Nicotinic acetylcholine receptor CHRNA5 is overexpressed in head and neck squamous cell carcinoma patients with a recent tobacco smoking history.

Tobacco smoking is a major driver of head and neck squamous cell carcinoma (HNSCC) occurrence, and previous studies have shed light on the precise molecular alterations in tobacco-related HNSCCs when compared to HNSCCs associated with other risk factors (ex: human papillomavirus/HPV status). In this study, we analyzed the gene expression differences in HNSCC cases with a recent smoking history and revealed that the nicotinic acetylcholine receptor CHRNA5 is differentially overexpressed in smoking-related HNSCCs. CHRNA5 overexpression in these HNSCCs corresponds with a worse prognosis and is inversely correlated with an immune expression signature commonly associated with better prognosis. From these results, our study highlights the potential role of the nicotine-activated CHRNA5 receptor in HNSCC progression and corresponds with other recent reports highlighting the potential role of nicotine induction in promoting cancer progression.

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

BACKGROUND: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. METHODS: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). RESULTS: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. CONCLUSIONS: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Cost-effectiveness of pembrolizumab plus chemotherapy as first-line treatment in PD-L1-positive metastatic triple-negative breast cancer.

Objective: This study evaluated the cost-effectiveness of pembrolizumab/chemotherapy combinations for previously untreated metastatic triple-negative breast cancer patients in the USA with PD-L1 combined positive score ≥10. Methods: A partitioned-survival model was developed to project health outcomes and direct medical costs over a 20-year time horizon. Efficacy and safety data were from randomized clinical trials. Comparative effectiveness of indirect comparators was assessed using network meta-analyses. A series of sensitivity analyses were performed to test the robustness of the results. Results: Pembrolizumab/chemotherapy resulted in total quality-adjusted life-year (QALY) gains of 0.70 years and incremental cost-effectiveness ratio of US$182,732/QALY compared with chemotherapy alone. The incremental cost-effectiveness ratio for pembrolizumab/nab-paclitaxel versus atezolizumab/nab-paclitaxel was US$44,157/QALY. Sensitivity analyses showed the results were robust over plausible values of model inputs. Conclusion: Pembrolizumab/chemotherapy is cost effective compared with chemotherapy as well as atezolizumab/nab-paclitaxel as first-line treatment for PD-L1-positive metastatic triple-negative breast cancer from a US payer perspective.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. FINDINGS: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). INTERPRETATION: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial.

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Online application for self-referral of the patients with breast symptoms.

INTRODUCTION: The study aimed to devise a self-referral mobile/web application for patients with new breast symptoms, giving them an outcome, thus bypassing the need for primary care consultation. METHODS: The online application was designed on the automated algorithm based on evidence-based guidelines for referral to breast onco-plastic units. A retrospective questionnaire-based anonymous survey was carried out at the breast unit in Southend University Hospital (January 2019 to March 2020). The outcome of the patients was recorded, the same data was entered in the software and its outcome was compared with their clinic outcome to assess and validate the software. Chi-square and t-test were used in formulating results. RESULTS: Data was collected for 366 patients who were referred urgently to the clinic. Only 50.5% (n = 186) were appropriately referred, with the main complaint being breast lump (94.1%). 39.6% of referred patients did not require a secondary care referral. Sensitivity and specificity for identifying patients requiring urgent referral was 100% and 98%, respectively. CONCLUSION: A significant number of urgent referrals to breast units do not require urgent specialist referral, and this results in a big strain on the hospital service. The discussed self-referral pathway is a promising alternative with the potential to reduce workload in primary and secondary care and improve patient satisfaction.

Efficacy of Brodalumab for Moderate to Severe Plaque Psoriasis: A Canadian Network Meta-Analysis.

BACKGROUND: Several treatments for plaque psoriasis are available, but it remains challenging for physicians to make informed treatment decisions due to a lack of head-to-head trials. OBJECTIVES: This network meta-analysis (NMA) compares the efficacy of brodalumab to other biologic agents in Canada for moderate-to-severe plaque psoriasis. METHODS: A systematic literature review of randomized controlled trials (RCTs) published before October 2017 was conducted to populate the NMA. Comparators included etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, guselkumab, and placebo. The primary outcome was the psoriasis area and severity index (PASI) response at the end of induction phase. A random effects Bayesian multinomial likelihood and probit link model analyzed PASI 75, 90, and 100 responses. Inconsistency and heterogeneity were assessed. Sensitivity analyses were conducted to explore potential effect modifiers like baseline PASI score, age, and weight. RESULTS: A total of 43 RCTs were included. Brodalumab 210 mg had significantly better PASI response than etanercept, ustekinumab, adalimumab, secukinumab, and guselkumab and comparable responses to infliximab and ixekizumab. Relative risk of PASI 90 response for brodalumab varied from 2.84 (95% credible interval [CrI]: 2.35-3.52, P < .05) to 0.99 (95% CrI: 0.88-1.11, ns) compared to etanercept and ixekizumab. This was similar across PASI 75 responses, but a larger relative risk between brodalumab and all comparators except ixekizumab was observed for PASI 100. No significant heterogeneity or inconsistencies were identified. The results were consistent across sensitivity analyses, indicating robustness of the results. CONCLUSION: Brodalumab 210 mg has efficacy superior to most biologic agents for moderate-to-severe plaque psoriasis in Canada.

The importance of appropriate reporting and investigation of incidental findings on computed tomography attenuation correction images during myocardial perfusion scintigraphy.

We present a case of lung cancer incidentally detected as a pulmonary nodule on computed tomography attenuation correction (CTAC) images during myocardial perfusion scintigraphy (MPS). Unfortunately, the incidental lesion was not fully investigated following MPS report and had developed into metastatic lung carcinoma when diagnosed over 1 year later, with failure of subsequent emergent chemotherapy. The disease appeared to be localized when initially detected during MPS. This case highlights the importance and potential clinical value of routine review of CTAC images in MPS with appropriate reporting and further investigation of suspicious incidental findings. In addition, the importance of effective communication between nuclear medicine department and treating team is clear to ensure suspicious incidental findings are given sufficient credence and thoroughly investigated promptly to avoid adverse clinical outcomes.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

ALS/FTD-associated FUS activates GSK-3ß to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations.

Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca(2+) uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca(2+) levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3ß (GSK-3ß), a kinase already strongly associated with ALS/FTD.

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs. OBJECTIVES: To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software. MAIN RESULTS: We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001).Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01). AUTHORS' CONCLUSIONS: In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Outcomes of emergency colectomy for fulminant Clostridium difficile colitis.

INTRODUCTION: Clostridium difficile has become increasingly a common cause of nosocomial infection with increasing antibiotic usage. Recently there has been an increase in the incidence of patients undergoing colectomy for fulminant C. difficile colitis (FCDC). Early surgical consultation is necessary to avoid delay in diagnosis. We present a retrospective review of the outcomes of colectomies for FCDC at our large district general hospital. MATERIALS AND METHODS: Over a twenty one month period, from January 2007 to September 2009, a total number of 20 patients underwent exploratory laparotomy for FCDC. A retrospective analysis of patients' case notes, was carried out retrieving all relevant. Data on haematology, biochemistry and imaging were extracted from the trust's on-line clinical databases. RESULTS: A total number of 528 diagnosed cases with C. difficile infection were identified. Of these, twenty patients underwent colectomy for FCDC (3.7%). All patients had received antibiotics prior to symptoms development. 45% of patients had multiple antibiotics. 35% of patients developed FCDC after having three doses of prophylactic antibiotic (Cefuroxime) for a surgical procedure. Time from referral to having surgery varied. Seventeen patients received subtotal colectomy and end ileostomy in a single operation. Mortality rate was 40%. CONCLUSION: Emergency colectomy for FCDC is associated with high mortality rate. The majority of patients who have significant co-morbidities (75%) did not survive following emergency colectomy. Therefore, it is crucial to identify those patients early in their disease course before they progress into FCDC and organ failure.

Deficiency of the copper chaperone for superoxide dismutase increases amyloid-ß production.

The copper chaperone for superoxide dismutase (CCS) binds to both the ß-site AßPP cleaving enzyme (BACE1) and to the neuronal adaptor protein X11α. BACE1 initiates AßPP processing to produce the amyloid-ß (Aß) peptide deposited in the brains of Alzheimer's disease patients. X11α also interacts directly with AßPP to inhibit Aß production. However, whether CCS affects AßPP processing and Aß production is not known. Here we show that loss of CCS increases Aß production in both CCS knockout neurons and CCS siRNA-treated SHSY5Y cells and that this involves increased AßPP processing at the BACE1 site.

Metastatic Hurthle Cell Carcinoma of the thyroid presenting as a Breast Lump: A Case Report.

BACKGROUND: Hurthle cell carcinoma of the thyroid is a rare form of thyroid cancer. It may present as a low grade tumour or can present as a more aggressive metastatic carcinoma. Hurthle cell carcinoma has the highest incidence of metastasis among all differentiated thyroid cancers. Most commonly haematogenous spread to lungs, bones and brain, however spread to regional lymph nodes is not uncommon. The breast is a rare site for metastasis from extramammary sources. We present the first case of breast metastasis from Hurthle cell carcinoma of the thyroid. CASE PRESENTATION: We report a 77 year old lady who had total thyroidectomy and bilateral neck dissection followed by radiotherapy for a high grade metastatic Hurthle cell carcinoma of the thyroid. Ten months later she presented to the breast clinic with left breast lump and a lump at the left axilla. Fine needle aspiration cytology of the lumps and histology after wide local excision of the breast lump confirmed metastatic Hurthle cell carcinoma. CONCLUSION: The presence of breast lumps in patients with history of extramammary cancer should raise the possibility of metastasis.

Attitudes of oncology health professionals to information from the Internet and other media.

OBJECTIVE: To investigate attitudes of Australian health professionals working in oncology to health-related information in the media and on the Internet and to patients who search for this information. DESIGN: Questionnaire-based survey. SETTING AND PARTICIPANTS: Questionnaires were mailed in January 2003 to all 333 health professionals belonging to the Victorian Cooperative Oncology Group. MAIN OUTCOME MEASURES: 27 items about attitudes to information in the media and the Internet, patient information-seeking and its effects on the doctor-patient relationship. RESULTS: 226 surveys (68%) were returned and assessable. Most respondents took notice of medical information reported on television/radio, in newspapers (80% each) and on the Internet (56%), mainly to be informed when patients ask questions (82%) and to check its accuracy (60%). Most were concerned about this accuracy (64% believed it accurate only sometimes, and 23% rarely), and 91% believed information from the Internet had the potential to cause harm to patients. Nevertheless, they generally supported patients' information-searching, believing it allowed them to be better informed (58%), and did not affect their ability to cope with their illness (49%), or their trust in, and relationship with, their doctor (69% and 67%, respectively). CONCLUSIONS: Oncology health professionals are aware of patients' use of the Internet and other media to obtain medical information. To ensure oncology patients find reliable and relevant information and to minimise the risk of harm, the health professionals treating them should provide guidance in finding information sources, and assistance in interpreting the information obtained.