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The obesity and hepatocellular carcinoma (HCC) risk association may differ by individuals' metabolic health status. To investigate the association between obesity categories and HCC risk among individuals with different metabolic health phenotypes. A case-control study among 518 HCC cases and 1,036 frequency-matched controls was conducted. Body mass index (BMI) was assessed before diagnosis. Pre-diagnosis data on dyslipidemia, hypertension, and diabetes were used to categorize participants as metabolically healthy or metabolically unhealthy. Participants were further categorized into metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW), and metabolically unhealthy obese (MHO). We used logistic regression to calculate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Being overweight (OR=1.68, 95%CI=1.21–2.34) or obese (OR=1.49, 95%CI=1.11–1.89) was associated with higher HCC risk. Among metabolically healthy participants, no association was found between being overweight or obese and HCC risk. However, among the metabolically unhealthy participants, being overweight (OR=1.89, 95%CI=1.31–2.72) or obese (OR=1.50, 95%CI=1.07–2.09) was associated with higher HCC risk. Compared to the MHNW phenotype, no association was found between the MHOW and MHO phenotypes and HCC risk, but the MUNW (OR=1.94, 95%CI=1.09–3.43), MUOW (OR=3.78, 95%CI=2.15–6.65), and MUO (OR=2.93, 95%CI=1.70–5.05) phenotypes were associated with higher HCC risk. The association between BMI and HCC appears to be restricted to individuals with underlying metabolic abnormalities. [ABSTRACT FROM AUTHOR]

Malignant biliary strictures can be difficult to diagnose, with up to 20% considered indeterminate after initial tissue sampling. This study aimed to determine the performance characteristics of transpapillary biopsy sampling (TPB) and fluorescence in situ hybridization (FISH) in isolation or in combination with standard brush cytology (BC) in patients who received trimodality sampling for biliary strictures. This single-center retrospective cohort study included patients with biliary strictures undergoing ERCP with trimodality sampling between September 2014 and April 2019. Performance characteristics for each diagnostic test alone and in combination were calculated. Two hundred four patients underwent trimodality biliary sampling, including 104 (51.0%) with malignancy. The diagnostic sensitivity for malignancy with BC (17.3%) significantly improved with dual modality (BC+FISH, 58.7%; BC+TPB, 40.4%) or trimodality sampling (68.3%; P <.001 for all comparisons). Trimodality sampling improved diagnostic sensitivity for malignancy compared with BC+FISH (P =.002) and BC+TPB (P <.001). There was no statistically significant difference in the sensitivity of trimodality sampling in detecting cholangiocarcinoma (79.7%) compared with pancreatic cancer (62.5%; P =.1). Among 57 patients with primary sclerosing cholangitis (PSC), the sensitivity of detecting biliary malignancy (n = 20) was 20% for BC and significantly improved with the addition of FISH (80%; P <.001) but not with TPB (35.0%; P =.25). Trimodality sampling did not further improve diagnostic sensitivity (85%) over BC+FISH (80%) for malignancy in the setting of PSC (P = 1). Trimodality sampling improves the diagnostic sensitivity for the detection of malignant biliary strictures with no significant difference in sensitivity for cholangiocarcinoma compared with pancreatic cancer. However, in patients with PSC, trimodality sampling was not superior to BC+FISH. [Display omitted] [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.icarus.2005.06.011 Byline: Melinda A. Kahre (a), James R. Murphy (a), Nancy J. Chanover (a), John L. Africano (b), Lewis C. Roberts (b), Paul W. Kervin (c) Keywords: Mars; surface; Mars; atmosphere; Atmospheres; Structure; Image processing; Data reduction techniques Abstract: High spatial resolution images of Mars were acquired with the Advanced Electro-Optical System (AEOS) 3.63-meter telescope at the Maui Space Surveillance System (MSSS) during both the 2001 and 2003 Mars apparitions. Comparisons are made of the surface albedo patterns obtained from these AEOS images to the surface albedo maps constructed from the Mars Global Surveyor (MGS) Thermal Emission Spectrometer (TES) data taken during the same time periods. These comparisons demonstrate that the images provide albedo information in a limited area surrounding the sub-Earth point that is consistent with the TES-derived albedo field. Additionally, it is shown that by employing adaptive optics (AO), the typical ground-based observing season of Mars can be extended. This is the only known published AO data set of Mars with temporal coverage over an entire apparition. Changes in the surface albedo affect the local ground temperature, which impacts the depth of the planetary boundary layer (PBL) above the surface. Since it is the state of the PBL that controls surface/atmospheric interaction, albedo variations have the power to alter the amount of dust that is lifted. A one-dimensional radiative/convective version of the NASA Ames Mars General Circulation Model is used to demonstrate that the measured albedo variations can alter the daytime ground temperatures by as much as 5 K, which in turn alters the structure of the planetary boundary layer (PBL). Therefore, albedo changes are thermodynamically important, and the ability to characterize them, should orbital observations become unavailable, is a valuable capability. Author Affiliation: (a) Department of Astronomy, New Mexico State University, Las Cruces, NM 88003, USA (b) The Boeing Company, 535 Lipoa Pkwy, Suite 200, Kihei, HI 96753, USA (c) Detachment 15, Air Force Research Laboratory, 535 Lipoa Pkwy, Suite 200, Kihei, HI 96753, USA Article History: Received 18 March 2005; Revised 10 May 2005 Article Note: (footnote) [star] Based in part on observations made at the Maui Space Surveillance System (MSSS) operated by Detachment 15 of the Air Force Research Laboratory's Directed Energy Directorate.

Most patients with localized cholangiocarcinoma (CCA) endure cancer relapse after curative resection underscoring the importance of systemic therapy. The current study attempts to determine the impact of perioperative chemotherapy (PC) on survival in patients with CCA undergoing resection. Patients diagnosed with CCA undergoing curative-intent resection between January 1, 2000, and December 31, 2019, in a tertiary care center were included. Cox proportional hazard modeling was used to determine the impact of PC on disease-free survival (DFS) and overall survival (OS). In addition, a nomogram was constructed to estimate 3-year DFS. Among the 182 patients included in the analysis, 102 underwent surgery alone, and 80 received surgery plus PC. Forty-two patients received neoadjuvant therapy, and 38 patients received adjuvant therapy. On multivariate analysis, PC was significantly associated with an improved DFS (HR, 95% CI: 0.63, 0.41–0.98; p = 0.04) and OS (HR, 95% CI: 0.46, 0.27–0.78; p < 0.01). In the interaction analysis, the survival benefit was especially seen in patients with positive resection margins and tumor size > 5 cm. In patients with CCA undergoing curative resection, receipt of PC was associated with improved DFS and OS. The nomogram constructed from this database provides an estimate of 3-year DFS after surgical resection. Randomized trials are needed to define the optimal regimen and sequence. [ABSTRACT FROM AUTHOR]

Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. cohort. The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0–8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P <.05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P <.001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54–4.07), years with cirrhosis (P =.004; OR, 1.06; 95% CI, 1.02–1.1), family history of liver cancer (P =.02; yes; OR, 2.69; 95% CI, 1.11–5.86), age (per 5 years; P =.02; OR, 1.17; 95% CI, 1.03–1.33), obesity (P =.02; yes; OR, 1.7; 95% CI, 1.08–2.73), aspartate aminotransferase (log(1+AST); P =.06; OR, 1.54; 95% CI, 0.97–2.42), alpha-fetoprotein (log(1+AFP); P =.07; OR, 1.32; 95% CI, 0.97–1.77), and albumin (P =.10; OR, 0.7; 95% CI, 0.46–1.07). Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years. [Display omitted] The multicenter (HEDS) Hepatocellular Carcinoma Early Detection Strategy study uses the largest, multicenter, geographically diverse and prospective U.S. patient cohort to validate several risk factors for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Chemotherapy is frequently used in cholangiocarcinoma as an adjunct to surgical resection, but the appropriate sequence of chemotherapy with surgery is unclear. Using the National Cancer Database, we identified patients who underwent surgery and chemotherapy for stage I-III cholangiocarcinoma between 2006 and 2014. The propensity score reflecting the probability of receiving neoadjuvant chemotherapy was estimated by multivariate logistic regression method. Patients in the neoadjuvant and adjuvant chemotherapy study arms were then propensity-matched in 1:3 ratios using the nearest neighbor method. Overall Survival (OS) in the matched data set was estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using Cox proportional hazard regression model. Of the 1450 patients who met our inclusion criteria, 299 (20.6%) received neoadjuvant chemotherapy while 1151 (79.3%) received adjuvant chemotherapy. The median age at diagnosis was 63 years. 278 patients in the neoadjuvant group were matched to 700 patients in the adjuvant group. In the matched cohort, patients who received neoadjuvant chemotherapy had a superior OS compared to those who received adjuvant chemotherapy (Median OS: 40.3 vs. 32.8 months; HR: 0.78; 95% CI: 0.64–0.94, p = 0.01). The 1- and 5-year OS rates for the neoadjuvant chemotherapy group were 85.8% and 42.5% respectively compared to 84.6% and 31.7% for the adjuvant chemotherapy group. In this large national database study, neoadjuvant chemotherapy was associated with a longer OS in a select group of patients with cholangiocarcinoma compared to those who underwent upfront surgical resection followed by adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer. [ABSTRACT FROM AUTHOR]

Background & Aims Glycogenic hepatopathy, a syndrome characterized by hepatomegaly and increased liver transaminases in patients with type 1 diabetes, has not been well characterized in adults. We describe the clinical, biochemical, and histopathology profile of a cohort of patients with glycogenic hepatopathy. We also examined differences between patients with type 1 diabetes with versus without glycogenic hepatopathy. Methods We performed a case–control study of patients with type 1 diabetes diagnosed with glycogenic hepatopathy and patients with type 1 diabetes without glycogenic hepatopathy (control subjects). Cases were identified in the database of electronic medical records at Mayo Clinic, Rochester from January 1, 1998, through January 1, 2014. Age- and sex-matched control subjects were identified from a Mayo Clinic registry of patients with type 1 diabetes who had normal levels of liver enzymes. Demographic, clinical, laboratory, and histopathology data were collected and compared between cases and control subjects. The primary outcome was difference in frequency of diabetic ketoacidosis episodes and hemoglobin (Hb) A 1c levels between cases and control subjects. Results Among the 36 patients diagnosed with glycogenic hepatopathy, 20 had undergone liver biopsy analysis. Most cases were female (n = 28; 77.8%). Abdominal pain was the most common symptom (n = 23; 63.9%); 28 patients (77.8%) had hepatomegaly. All patients had poor control of diabetes (mean HbA 1c level, 11.2 ± 2.4%). A higher proportion of cases had recurrent episodes of diabetic ketoacidosis (61%) than control subjects (9%) ( P = .009), and cases had a higher mean level of HbA 1c (11.2 ± 2.4% vs 9.0 ± 2.2% in control subjects; P = .0004). Adult cases had higher levels of aspartate transaminase (312.5 IU/L; range, 245.5–775 IU/L) than pediatric cases (157; range, 104–267 IU/L; P = .02) and lower serum levels of albumin (3.7 ± 0.5 g/dL vs 4.3 ± 0.4 g/dL for pediatric cases; P = .008). Only 16.7% of pediatric patients with glycogenic hepatopathy had growth retardation. Levels of liver transaminases were normalized at follow-up examinations of 18 of 21 adult or pediatric patients with glycogenic hepatopathy. Conclusions More than half of patients with glycogenic hepatopathy and type 1 diabetes have recurrent episodes of diabetic ketoacidosis, and these patients have higher levels of HbA 1c than patients with type 1 diabetes without glycogenic hepatopathy. We observed growth retardation in only about 17% of pediatric patients with glycogenic hepatopathy. [ABSTRACT FROM AUTHOR]

Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response. [ABSTRACT FROM AUTHOR]

Background and Aims Fluorescence in situ hybridization (FISH) has improved the diagnostic performance of cytology for the evaluation of malignant biliary strictures in the United States and Europe. The utility of FISH for the diagnosis of biliary strictures in Asia is currently unknown. We aimed to compare the sensitivity of FISH and conventional cytology for the diagnosis of malignant biliary strictures in Thai patients. Methods A prospective study was performed at 2 university hospitals between 2010 and 2013. Patients being evaluated for malignant-appearing biliary strictures were included (N = 99). Bile duct brushings were collected and assessed by cytology and FISH. Sensitivities with 95% confidence intervals of cytology and FISH were the main outcome measures. Results The overall sensitivities of cytology and FISH were 38% and 55%, respectively ( P = .001). For those with a diagnosis of cancer based on clinical evidence without biopsy confirmation (n = 44), the sensitivities of cytology and FISH were 43% and 57%, respectively ( P = .06). For the 49 patients for whom a cancer diagnosis was confirmed by pathology, FISH had a significantly higher sensitivity than cytology, with a sensitivity of 53% versus 33%, respectively ( P = .008). Conclusions FISH improves the diagnostic performance of cytology and can be used as a complementary tool to bile duct brushing and biopsy for the evaluation of malignancy in biliary strictures in Asian populations. [ABSTRACT FROM AUTHOR]

In many clinical settings, there is a high comorbidity between substance use disorders, psychiatric disorders, and traumatic stress. Novel therapies are needed to address these co-occurring issues efficiently. The aim of the present study was to conduct a pragmatic randomized controlled trial comparing Mindfulness-Oriented Recovery Enhancement (MORE) to group Cognitive-Behavioral Therapy (CBT) and treatment-as-usual (TAU) for previously homeless men residing in a therapeutic community. Men with co-occurring substance use and psychiatric disorders, as well as extensive trauma histories, were randomly assigned to 10 weeks of group treatment with MORE (n = 64), CBT (n = 64), or TAU (n = 52). Study findings indicated that from pre-to post-treatment MORE was associated with modest yet significantly greater improvements in substance craving, post-traumatic stress, and negative affect than CBT, and greater improvements in post-traumatic stress and positive affect than TAU. A significant indirect effect of MORE on decreasing craving and post-traumatic stress by increasing dispositional mindfulness was observed, suggesting that MORE may target these issues via enhancing mindful awareness in everyday life. This pragmatic trial represents the first head-to-head comparison of MORE against an empirically-supported treatment for co-occurring disorders. Results suggest that MORE, as an integrative therapy designed to bolster self-regulatory capacity, may hold promise as a treatment for intersecting clinical conditions. [ABSTRACT FROM AUTHOR]

New biomarkers of hepatocellular carcinoma (HCC) have been identified using advanced genomic, proteomic, and metabolomics technologies. These are being developed not only for use in diagnosis of HCC, but also in prediction of patient and treatment outcomes and individualization of therapy. Some HCC biomarkers are currently used in surveillance to detect early stage HCCs and reduce mortality. Further studies are needed to determine whether the recently identified HCC biomarkers can be used in clinical practice; most are only in phase 1 or 2 studies. The diagnostic and predictive abilities of biomarkers are limited by the heterogeneous nature of HCCs; there is no perfect single biomarker of this tumor. To improve performance, combinations of biomarkers (panels), or combinations of biomarkers and clinical parameters or laboratory test results, might be required. We describe recently discovered biomarkers of HCC and discuss challenges to their development and application. [ABSTRACT FROM AUTHOR]

Serum α-fetoprotein (AFP), a well-established biomarker for hepatocellular carcinoma (HCC), increases the sensitivity of ultrasound-based surveillance programs for early stage HCC detection.1,2 Multiple factors, including tumor burden, can affect AFP levels in patients with HCC.3 Nontumoral factors, such as race/ethnicity and liver disease etiology, are also known to be associated with elevated AFP.3 With the increasing trend of earlier stage HCC detection and shift from viral to nonviral etiology, we hypothesized that AFP level at HCC diagnosis would decrease in the United States. [ABSTRACT FROM AUTHOR]

Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore potential predictors of self-reported paretic arm use at baseline and after task-specific training (TST) in survivors of stroke. Design: Data were obtained from a randomized controlled trial of somatosensory stimulation and upper limb TST in chronic stroke. Setting: University laboratory. Participants: Chronic (≥3mo) survivors of stroke (N=33; mean age, 62y; mean stroke duration, 38mo). Interventions: Participants received 12 sessions of TST preceded by either active (n=16) or sham (n=17) somatosensory stimulation to all 3 peripheral nerves. Main Outcome Measures: Demographic and clinical characteristics were entered stepwise into multiple linear regression analyses to determine the factors that best predict baseline Motor Activity Log (MAL) amount of use rating and change 3 months after TST. Results: The Action Research Arm Test (ARAT) score predicted the amount of use at baseline (R 2=.47, P<.001); in using this model, an ARAT score of 54 (maximum of 57) is required to score 2.5 on the MAL (use described as between rarely and sometimes). After TST the change in the ARAT score predicted the change in the amount of use (R 2=.31, P=.001). The predictive power of the model for change at 3 months increased if the Fugl-Meyer Assessment wrist component score was added (R 2=.41, P=.001). Conclusions: Utilization of the paretic upper limb in activities of daily living requires high functional ability. The increase in self-reported arm use after TST is dependent on the change in functional ability. These results provide further guidance for rehabilitation decisions. [Copyright &y& Elsevier]

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1 , TSPYL5 , and B3GALT6), AFP, and sex. In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P <.0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P =.03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is a highly lethal cancer of the biliary tract. The intrahepatic subtype of cholangiocarcinoma is increasing in incidence globally. Despite technologic advancements over the past decade, little is known about the somatic changes that occur in these tumors. The goal of this study was to determine the frequency of common oncogenes in resected cholangiocarcinoma specimens that could provide potential therapeutic targets for patients diagnosed with cholangiocarcinoma. Formalin-fixed, paraffin-embedded tissue blocks from 94 resected cholangiocarcinomas were used to extract DNA from areas comprising more than 20% tumor. Specimens were evaluated using the Sequenom MassARRAY OncoCarta Mutation Profiler Panel (San Diego, CA). This matrix-assisted laser desorption/ionization- time of flight mass spectrometry single genotyping panel evaluates 19 oncogenes for 238 somatic mutations. Twenty-five mutations were identified in 23 of the 94 cholangiocarcinomas within the following oncogenes: KRAS (n = 12), PIK3CA (n = 5), MET (n = 4), EGFR (n = 1), BRAF (n = 2), and NRAS (n = 1). Mutations were identified in 7 (26%) of 27 extrahepatic cholangiocarcinomas and 16 (24%) of 67 intrahepatic cholangiocarcinomas. When combined with IDH1/2 testing, 40 (43%) of the 94 cholangiocarcinomas had a detectable mutation. MassARRAY technology can be used to detect mutations in a wide variety of oncogenes using paraffin-embedded tissue. Clinical testing for somatic mutations may drive personalized therapy selection for cholangiocarcinomas in the future. The variety of mutations detected suggests that a multiplexed mutation detection approach may be necessary for managing patients with biliary tract malignancy. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to traumatic events often results in severe distress which may elicit self-medication behaviors. Yet, some individuals exposed to trauma do not develop post-traumatic stress symptoms and comorbid addictive impulses. In the wake of traumatic events, psychological processes like thought suppression and mindfulness may modulate post-traumatic stress and craving for substances. We examined the differential roles of mindfulness and suppression in comorbid post-traumatic stress and craving among a sample of 125 persons with extensive trauma histories and psychiatric symptoms in residential treatment for substance dependence. Results indicated that thought suppression, rather than extent of trauma history, significantly predicted post-traumatic stress symptom severity while dispositional mindfulness significantly predicted both post-traumatic stress symptoms and craving. In multiple regression models, mindfulness and thought suppression combined explained nearly half of the variance in post-traumatic stress symptoms and one-quarter of the variance in substance craving. Moreover, multivariate path analysis indicated that prior traumatic experience was associated with greater thought suppression, which in turn was correlated with increased post-traumatic stress symptoms and drug craving, whereas dispositional mindfulness was associated with decreased suppression, post-traumatic stress, and craving. The maladaptive strategy of thought suppression appears to be linked with adverse psychological consequences of traumatic life events. In contrast, dispositional mindfulness appears to be a protective factor that buffers individuals from experiencing more severe post-traumatic stress symptoms and craving. [Copyright &y& Elsevier]

Summary: Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change (P < .001) and poorly differentiated histology (P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases. [Copyright &y& Elsevier]

Abstract: Purpose: To develop a translational rat hepatocellular carcinoma (HCC) disease model for magnetic resonance (MR) imaging and image-guided interventional oncologic investigations. Materials and Methods: Male rats underwent sham control surgery (n = 6), selective bile duct ligation (SBDL; n = 4), or common bile duct ligation (CBDL; n = 6), with procedure optimization in four rats and N1S1 hepatoma cell injection into two or three sites in the livers of 12 rats. All rats subsequently underwent MR imaging to assess tumor establishment and volume. Mesenteric angiography and percutaneous MR-guided laser ablation of the liver were performed in a subgroup of animals (n = 4). Animal weight and liver test results were monitored. After harvesting, the livers were subjected to gross and microscopic analysis. Tumor volume and laboratory parameters were assessed between ligation groups. Results: MR imaging demonstrated hyperintense T2 and hypointense T1 lesions with tumor induction in five of 10 (50.0%), seven of eight (87.5%), and 12 of 12 (100%) sites in the control, SBDL, and CBDL groups, respectively. Tumor volumes differed significantly by group (P < .02). Mesenteric angiography demonstrated an enhancing tumor stain. Clinical and laboratory assessment revealed a significant decrease in weight (P = .01) and albumin level (P < .01) and an increase in total bilirubin level (P = .02) in CBDL rats but not SBDL rats (P = 1.0). Histologic examination showed high-grade HCCs with local and vascular invasion within the context of early fibrosis in CBDL and SBDL rats. MR-guided laser ablation generated a 1–2-cm ablation zone with histologic findings consistent with reversible and irreversible injury. Conclusions: A biologically relevant rat HCC disease model has been developed for MR imaging and preliminary interventional oncologic applications. [Copyright &y& Elsevier]

Background & Aims: There are few data available about the prevalence or effects of cirrhosis in patients with hepatocellular carcinoma (HCC) from viral hepatitis. We compared patients with HCC and hepatitis B virus (HBV) or hepatitis C virus (HCV) infections to determine the proportions of cirrhosis in each group, virologic and tumor characteristics, and overall survival. Methods: This analysis included patients with HBV (n = 64) or HCV (n = 118) infection who were diagnosed with HCC at the Mayo Clinic in Rochester, Minnesota from 1994–2008; groups were matched for age and sex. The diagnosis of cirrhosis was based on histology and, if histologic information was insufficient or unavailable, clinical indicators that included ascites or varices, thrombocytopenia or splenomegaly, and radiographic configuration of cirrhosis. Virologic characteristics, tumor stage, and patient survival were also assessed. Results: The prevalence of histologic cirrhosis was 88% among patients with HBV infection and 93% among those with HCV infection (P = .46). When the most inclusive criteria for cirrhosis were applied, cirrhosis was present in 94% of patients with HBV and 97% with HCV (P = .24). Among HCV patients, 5.2% were negative for HCV RNA after antiviral treatment; 63.4% of HBV patients had HBV DNA <2000 IU/mL with or without treatment. Patients with HBV tended to have less surveillance and more advanced stages of HCC, without differences in survival from those with HCV infection (P = .75). Conclusions: Most patients with HCC and chronic viral hepatitis had evidence of cirrhosis, including those with HBV infection and those without active viral replication. [Copyright &y& Elsevier]

Purpose: To evaluate the impact of identifiable hepatic vein tumor thrombus on the ability to safely deliver TheraSphere (yttrium 90–containing glass microspheres) for the treatment of hepatocellular carcinoma (HCC). Materials and Methods: A retrospective review was performed of 87 patients (71 men, 16 women; mean age, 64.5 years; age range, 25–83 y) referred for TheraSphere therapy for HCC during a 2-year period between April 2005 and May 2007. Evaluation included contrast-enhanced computed tomography or magnetic resonance imaging, selective mesenteric angiography, and radionuclide perfusion scintigraphy to measure the arteriovenous shunting through the tumor. Results: Of the 87 patients, 83 underwent angiography and perfusion scintigraphy; 53 were ultimately treated with 65 glass microsphere infusions. Twelve of 83 were identified as having tumor thrombus in a hepatic vein or extending into the inferior vena cava. The mean lung shunt for the patients with hepatic vein tumor thrombus was 30% (range, 11%–60%), compared with 8.2% (range, 3%–23%) for patients without identifiable tumor thrombus. Two of the 12 patients were treated with reduced doses of glass microspheres, and the remaining 10 were offered alternative therapies. Conclusions: The presence of hepatic vein tumor thrombus is a risk factor for an increased lung shunt that may prohibit delivery of a therapeutic dose of TheraSphere to hepatic tumor. [Copyright &y& Elsevier]

Background & Aims: α-Fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with cirrhosis. Des-γ carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The aims of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels. Methods: We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory. Results: A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77–0.84), followed by DCP (0.72, 95% CI: 0.68–0.77) and AFP-L3% (0.66, 95% CI: 0.62–0.70) for early stage HCC. The optimal AFP cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72–0.85) leading to a sensitivity of 65% at the same cutoff. Conclusions: AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL. [Copyright &y& Elsevier]

Background & Aims: Ancillary cytologic tests including digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have been developed to improve the sensitivity of routine cytology (RC) for the diagnosis of malignancy in pancreatobiliary strictures. The goal of this study was to retrospectively compare the performance of RC, DIA, and FISH on clinical brushing specimens. Methods: Endoscopic retrograde cholangiopancreatography brushings were obtained from 498 consecutive patients with pancreatobiliary strictures and analyzed by RC, DIA, and FISH as per standard practice. RC diagnostic categories included negative, atypical, suspicious, or positive. Aneuploid/tetraploid histograms were considered positive for DIA. FISH was performed using UroVysion (Abbott Molecular, Inc, Des Plaines, IL) and classified as negative, trisomy, tetrasomy, or polysomy. Results: The sensitivity of polysomy FISH (42.9%) was significantly higher than RC (20.1%) when equivocal RC results were considered negative (P < .001) with identical specificity (99.6%). There was a significant difference in time for diagnosis of carcinoma between FISH diagnostic categories (P < .001) and between RC diagnostic categories (P < .001). Logistic regression analysis revealed that polysomy FISH, trisomy FISH, suspicious cytology, primary sclerosing cholangitis status, and age were associated with carcinoma (P < .05). Conclusions: Polysomy FISH had high sensitivity without compromise to specificity. DIA was not a significant independent predictor of malignancy. Multivariable modeling using RC, FISH, age, and primary sclerosing cholangitis status can be used to estimate the probability of carcinoma for an individual patient. We recommend including FISH as a routine test where available, along with RC, in the evaluation of indeterminate pancreatobiliary strictures. [Copyright &y& Elsevier]

Hepatocellular carcinoma (HCC) can be treated effectively if detected at an early stage. Recommended surveillance strategies for at-risk patients include ultrasound with or without α-fetoprotein (AFP), but their sensitivity is suboptimal. We sought to develop a novel, blood-based biomarker panel with improved sensitivity for early-stage HCC detection. In a multicenter, case-control study, we collected blood specimens from patients with HCC and age-matched controls with underlying liver disease but without HCC. Ten previously reported methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins, including AFP, were assayed and analyzed by a logistic regression algorithm to predict HCC cases. The accuracy of the multi-target HCC panel was compared with that of other blood-based biomarkers for HCC detection. The study included 135 HCC cases and 302 controls. We identified a multi-target HCC panel of 3 MDMs (HOXA1, EMX1, and TSPYL5), B3GALT6 and 2 protein markers (AFP and AFP-L3) with a higher sensitivity (71%, 95% CI: 60–81%) at 90% specificity for early-stage HCC than the GALAD score (41%, 95% CI: 30–53%) or AFP ≥7.32 ng/mL (45%, 95% CI: 33–57%). The AUC for the multi-target HCC panel for detecting any stage HCC was 0.92 compared with 0.87 for the GALAD score and 0.81 for AFP alone. The panel performed equally well in important subgroups based on liver disease etiology, presence of cirrhosis, or sex. We developed a novel, blood-based biomarker panel that demonstrates high sensitivity for early-stage HCC. These data support the potential for liquid biopsy detection of early-stage HCC to clinically benefit at-risk patients. This study was registered on ClinicalTrials.gov (NCT03628651). [ABSTRACT FROM AUTHOR]

Background: Studies indicate enhanced diagnostic accuracy for digital image analysis (DIA) and fluorescence in situ hybridization (FISH) versus routine cytology examination (RC) when biliary strictures are evaluated. These tumor markers have not been applied to EUS-guided FNA. Objective: Our purpose was to determine the accuracy of RC versus the composite results of DIA/FISH. Design: Patients enrolled with known or suspected malignancy. The final diagnosis was based on strict cytopathologic and imaging criteria and 12-month follow-up. Settings: Tertiary referral center. Patients: A total of 39 patients were enrolled in whom each diagnostic test was performed on samples from 42 sites to evaluate lymphadenopathy (n = 19), pancreatic mass (n = 19), esophageal or gastric wall mass (n = 3), and thyroid mass (n = 1). Interventions: EUS-guided FNA with RC, DIA, and FISH. Main Outcome Measurement: Diagnostic accuracy of RC, DIA, and FISH. Results: Malignancy was diagnosed in 30 of 42 patients, including esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, pancreatic mucinous cystic neoplasia, intraductal papillary mucinous neoplasia, metastatic forearm sarcoma, small cell and non–small cell lung cancer, thyroid carcinoma, malignant GI stromal tumor, melanoma, adenocarcinoma of unknown primary, and lymphoma. The sensitivity, specificity, and accuracy of DIA/FISH versus RC for detecting malignancy were 97%, 100%, and 98% versus 87%, 100%, and 90%, respectively. Limitations: Single-center pilot study. Conclusions: Our findings suggest that DIA and FISH processing of EUS-guided FNA specimens provides higher diagnostic accuracy than RC does. These data suggest that these tumor markers incorporate generic targets as suggested by the high diagnostic sensitivity in this patient cohort with diverse pathologic conditions. [Copyright &y& Elsevier]