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Introduction Significant impairments in health-related quality of life (HRQL) in patients with non-alcoholic fatty liver disease have been previously described. The disease-specific HRQL among patients with non-alcoholic steatohepatitis (NASH), however, remains unknown. Aim To determine the degree of construct validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with NASH. Methods Participants referred for the evaluation of histology-proven NASH at Mayo Clinic, Rochester, between 1996 and 2000, were evaluated. HRQL assessment by the Short-Form 36 (SF-36) Health Survey and CLD) was performed. The primary outcome was to determine the level of correlation between overall and subscale scores for the CLDQ and SF-36 instruments. Results Among 79 participants (70%) with NASH completing both questionnaires (mean age, 51.2 years with 64% female gender), excellent reliability was noted for the CLDQ instrument. Significant reductions in all SF-36 domains (p<0.05 for all) including PCS and MCS scores (p<0.02 for both) among participants with NASH compared with normative data from an age-matched and sex-matched US general population sample was observed. Highly significant correlations were observed between overall CLDQ score with SF-36 PCS (r=0.82, p<0.0001) and SF-36 MCS (r=0.67, p<0.0001) scores. Similar degrees of correlation were observed between relevant subscales of the CLDQ and SF-36 as well. Discussion The CLDQ has excellent reliability and validity of construct for HRQL assessment in adults with NASH when compared with the SF-36. Future investigations among participants with NASH require assessing the responsiveness of the CLDQ to medical therapies and disease progression.

Abstract Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.

ObjectivesTo compare reconstructive techniques, operative times, duration of hospitalization, and need for subsequent flap revisions between reconstructive approaches to lateral skull base defects.Study DesignCase series with chart review.SettingTertiary academic referral center.SubjectsPatients (n = 31) undergoing reconstruction of composite lateral skull base defects from 2002 to 2014.MethodsData were analyzed for demographics, tumor characteristics, reconstructive technique, operative time, duration of hospitalization, complications, and outcomes.ResultsThirty‐one patients were identified for inclusion. Lateral temporal bone defects resulted from resection of malignant lesions, including squamous cell carcinoma (n = 25), basal cell carcinoma (n = 2), and other carcinoma (n = 4). Defects were reconstructed with submental flaps (n = 16), pedicled latissimus dorsi flaps (n = 6), and free anterolateral thigh flaps (n = 9). All cases involved neurosurgery, neurotology, and head and neck surgery services. Although time of surgical resection was similar, time saving was noticed with submental reconstruction. Compared with free flaps, submental flap reconstruction was associated with significantly reduced total operative time (mean, 544 vs 683 min; P =. 00817) and duration of hospitalization (4.9 vs 9.8 days; P =. 02067). Submental flaps were significantly less likely to require revision debulking procedures (mean = 0.6) compared with latissimus dorsi flaps (mean, 1.3; P <. 00001) and free flaps (mean, 1.6; P <. 00001). There was 100% flap survival.ConclusionThe musculocutaneous submental flap provides an excellent option for reconstruction of lateral skull base defects given its proximity, reliability, ease of harvest, and exceptional color match. Submental flap reconstruction was associated with reduced operative time, hospitalization duration, and flap revisions.

AbstractIntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver disease and reduced life expectancy. PSC primarily affects young and middle-aged men, often in association with underlying inflammatory bowel disease. The etiology of PSC includes immune-mediated components and elements of undefined nature. A cholestatic picture of liver biochemistries with elevations in serum alkaline phosphatase, nonspecific autoantibodies such as perinuclear antineutrophilic antibody, antinuclear antibodies and smooth muscle antibodies, and diffuse multifocal biliary strictures, resulting in a ‘beaded’ appearance on radiographic studies, are the hallmarks of the disease. No effective medical therapy is currently available, although clinical studies are in progress. Ursodeoxycholic acid at high doses (28 mg/kg/day to 30 mg/kg/day) is the most promising agent but is unproven so far. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease, although recurrent disease can be observed in the transplanted liver. The multiple complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, peristomal varices, bacterial cholangitis, dominant biliary strictures, gallbladder stones and polyps, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of PSC.

OBJECTIVE: To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn’s disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy.METHODS: Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada.RESULTS: Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients.CONCLUSIONS: Adalimumab therapy induced and sustained steroid-free remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.

BACKGROUND: Autoimmune hepatitis has diverse clinical phenotypes and outcomes that challenge current diagnostic criteria and management algorithms.OBJECTIVES: To highlight the major difficulties in diagnosis and management, describe the efforts to ease them and encourage further progress in problem solving.METHODS: The MEDLINE database was reviewed for published experiences from 1984 to 2013.RESULTS: Acute or acute severe (fulminant) hepatitis, asymptomatic mild disease, and histological findings of centrilobular necrosis or bile duct injury can confound diagnosis and treatment. Continuation of conventional therapy until normal liver test results and liver tissue reduces the frequency of relapse, but does not prevent its occurrence. Problematic patients can be identified using mathematical models, clinical phenotype, serological markers and the speed of improvement after treatment; however, their recognition and treatment are inconsistent. Mycophenolate mofetil can rescue patients with azathioprine intolerance but is less effective for refractory disease. Budesonide in combination with azathioprine can be used frontline, but is effective primarily in noncirrhotic, uncomplicated disease. Molecular and cellular interventions are feasible but largely unevaluated.DISCUSSION: Resolution of the current challenges requires revision of diagnostic criteria, characterization of biological markers that reflect pathogenic pathways, development of dynamic indexes based on changes in disease behaviour, and introduction of new pharmacological, molecular and cellular interventions that have undergone rigorous evaluation.CONCLUSION: These challenges reflect important remediable deficiencies in current management.

Diffuse pulmonary lymphangiomatosis (DPL) is a rare disease characterized by infiltration of the lung, pleura and mediastinum with thin-walled lymphangiomas. DPL can result in mass effect from infiltrative disease, restrictive and obstructive pulmonary physiology, chylous effusions and respiratory failure. The present article discusses clinical, radiographic and pathological features, and treatment options for DPL.