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Douillard J.-Y.,Institute Of Cancerologie Of Louest Ico Rene Gauducheau | Oliner K.S.,Amgen Inc. | Siena S.,Ospedale Niguarda Ca Granda | Tabernero J.,Autonomous University of Barcelona | And 18 more authors.
New England Journal of Medicine

BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P = 0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P = 0.04). A total of 108 patients (17%) with non-mutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. Copyright © 2013 Massachusetts Medical Society. Source

Jain S.,University of Toronto | Yang P.,Credit Valley Hospital | Farrell S.A.,Credit Valley Hospital
European Journal of Medical Genetics

Nablus mask-like facial syndrome (NMLFS) has been reported in six patients with a recognizable facial appearance, along with other clinical features. Microdeletions of 8q21.3-8q22.1 were identified in all six cases, with the deleted region in common being 8q22.1 (2.78 Mb in length). In this report, we describe a child with speech delay and features of an autistic spectrum disorder and with a 1.6 Mb deletion of 8q22.1. The deletion has significant chromosomal overlap with previously reported examples of NMLFS, but our patient lacks the clinical features noted in the published cases. © 2010 Elsevier Masson SAS. All rights reserved. Source

Hill K.,University of Toronto | Hill K.,Curtin University Australia | Hill K.,University of Western Australia | Dolmage T.E.,University of Toronto | And 4 more authors.

Background: The aims of this study were to determine which tests of exercise capacity relate to average daily energy expenditure (DEE) and to quantify aerobic reserve during daily life in people with COPD. Methods: A cross-sectional study was undertaken in 26 people with COPD (16 men; FEV 1, 50% ± 16%). Six-min walk distance (6MWD) and incremental shuttle walk distance (ISWD) measures were collected, and peak oxygen uptake (VO 2 peak) was measured during a symptom-limited ramp cycle ergometry test. The SenseWear Armband was worn during the waking hours for 4.4 ± 1.1 days to measure DEE. The intensity at which activities of daily living were undertaken was expressed as a percentage of VO 2 peak. Results: DEE was associated with 6MWD(r = 0.40, P =.046) and ISWD(r = 0.52, P =.007) but not VO 2 peak (mL/kg per min)(r = 0.07, P =.74). Stronger associations were observed between DEE and the body weight-walking distance product for the 6MWD(r = 0.73, P<.001) and ISWD (r = 0.75, P<.001). The average intensity of daily activity was equivalent to 58% ± 11% of VO 2 peak, leaving an average aerobic reserve of 42%. Conclusions: Both 6MWD and ISWD, but not VO 2 peak, were related to DEE. Because activities of daily living were performed at a high percentage of VO 2 peak, it may be more realistic to optimize habitual DEE in COPD by increasing the frequency or duration rather than the intensity of physical activity. © 2012 American College of Chest Physicians. Source

Al-Saleh K.,King Saud University | Quinton C.,Credit Valley Hospital | Ellis P.M.,McMaster University
Current Oncology

Purpose Platinum-based regimens represent the standard first-line treatment for non-small-cell lung cancer (NSCLC). However, newer data have established a role for pemetrexed in the treatment of this disease. Such data suggest that histology represents a determining factor in the selection of treatment. Methods We undertook a systematic review of the literature for randomized controlled trials that compared the efficacy of pemetrexed with that of other treatments in advanced NSCLC. Data and study quality were assessed according to published guidelines. Results We identified five trials that compared pemetrexed with other treatments or with placebo. Overall survival for patients treated with pemetrexed was superior to that with other treatments: hazard ratio (HR): 0.89; 95% confidence interval (CI): 0.80 to 0.99. The survival benefit was limited to patients with non-squamous histology: hr: 0.82; 95% ci: 0.73 to 0.91. Pemetrexed was inferior to other chemotherapy options in patients with squamous histology: hr: 1.19; 95% ci: 0.99 to 1.43. Conclusions Compared with other chemotherapy agents, pemetrexed is more effective for the treatment of nsclc in patients with non-squamous histology. © 2012 Multimed Inc. Source

Lipsman N.,University of Toronto | Woodside D.B.,University of Toronto | Giacobbe P.,University of Toronto | Hamani C.,University of Toronto | And 8 more authors.
The Lancet

Background Anorexia nervosa is characterised by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder. Deep brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results. We aimed to assess the safety of DBS to modulate the activity of limbic circuits and to examine how this might aff ect the clinical features of anorexia nervosa. Methods We did a phase 1, prospective trial of subcallosal cingulate DBS in six patients with chronic, severe, and treatment-refractory anorexia nervosa. Eligible patients were aged 20-60 years, had been diagnosed with restricting or binge-purging anorexia nervosa, and showed evidence of chronicity or treatment resistance. Patients underwent medical optimisation preoperatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation. Patients were followed up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit. Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals. This trial is registered with ClinicalTrials.gov, number NCT01476540. Findings DBS was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious. Other related adverse events were panic attack during surgery, nausea, air embolus, and pain. After 9 months, three of the six patients had achieved and maintained a BMI greater than their historical baselines. DBS was associated with improvements in mood, anxiety, aff ective regulation, and anorexia nervosa-related obsessions and compulsions in four patients and with improvements in quality of life in three patients after 6 months of stimulation. These clinical benefi ts were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder. Interpretation Subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory anorexia nervosa. Source

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