The Cholangiocarcinoma in the Young (CITY) Study: Tumor Biology, Treatment Patterns, and Survival Outcomes in Adolescent Young Adults With Cholangiocarcinoma.

PURPOSE: Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS: A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS: Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation (P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION: Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma.

BACKGROUND: Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. METHODS: This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. RESULTS: Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P < .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P < .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P < .001). CONCLUSIONS: Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

Prevalence and Clinicopathologic Characteristics of Hypercalcemia in Patients With Cholangiocarcinoma.

This cohort study investigates clinicopathologic and prognostic associations of hypercalcemia in patients with intrahepatic or extrahepatic cholangiocarcinoma.

Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Patient Navigation Increases Linkage to Care and Receipt of Direct-acting Antiviral Therapy in Patients with Hepatitis C.

BACKGROUND & AIMS: Patient navigation interventions can improve health outcomes in underserved, low-income, and racial and ethnic minority groups, who often experience health disparities. We examined the effectiveness of patient navigation to improve linkage to hepatitis C virus (HCV) treatment receipt in a socioeconomically disadvantaged, racially diverse patient population. METHODS: We performed a pre-post analysis evaluating the effectiveness of a patient navigation program among baby boomers who tested positive for HCV in a safety-net health system. The usual care group (June 2013 to May 2015) and patient navigation group (January 2016 to December 2017) were balanced using a stabilized inverse probability of treatment weighting approach. We used logistic regression analyses to evaluate associations between patient navigation and linkage to care for HCV treatment evaluation, treatment initiation, and sustained virologic response. RESULTS: Among 1353 patients (62% black, 61% uninsured, 16% homeless), 769 were in the usual care group, and 584 were in the patient navigation group. The patient navigation group had significantly higher odds of linkage to care (odds ratio [OR], 3.7; 95% confidence interval [CI], 2.9-4.8) and treatment initiation (OR, 3.2; 95% CI, 2.3-4.2) within 6 months. The patient navigation group continued to have increased linkage to care (OR, 3.4; 95% CI, 2.7-4.3) and treatment initiation (OR 2.3; 95% CI, 1.7-3.0) at 12 months. However, there was no significant difference in sustained virologic response between the groups (86.9% vs 86.1%; P = .78). CONCLUSIONS: Patient navigation was associated with significantly increased linkage to care and treatment initiation among patients with HCV infection. Patient navigation programs can be used to promote HCV elimination among traditionally difficult-to-reach patient populations.

FGFR mRNA Expression in Cholangiocarcinoma and Its Correlation with FGFR2 Fusion Status and Immune Signatures.

PURPOSE: Selective FGFR inhibitors are effective against cholangiocarcinomas that harbor gene alterations in FGFR2. Clinical trials suggest that expression of wild-type FGFR mRNA can predict sensitivity to FGFR inhibitors, but this biomarker has not been well characterized in cholangiocarcinoma. This study explores the prevalence of FGFR mRNA overexpression in cholangiocarcinoma, its role in predicting sensitivity to FGFR inhibitors, and its association with immune markers. EXPERIMENTAL DESIGN: Tissue microarrays of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) resected between 2004 and 2015 were used to evaluate FGFR1-4 mRNA expression levels by RNA in situ hybridization (ISH). Expression levels of FGFR2 mRNA were correlated with FGFR2 fusion status and with patient outcomes. Immune markers expression was assessed by IHC and CSF1 and CSF1 receptor expression were examined by RNA ISH. RESULTS: Among 94 patients with resected cholangiocarcinoma, the majority had ICC (77%). FGFR2 fusions were identified in 23% of ICCs and 5% of ECCs. High levels of FGFR mRNA in FGFR2 fusion-negative ICC/ECC were seen for: FGFR1 (ICC/ECC: 15%/0%), FGFR2 (ICC/ECC: 57%/0%), FGFR3 (ICC/ECC: 53%/18%), and FGFR4 (ICC/ECC: 32%/0%). Overall, 62% of fusion-negative cholangiocarcinomas showed high levels of FGFR mRNA. In patients with advanced FGFR2 fusion-positive ICC, high levels of FGFR2 mRNA did not correlate with clinical benefit. FGFR2 fusion-positive tumors showed a paucity of PD-L1 on tumor cells. CONCLUSIONS: FGFR mRNA overexpression occurs frequently in cholangiocarcinoma in the absence of genetic alterations in FGFR. This study identifies a molecular subpopulation in cholangiocarcinoma for which further investigation of FGFR inhibitors is merited outside currently approved indications.

Development of a Mobile Application to Enhance Knowledge, Awareness and Communication of Dry Mouth Amongst Dental Practitioners and Patients: A South Texas Oral Health Network Study.

BACKGROUND: Dry mouth, also commonly known as "xerostomia", is a prominent symptom that is often overlooked by dental practitioners and patients. The purpose of this study was to pilot the development of a mobile application for assessing dry mouth symptoms. The application will allow patients to self-assess and enhance knowledge, awareness and communication with dental practitioners in their management of dry mouth. METHOD: The first phase of the study was to draw on common knowledge and awareness by conducting two focus groups of dental professionals and community members on content, practicality, functionality, design, and effectiveness. The second phase of the study was the development of the dry mouth mobile application followed by the third phase of the study that consisted of face-validity interviews to obtain feedback on the application. RESULTS: Fifty two percent (n=15) of the dental professionals estimated being aware of the prevalence of dry mouth in 40% or more of their patients. Thirty Nine percent of (n=9) community estimated being aware of the prevalence of dry mouth in 40% or more of the community. When asked about their awareness of the etiologies of dry mouth, 100% (n=29) of dental professionals reported that multiple medications and smoking were primary factors whereas the community members indicated that illness and dehydration (87%, n=20) were primary factors in dry mouth. Dental professional's (25% n=7) were very confident in recognizing symptoms and 28% (n=8) were very confident they knew how to manage dry mouth symptoms. Furthermore, 22% (n=5) of the community members were also very confident about recognizing dry mouth symptoms and 13% (n=3) were very confident knowing how managing it. The ToP report generated from the discussions identified "themes" that were utilized in the development of the mobile application. Most individuals who participated in the validity interviews agreed that the dry mouth mobile application was useful, appealing, easy to use and the self-assessment test gave clear and concise information. The application was made available to download from the iTunes Appstore (2019-2020). CONCLUSION: The dry mouth pilot study indicated that the mobile application was beneficial for self-assessment and easy to use. Development of advanced technology tools such as the dry mouth application can promote communication between patients and their dental practitioners to discuss management options for dry mouth.

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

Pilot Study of Quantitative Methods for Differentiating Pharyngeal Swallowing Mechanics by Dysphagia Etiology.

Quantitative analysis of modified barium swallow (MBS) imaging is useful to determine the impact of various disease states on pharyngeal swallowing mechanics. In this retrospective proof of concept study, kinematic analysis and computational analysis of swallowing mechanics (CASM) were used to demonstrate how these methods differentiate swallowing dysfunction by dysphagia etiology. Ten subjects were randomly selected from four cohorts of dysphagic patients including COPD, head and neck cancer (HNC), motor neuron disease, and stroke. Each subject was age- and gender-matched with healthy, non-dysphagic controls. MBS videos of 5 ml thin and 5 ml thick bolus trials from each subject were used. A MATLAB tracker tool was adapted and updated to collect and compile data for each video (n = 160). For kinematic measurements, a MANOVA was performed with post-hoc analyses to determine group differences. For CASM measurements, a morphometric canonical variate analysis with post hoc analysis was performed to determine group differences. Kinematic analyses indicated statistically significant differences between HNC cohort and controls in distance measurements for hyolaryngeal approximation (p = .001), laryngeal elevation (p = 0.0001), pharyngeal shortening (p = 0.0002), and stage transition duration timing (p = 0.002). Timing differences were noted between the stroke cohort and controls for pharyngeal transit time (p = 0.007). Multivariate morphometric canonical variate analysis showed significant differences between etiology groups (p < 0.0001) with eigenvectors indicating differing patterns of swallowing mechanics. This study demonstrated that swallowing mechanics among cohorts of dysphagic patients can be differentiated using kinematics and CASM, providing different but complementary quantitative methods for investigating the impact of various disease states on swallowing function.

An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.

OBJECTIVE: The underlying mechanisms of depression remain unclear; however, current literature suggests a relationship between inflammation and depression. The association between the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) and depression has been previously investigated, but the relationship between GlycA, a novel spectroscopic inflammatory biomarker, and depression does not appear to have been examined. METHODS: Data were obtained from The Dallas Heart Study (DHS, conducted between 2000 and 2002), which consisted of a large community-based sample of Dallas County residents (N = 3,033). Depressive symptom severity was assessed with the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). It was hypothesized that the serum GlycA level would be a statistically significant predictor of QIDS-SR scores after control for demographic covariates. Multiple linear regression was used to assess the relationship between GlycA level and QIDS-SR scores. The role of hs-CRP in predicting QIDS-SR scores was also explored. RESULTS: GlycA level was a statistically significant positive predictor of QIDS-SR score (ß = .053, P = .038) with control for sex, age, antidepressant use, ethnicity, smoking status, drinking status, body mass index, and years of education. In a subset of adults with moderate-to-severe depression, GlycA level was not associated with QIDS-SR scores. Additionally, hs-CRP level was not a statistically significant predictor of QIDS-SR scores. CONCLUSIONS: This study found a positive association between the inflammatory biomarker GlycA, but not hs-CRP, and depressive symptom severity in a large multiethnic and multiracial community-based sample. Thus, these results provide the first indication that GlycA may be a potentially useful novel biomarker of depression.

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

Connecting and Collaborating: Developing National Dental PBRN Study Concepts Through POD Engagement.

PURPOSE: This article illustrates the process by which the Southwest Region of the National Dental Practice-Based Research Network (www.NationalDentalPBRN.org) fosters collaboration among practitioners and researchers in study concept development through protocol development groups (PODs). The Southwest Region begins this process by engaging PODs, which comprise dentists, hygienists, and/or academic faculty who share research interests related to improving dental care. METHOD: The PODs use the Tuckman four-stage model of group development (forming, storming, norming, and performing) to develop study concepts. This well-structured model encourages engagement among group members and enables quality discussion through organized sessions. This model provides milestones for the group's progression and for the members' interactions. The Southwest Region Directors play a crucial role in guiding and directing the development of PODs by aligning the members' research interests with the goals of the National Network. RESULTS: POD engagement using Tuckman's stages has been successful in developing study concepts for submission to the National Network. Between 2012 and 2014, the Southwest Region has developed 14 PODs from 275 research ideas. Five of these study concepts have been submitted to the National Network for approval, including the Novel Tobacco Products POD, which showcases the applicability of Tuckman's model. CONCLUSION: Overall, the POD concept is a collaborative effort that brings together practitioners and academicians through shared research interests and capitalizes on participants' expertise and experiences. The Southwest Region will continue to develop PODs to foster new ideas for future studies in the Network.

Patterns of FOS expression in the spinal cord and periaqueductal grey matter of 6OHDA-lesioned rats.

A less well-known feature of Parkinson disease is that up to 40% of patients experience distinct sensory disturbances, including hyperalgesia and chronic pain. There is a limited understanding of the neural mechanisms that generate these symptoms, however. This study explores the patterns of Fos expression (a well-known marker for changes in cell activity) in the spinal cord and periaqueductal grey matter (PaG), two major sensory (nociceptive) centers, of hemiParkinsonian rats. The medial forebrain bundle (mfb; major tract carrying dopaminergic nigrostriatal axons) was injected with either 6OHDA or saline (controls). A week later, some rats were subjected to mechanical stimulation (pinching) of the hindpaw for 2 h, whereas others received no stimulation. Thereafter, brains were processed using routine tyrosine hydroxylase (marker for dopaminergic cells) or Fos immunocytochemistry. In the PaG, there were many more Fos(+) cells in the 6OHDA-lesioned than in the Control group, in both the stimulation and, in particular, the non-stimulation cases. In the spinal cord, there were also more Fos(+) cells in the 6OHDA-lesioned than in the Control group, but in the stimulation cases only. Overall, the results show distinct changes in Fos expression in the spinal cord and PaG of 6OHDA-lesioned rats, suggesting a substrate for some of the abnormal sensory (nociceptive) circuits that may be evident in parkinsonian cases.