Citations

Abstract This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

Background: Adjacent segment pathology is a known complication after spinal fusion, but little has been reported on junctional failure. A series of adolescent patients presented with acute distal junctional failure (DJF). We sought to determine any common features of these patients to develop a prevention strategy. Methods: A retrospective review was conducted of pediatric patients who developed DJF after instrumented spinal fusion performed at 2 institutions from 1999 to 2013. Patients with proximal junctional failure or junctional kyphosis without failure were excluded. Results: Fifteen subjects were identified with mean follow-up of 38 months. Distal failure occurred a mean of 60 days after index surgery, with history of minor trauma in 4 patients. Failures included 3-column Chance fracture (11) or instrumentation failure (4). Thirteen patients presented with back pain and/or acute kyphosis, whereas 2 asymptomatic patients presented with healed fractures. Two patients also developed new onset of severe lower extremity neurological deficit after fracture, which improved but never resolved after revision. A total of 13/15 subjects required revision surgery, typically within 1 week. Complications associated with revision surgery were encountered in 8 patients (62%). Major complications that required return to the operating room included 2 deep infections, 2 instrumentation failures, and dense lower extremity paralysis that improved after medial screw revision and decompression. At final follow-up, 10 patients are asymptomatic, 2 have persistent neurological deficit, 2 have chronic pain, and 1 has altered gait with gait aid requirement. Conclusions: This study analyzes a heterogenous cohort of spinal fusion patients who developed DJF from 3-column Chance fracture or instrumentation failure. Revision surgery is typically required, but has a high complication rate and can result in severe neurological deficit, highlighting the morbidity of this complication. It is unclear whether level of the lowest instrumented vertebra contributes to DJF. Increased awareness of junctional failure in children may prompt additional studies to further characterize risk factors and preventative strategies. Level of Evidence: Level IV—study-type case series.

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL‐6], IL‐8, interferon gamma–induced protein 10, IL‐4, IL‐9, IL‐10, fibroblast growth factor 2, IL‐7, IL‐15, and transforming growth factor alpha) but lower levels of the anti‐inflammatory macrophage‐derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon‐gamma in response to T‐cell stimulation. Up‐regulated IL‐6, IL‐8, CD38, and CD69 and down‐regulated macrophage‐derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of macrophage‐derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL‐8, IL‐10, fibroblast growth factor 2, and IL‐7 remained higher. Conclusion: AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575–590).

Background/Aim: The epidemiology of hepatocellular carcinoma (HCC) has changed in the United States recently. The aim of this study is to evaluate the recent trends of HCC epidemiology in Olmsted County, MN. Methods: Residents aged over 20 with newly diagnosed HCC were identified using the Rochester Epidemiology Project database. Clinical information was compared among patients diagnosed between 2000 and 2009 (era 1) and 2010 to 2014 (era 2). Results: Over 1.6 million person years of follow-up, 93 residents were diagnosed with HCC. The mean age was 67 and 71% were male. The age-adjusted and sex-adjusted incidence rates were 6.3 and 7.0 per 100,000 person years in the first and second eras (P=0.64). The proportion with hepatitis B virus etiology increased from 4% to 21% between the 2 eras (P<0.01), whereas there was a trend toward a decreasing proportion of hepatitis C virus etiology from 42% to 29% (P=0.20). Only 39% of HCC surveillance candidates had HCCs detected under surveillance and 41% of cirrhotic patients had unrecognized cirrhosis at the time of HCC diagnosis. Nonalcoholic fatty liver disease was associated with unrecognized cirrhosis and absence of cirrhosis at HCC diagnosis. More than half (56%) of patients presented at Barcelona Clinic Liver Cancer stage C or D and the median survival was 9.7 months. The overall survival had not changed over time. Conclusions: The incidence of HCC remained stable after 2010 in Olmsted County. The proportion of hepatitis B virus-induced HCC increased, whereas there was a trend of decreasing proportion of hepatitis C virus-induced HCC. The overall survival in community residents with HCC remains poor.