULTS: Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%). CONCLUSION: This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway.

New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. METHODS: DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 µm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. RESULTS: The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). CONCLUSION: Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.

Molecular characterization of gallbladder cancer using somatic mutation profiling.

Gallbladder cancer is relatively uncommon, with a high incidence in certain geographic locations, including Latin America, East and South Asia, and Eastern Europe. Molecular characterization of this disease has been limited, and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n = 72) was examined for the presence of targetable, somatic mutations. All cases were formalin fixed and paraffin embedded (FFPE). Two approaches were used: (a) mass spectroscopy-based profiling for 159 point ("hot spot") mutations in 33 genes commonly involved in solid tumors and (b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hot spot mutations; and 15, for NGS. Fourteen hot spot mutations were identified in 9 cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (n = 2) and ALK (n = 1). On NGS, 26 mutations were noted in 15 cases. TP53 and PI3 kinase pathway (STK11, RICTOR, TSC2) mutations were common. One case had FGF10 amplification, whereas another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular, may be a useful platform for identifying novel mutations for targeted therapy.