Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. PROCEDURE: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2 ) and temsirolimus (15 mg/m2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. RESULTS: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m2 , vinblastine 4 mg/m2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months). CONCLUSION: The combination of weekly temsirolimus (15 mg/m2 ) and vinblastine (4 mg/m2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

Determinants of agricultural injury: a novel application of population health theory.

OBJECTIVES: (1) To apply novel population health theory to the modelling of injury experiences in one particular research context. (2) To enhance understanding of the conditions and practices that lead to farm injury. DESIGN: Prospective, cohort study conducted over 2 years (2007-09). SETTING: 50 rural municipalities in the Province of Saskatchewan, Canada. SUBJECTS: 5038 participants from 2169 Saskatchewan farms, contributing 10,092 person-years of follow-up. MAIN MEASURES: Individual exposure: self-reported times involved in farm work. Contextual factors: scaled measures describe socioeconomic, physical, and cultural farm environments. OUTCOME: time to first self-reported farm injury. RESULTS: 450 farm injuries were reported for 370 individuals on 338 farms over 2 years of follow-up. Times involved in farm work were strongly and consistently related to time to first injury event, with strong monotonic increases in risk observed between none, part-time, and full-time work hour categories. Relationships between farm work hours and time to first injury were not modified by the contextual factors. Respondents reporting high versus low levels of physical farm hazards at baseline experienced increased risks for farm injury on follow-up (HR 1.54; 95% CI 1.16 to 1.47). CONCLUSIONS: Based on study findings, firm conclusions cannot be drawn about the application of population health theory to the study of farm injury aetiology. Injury prevention efforts should continue to focus on: (1) sound occupational health and safety practices associated with long work hours; (2) physical risks and hazards on farms.

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226.

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.

Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit.

BACKGROUND: Oral antihistamines that target the histamine receptor-1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise. METHODS: Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396). RESULTS: PF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events. CONCLUSIONS: PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.

Loud snoring is a risk factor for occupational injury in farmers.

BACKGROUND: Loud snoring is a common symptom in the general population. The evidence-based literature indicates that snoring may be associated with sleep fragmentation and sleep apnea, which may affect cognitive function and predispose to occupational injury. High rates of occupational injury occur on farms and may be related to personal and health factors. Thus, loud snoring may not be a trivial symptom and should be considered as important in medical assessments. METHODS: A prospective cohort study was conducted in Saskatchewan. Baseline questionnaires were completed for 5502 individuals by representatives from 2390 farms. Sleep patterns at baseline were categorized as the following: no reported sleep disorders; physician-diagnosed sleep apnea (treatment unknown); and loud snoring. Survival analyses were used to relate sleep patterns with subsequent injury. RESULTS: A total of 6.7% (369 of 5502) of participants reported a possible sleep disorder. Of these, 69.4% (256 of 369) reported loud snoring only. Loud snoring was only associated with a consistent increase in risk (eg, HR 1.45 [95 CI 1.07 to 1.99 for work-related injury]) for five farm injury outcomes. Relationships between physician-diagnosed sleep apnea and time to first injury were not significant, presumably because a diagnosis of sleep apnea implied treatment for sleep apnea. DISCUSSION: Sleep disorders are an important potential risk factor for occupational injury on farms. Substantial proportions of farm residents report loud snoring and this is related to subsequent injury. Some of these cases may represent sleep fragmentation or undiagnosed obstructive sleep apnea. Identification and clinical management of sleep disorders related to snoring should be part of health assessments conducted by physicians.

Phase II cancer clinical trials with a one-sample log-rank test and its corrections based on the Edgeworth expansion.

The response rate has been frequently used as the primary endpoint of phase II cancer clinical trials. It may not be an appropriate endpoint when a new treatment is not expected to produce any tumour shrinkage. When a large database for a historical control is available, the direct comparison of survival curves between a new treatment and the historical control may be made in phase II cancer clinical trials. In this paper, a one-sample log-rank test is introduced for the design and analysis of phase II cancer clinical trials with time-to-event endpoints. Corrections to the one-sample log-rank test are also derived based on the Edgeworth expansion. Simulations showed that the original one-sample log-rank test may be preferred if strictly controlling for type I error is important or when the sample size of a phase II trial is as large as 50, and a corrected one-sample log-rank test is used if the sample size of a phase II trial is small. A data set from a clinical trial conducted by the NCIC Clinical Trials Group is used to illustrate the proposed procedures.

Socioeconomic status and injury in a cohort of Saskatchewan farmers.

PURPOSE: To estimate the strength of relationships between socioeconomic status and injury in a large Canadian farm population. METHODS: We conducted a prospective cohort study of 4,769 people from 2,043 farms in Saskatchewan, Canada. Participants reported socioeconomic exposures in 2007 and were followed for the occurrence of injury through 2009 (27 months). The relative hazards of time to first injury according to baseline socioeconomic status were estimated via Cox proportional hazards models. FINDINGS: Risks for injury were not consistent with inverse socioeconomic gradients (adjusted HR 1.07; 95% CI: 0.76 to 1.51 for high vs low economic worry; adjusted HR 1.72; 95% CI: 1.23 to 2.42 for completed university education vs less than high school). Strong increases in the relative hazard for time to first injury were identified for longer work hours on the farm. CONCLUSIONS: Socioeconomic factors have been cited as important risk factors for injury on farms. However, our findings suggest that interventions aimed at the prevention of farm injury are better focused on operational factors that increase risk, rather than economic factors per se.

Impact of enteral feeding protocols on enteral nutrition delivery: results of a multicenter observational study.

BACKGROUND: To evaluate the effect of enteral feeding protocols on key indicators of enteral nutrition in the critical care setting. METHODS: International, prospective, observational, cohort studies conducted in 2007 and 2008 in 269 intensive care units (ICUs) in 28 countries were combined for the purposes of this analysis. The study included 5497 consecutively enrolled, mechanically ventilated, adult patients who stayed in the ICU for at least 3 days. Sites recorded the presence or absence of a feeding protocol operational in their ICU. They provided selected nutritional data on enrolled patients from ICU admission to ICU discharge for a maximum of 12 days. Sites that used a feeding protocol were compared with those that did not. RESULTS: On average, protocolized sites used more enteral nutrition (EN) alone (70.4% of patients vs 63.6%, P = .0036), started EN earlier (41.2 hours from admission to ICU vs 57.1, P = .0003), and used more motility agents in patients with high gastric residual volumes (64.3% of patients vs 49.0%, P = .0028) compared with sites that did not use a feeding protocol. Overall nutritional adequacy (61.2% of patients' caloric requirements vs 51.7%, P = .0003) and adequacy from EN were higher in protocolized sites compared with nonprotocolized sites (45.4% of requirements vs 34.7%, P < .0001). EN adequacy remained significantly higher after adjustment for pertinent patient and ICU level baseline characteristics. CONCLUSIONS: The presence of an enteral feeding protocol is associated with significant improvements in nutrition practice compared with sites that do not use such a protocol.