Search

OBJECTIVES:We examined the trends in the rate of Henoch-Schönlein purpura (HSP) hospitalizations and the associated resource use among children in the United States from 2006 through 2014.METHODS:Pediatric hospitalizations with HSP were identified by using International Classification of Diseases, Ninth Revision, code 287.0 from the National Inpatient Sample. HSP hospitalization rate was calculated by using the US population as the denominator. Resource use was determined by length of stay (LOS) and hospital cost. We used linear regression for trend analysis.RESULTS:A total of 16 865 HSP hospitalizations were identified, and the HSP hospitalization rate varied by age, sex, and race. The overall HSP hospitalization rate was 2.4 per 100 000 children, and there was no trend during the study period. LOS remained stable at 2.8 days, but inflation-adjusted hospital cost increased from $2802.20 in 2006 to $3254.70 in 2014 (P < .001).CONCLUSIONS:HSP hospitalization rate in the United States remained stable from 2006 to 2014. Despite no increase in LOS, inflation-adjusted hospital cost increased. Further studies are needed to identify the drivers of increased hospitalization cost and to develop cost-effective management strategies.

Purpose FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. Patients and Methods Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. Results Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS. Conclusion CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

BACKGROUND Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit. METHODS Hybrid capture–based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model. RESULTS The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P

Background Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). Results When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. Conclusions In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.

Biliary tract cancers are relatively uncommon, have an aggressive disease course and a dismal clinical outcome. Until recently, there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy. The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease. Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice. Mutation profiling has highlighted the genomic differences between the intra, extrahepatic cholangiocarcinoma, and gallbladder cancer. The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity. There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma. KRAS and p53 mutations are associated with an aggressive disease prognosis while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma. FGFR and IDH mutations have promising agents in clinical trials at this time. An estimated 15 % of gallbladder cancers have Her2/neu amplification and can be targeted by trastuzumab. On the other hand, an estimated 10-15 % of cholangiocarcinomas have DNA repair mutations and may be candidates for immune therapies with checkpoint inhibitors. The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed, prospective, and multi-center clinical trials.

Background: BRCA-associated protein 1, an enzyme encoded by the BAP1 gene, is commonly mutated in uveal melanoma, mesothelioma, and renal cancers. Tumors with BAP1 mutation follow an aggressive course. BAP1 mutations have also been observed in cholangiocarcinoma (CCA). The clinical phenotype of BAP1 mutant CCA may yield useful prognostic and therapeutic information but has not been defined. Methods: The records of CCA patients who underwent next-generation sequencing (NGS) were reviewed, and data on clinical, histopathological, genetic, and radiological features; response to therapy; time to progression; and survival were analyzed. Results: Twenty-two cases of BAP1 -mutation associated CCA were diagnosed from January 1, 2009, to February 1, 2015, at our center. Twenty patients had intrahepatic CCA and two had extrahepatic CCA. Tumor sizes (largest dimension) ranged from 2 to 16 cm (mean, 8.5 cm). Twelve patients had tumors that were poorly differentiated. Majority of the patients had advanced disease at presentation and 13 had bone metastases. Thirteen patients (59%) experienced rapidly progressive disease following primary therapy (chemotherapy or surgical resection). The mean time to tumor progression was 3.8 months after the first line chemotherapy. Conclusions: BAP1 mutation in CCA may be associated with aggressive disease and poor response to standard therapies. Therefore, BAP1 -targeted therapies need to be investigated.

Background Recently released American College of Cardiology/American Heart Association (ACC/AHA) guideline recommends the Pooled Cohort equations for evaluating atherosclerotic cardiovascular risk of individuals. The impact of the clinical input variable uncertainties on the estimates of ten-year cardiovascular risk based on ACC/AHA guidelines is not known. Methods Using a publicly available the National Health and Nutrition Examination Survey dataset (2005–2010), we computed maximum and minimum ten-year cardiovascular risks by assuming clinically relevant variations/uncertainties in input of age (0–1 year) and ±10 % variation in total-cholesterol, high density lipoprotein- cholesterol, and systolic blood pressure and by assuming uniform distribution of the variance of each variable. We analyzed the changes in risk category compared to the actual inputs at 5 % and 7.5 % risk limits as these limits define the thresholds for consideration of drug therapy in the new guidelines. The new-pooled cohort equations for risk estimation were implemented in a custom software package. Results Based on our input variances, changes in risk category were possible in up to 24 % of the population cohort at both 5 % and 7.5 % risk boundary limits. This trend was consistently noted across all subgroups except in African American males where most of the cohort had ≥7.5 % baseline risk regardless of the variation in the variables. Conclusions The uncertainties in the input variables can alter the risk categorization. The impact of these variances on the ten-year risk needs to be incorporated into the patient/clinician discussion and clinical decision making. Incorporating good clinical practices for the measurement of critical clinical variables and robust standardization of laboratory parameters to more stringent reference standards is extremely important for successful implementation of the new guidelines. Furthermore, ability to customize the risk calculator inputs to better represent unique clinical circumstances specific to individual needs would be highly desirable in the future versions of the risk calculator. Electronic supplementary material The online version of this article (doi:10.1186/s12872-016-0352-x) contains supplementary material, which is available to authorized users.

Gallbladder cancer (GBC) is an aggressive malignancy. Although surgical resection may be curable, most patients are diagnosed at an advanced unresectable disease stage. Cholelithiasis is the major risk factor; however the pathogenesis of the disease, from gallstone cholecystitis to cancer, is still not understood. To understand the molecular genetic underpinnings of this cancer and explore novel therapeutic targets for GBC, we examined the key genes and pathways involved in GBC using RNA sequencing. We performed gene expression analysis of 32 cases of surgically-resected GBC along with normal gallbladder tissue controls. We observed that 519 genes were differentially expressed between GBC and normal GB mucosal controls. The liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor (FXR) /RXR pathways were the top canonical pathways involved in GBC. Key genes in these pathways, including SERPINB3 and KLK1, were overexpressed in GBC, especially in female GBC patients. Additionally, ApoA1 gene expression suppressed in GBC as compared with normal control tissues. LXR and FXR genes, known to be important in lipid metabolism also function as tumor suppressors and their down regulation appears to be critical for GBC pathogenesis. LXR agonists may have therapeutic value and as potential therapeutic targets.

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was >550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

428 Background: Acute cholangitis due to malignant biliary obstruction is frequent in patients with pancreatic and hepatobiliary cancers. Recurrent cholangitis (RC) results in repeated hospitalization and delayed cancer care. The risk factors associated with RC are not yet defined. Methods: A pilot review was done on 146 patients admitted with a diagnosis of cholangitis from 2005 to 2014. We included demographics, cancer stage, details of first admission (FA) and interventions. Univariate and multivariate Fine-Gray models were used for statistical analysis. Results: The mean age at FA was 62 yrs, 84 (58%) were males and 99 (68%) were white. Most common cancer was pancreatic 100(69%) and 27(19%) pts had primary cholangitis at FA. During FA, interventions were performed in 114(78%), of whom 51 (45%) had percutaneous drainage (PTBD) and 63 (55%) had endoscopic drainage (ED). Readmission with cholangitis was noted in 35 (24%) cases. Univariate analysis did not show a difference between PTBD and ED. However, subgroup analysis showed external only PTBD and covered metallic stent ED had lower risk of RC. These variables remained significant on multivariate analysis (Subdistribution HR= 0.00, p

240 Background: As seen in lung cancer, young patients with cancer can have different risk factors, presentation, and tumor genotype than older patients with the same disease. The clinical and molecular features of young patients with CCA have yet to be well characterized. Methods: Retrospective chart review was performed on patients with intrahepatic (ICC) or extrahepatic cholangiocarcinoma (ECC) across 5 institutions. Data on demographics, risk factors, treatments, pathology, and overall survival (OS) were collected. Tumor genotyping results from MGH SNaPShot and Foundation Medicine were analyzed. Log-rank tests and Kaplan-Meier survival curves were used for statistical analysis. Results: Of 567 patients analyzed, 134 (23.6%) were < 50 years old (yo) and 455 (80.2%) had ICC. When assessed for risk factors, younger patients ( < 50yo) were more likely to have primary sclerosing cholangitis (PSC) (p < 0.001) and less likely to have diabetes (p = 0.05), compared to older patients ( ≥ 50yo). Surgical resection rates were similar in younger vs older patients (41.9 vs 42.6%, p = 0.890), but younger patients had larger tumors (median size 7.1 vs 5.3cm p = 0.012). Younger patients were also more likely to receive palliative systemic chemotherapy (p < 0.001) and more lines of therapy (median, 2 vs 1 line, p < 0.001). Frequency of treatment with liver directed therapy did not differ between the two groups. Molecular testing was performed on 222/567 (39.1%) patients of which 84/134 (62.7%) were younger patients and 138/433 (31.9%) were older patients. FGFR aberrations were more common in younger patients versus older patients (17.6 vs. 5.7%, p = 0.002). Targeted therapy was given to 15/84 (17.9%) younger and 28/138 (20.3%) older patients based on results of mutational profiling. Finally, no significant difference was seen in OS between younger and older patients (22.9 vs 22.7 months, p = 0.89). Conclusions: Younger patients with CCA may have different risk factors, tumor biology, and tolerance of systemic therapy compared to older patients. Further study is needed as referral patterns to tertiary care centers and motivation of younger patients to seek tertiary care may impact these results.

109Background: FGFR pathway genetic aberrations (GAs) occur in an estimated 10% of intrahepatic cholangiocarcinomas (IHCCA). The most common are FGFR2 mutations (mut). The advent of FGFR targeted inhibitors may alter the outcome of this disease subtype. The natural history of FGFR mutant CCA and prognostic role of co-existing mut is unknown. Methods: We reviewed the records of CCA patients (pts) with FGFR pathway GAs identified on next generation sequencing (NGS). Data reviewed included demographics, treatments, progression-free survival (PFS) with first-line chemotherapy, overall survival (OS) and mut data (Foundation Medicine or Institutional NGS). KM plots and log rank tests were used for statistical analysis. Results: A total of 54 pts with FGFR pathway GAs were identified from our database of 321 biliary cancer pts who had NGS. These included: 32 FGFR2 mut, which occurred almost exclusively in IHCCA (except 1 GB cancer pt). Of these, FGFR fusions occurred in 27. Most common FGFR fusion was FGFR2-BICC...

287 Background: aBTC is uncommon and has a dismal prognosis with limited therapeutic options. First-line therapy for untreated aBTC is GC, with no approved therapies in the refractory setting. To assess for tumor-specific genetic variants that affect outcomes in patients (pts) who received GC in aBTC, we performed NGS in pts treated with who received GC as first-line therapy. Methods: Archival formalin-fixed, paraffin-embedded samples from pts with mBTC from Ohio State University and MD Anderson Cancer Center who received GC in the first-line and underwent NGS as part of routine care. 315 cancer-related genes plus select introns from 28 genes altered in solid tumors were included in the NGS panel. Univariate Cox regression model was used to determine the association between gene mutations with progression free survival (PFS) and (OS). Results: 80 evaluable pts with aBTC treated with first-line GC chemotherapy underwent successful genomic profiling. A total of 414 cancer-specific mutations were identified, where 49 (12%) genes had mutations with > 5% frequency. 17 of the 49 were known mutations. From the comprehensive analysis, somatic mutations in IDH1 (11 of 80 pts; 13%) (HR 0.31; p = 0.035) was associated with improved overall survival (OS) and progression free survival (PFS). Pts wild type for IDH1 had a median OS of 17.7 months and PFS of 4.5 months, while those with an IDH1 mutation had a median OS that was not reached and an improved PFS of 5.7 months. Conclusions: Somatic mutations in IDH1 were associated with improved clinical outcomes in pts with aBTC who received GC as first-line therapy which is consistent with other solid tumor malignancies. IDH1 is a therapeutic target of interest, where future prospective studies will be necessary to validate the predictive utility and its relevance in pt outcomes in aBTC.

244 Background: Biliary tract cancers (BTC) exhibit a diverse and high frequency of actionable mutations detectable using next generation sequencing (NGS). The Breast Cancer Linkage Consortium reported that BRCA2 mutation carriers are at increased risk for BTC with estimated relative risk of 4.97, (95% CI = 1. 50-16.52). The purpose of this study was to evaluate the clinical characteristics of germline/somatic BRCA1/2mutations in CCA patients. Methods: Multi-center retrospective analysis of patients with germline/somatic BRCA1/2- associated CCA diagnosed between January 2000 and December 2013. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures and systemic chemotherapy or radiation were extracted from patient records. Results: Overall, we identified 18 cases including 5 carriers of germline BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic mutations (7 BRCA1; 6 BRCA2) using a NGS panel testing tumor for 'actionable' mutations. One patient presented with two different somatic mutations in the BRCA2gene. Mean age at diagnosis was 60 years (range 36-75), male: females (61.2% vs 38.8%, respectively). Stage at diagnosis: I (n = 4), II (n = 3), III (n = 3) and IV (n = 8). Six patients had extrahepatic CAA; twelve patients had intrahepatic CCA. Prior therapy in 13 patients included platinum-based therapy with one patient receiving prior olaparib. Median overall survival for patients with stage I/II is 34.7 months (95% CI, 7.06-62.9) and for stages III/IV is 25 months (95% CI, 12.02-35.84). Conclusions: BRCA associated CCA may have an enhanced therapeutic sensitivity to DNA damaging agents. This needs confirmation in a larger cohort of patients.