Timothy Dobbins

A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis

To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated.

Australian national birthweight percentiles by sex and gestational age, 1998-2007

Objective: To present updated national birthweight percentiles by gestational age for male and female singleton infants born in Australia.

Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets.

This study provides Australian data on the incidence of human papillomavirus (HPV)-related oropharyngeal cancer to aid the debate on extending the HPV vaccination programme to males. The HPV status for 302 oropharyngeal cancers diagnosed between 1987 and 2006 was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. The overall HPV-positivity rate was 36% (94% types 16 and 18). HPV-related cancer increased from 19% (1987-1990) to 47% (2001-2005). HPV data used in conjunction with Australian cancer incidence data 2001-2005 showed that 1.56 cases of oropharyngeal cancer per 100,000 males per year were associated with HPV types targeted by the vaccine. Vaccinating males may substantially reduce the burden of oropharyngeal cancer in Australia.

Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy

Objective:This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy.Methods:One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Coxs regression with censoring at follow-up dates.Results:Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy (n=110), definitive radiotherapy-alone (n=24) and definitive radiotherapy with chemotherapy (n=47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis.Conclusion:HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy±chemotherapy.

Trends in the prevalence of overweight and obesity among young Australians, 1985, 1997 and 2004

Objective: To determine secular trends in overweight/obesity among 7‐ to 15‐year‐olds for the periods 1985, 1997, and 2004.

Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer

PURPOSE This study examines the prognostic significance of epidermal growth factor receptor (EGFR) expression in relation to human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma (SCC). MATERIALS AND METHODS Pathological diagnosis of 270 oropharyngeal SCCs was verified by the study pathologist; clinical details were extracted from institutional databases. Recurrence in any form or death from any cause was recorded for a median of 2.5 (range: 0-19.3) years after diagnosis. HPV status was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry; EGFR expression was evaluated by semiquantitative immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox regression with censoring at dates of last follow-up. RESULTS Thirty-seven percent of cancers were HPV-positive (91% type 16). HPV was a predictor of loco-regional recurrence, event-free and overall survival after adjustment for clinicopathological variables and EGFR. Patients with EGFR-positive cancers were 5-fold more likely to have loco-regional failure relative to those with EGFR-negative cancers. Patients with HPV-negative/EGFR-positive cancers had an adjusted 13-fold increased risk of having a loco-regional failure, an almost 4-fold increased risk of having an event and more than a 4-fold increased risk of dying of any cause relative to those with HPV-positive/EGFR-negative cancers. There was weak evidence that the effects of EGFR on outcome were limited to patients with HPV-negative cancers. CONCLUSIONS HPV and EGFR are independent prognostic markers in oropharyngeal SCC. Combining testing for HPV and EGFR appears to provide additional prognostic information.

The impact of opioid substitution therapy on mortality post-release from prison: retrospective data linkage study

AIMS Release from prison is a high-risk period for mortality. We examined the impact of opioid substitution therapy (OST), for opioid dependence during and after incarceration, upon mortality post-release. DESIGN A cohort was formed of all opioid-dependent people who entered OST between 1985 and 2010 and who, following first OST entry, were released from prison at least once between 2000 and 2012. We linked data on OST history, court and prison records and deaths. SETTING New South Wales (NSW), Australia. PARTICIPANTS A total of 16,453 people released from prison 60,161 times. MEASUREMENTS Crude mortality rates (CMRs) were calculated according to OST retention; multivariable Cox regressions for post-release periods were undertaken to examine the association between OST exposure (a time-dependent variable) and mortality post-release, for which covariates were updated per-release. FINDINGS There were 100,978 person-years (PY) post-release; 1050 deaths occurred. Most received OST while incarcerated (76.5%); individuals were receiving OST in 51% of releases. Lowest post-release mortality was among those continuously retained in OST post-release CMR 4 weeks post-release = 6.4 per 1000 PY; 95% confidence interval (CI) = 5.2, 7.8, highest among those with no OST (CMR = 36.7 per 1000 PY; 95% CI = 28.8, 45.9). Multi-factorial models showed OST exposure in the 4 weeks post-release reduced hazard of death by 75% (adjusted hazard ratio 0.25; 95% CI = 0.12, 0.53); OST receipt in prison had a short-term protective effect that decayed quickly across time. CONCLUSION In New South Wales, Australia, opioid substitution therapy in prison and post-release appears to reduce mortality risk in the immediate post-release period.

The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis

BACKGROUND The addition of HER2-targeted agents to standard treatment has been shown to improve outcomes for HER2 positive metastatic breast cancer patients. We undertook a meta-analysis to evaluate the efficacy of HER2-targeted therapy in addition to standard treatment in metastatic breast cancer patients. PATIENTS AND METHODS Eligible trials were randomised controlled trials (RCTs) comparing the addition of HER2 therapy to standard treatment (hormone or chemotherapy) reporting overall survival (OS), time to progression (TTP), progression-free survival (PFS) and/or response rates. RESULTS Eight trials comprising 1848 patients were eligible for inclusion. HER2-targeted agents were trastuzumab and lapatinib and therapeutic partners were taxanes (4 RCTs), anthracyclines (1), capecitabine (2), anastrozole (1) and letrozole (1). The addition of HER2-targeted agents improved OS [hazard ratios (HR) 0.78; 95% confidence interval (CI) 0.67-0.91], TTP (HR 0.56; 95% CI 0.48-0.64), PFS (HR 0.63; 95% CI 0.53-0.74) and overall response rate (relative risk 1.67; 95% CI 1.46-1.90). CONCLUSIONS Our meta-analysis confirms the benefit of adding HER2-targeted therapy to standard treatment in HER2 positive metastatic breast cancer. Compared with OS, TTP, PFS and ORR overestimate treatment benefit. Trials in our meta-analysis differed in terms of partner drug or HER2 agents, yet delivered comparable outcomes.

Body mass index, waist circumference, and chronic disease risk factors in Australian adolescents.

OBJECTIVE To determine the association between measures of adiposity (body mass index and waist circumference) and risk factors for heart disease, type 2 diabetes, fatty liver disease, and the clustering of risk factors in middle adolescence. DESIGN Cross-sectional study. SETTING Secondary schools in Sydney. PARTICIPANTS Grade 10 students (N = 496; 58.4% boys; mean [SD] age, 15.4 [0.4] years). MAIN EXPOSURES Height, weight, waist circumference, blood pressure, and fasting blood samples. OUTCOME MEASURES Participants were categorized as overweight or obese using the International Obesity Task Force cut points and the UK waist circumference cut points. Blood was analyzed for high- and low-density lipoprotein cholesterol, triglycerides, insulin, glucose, alanine aminotransferase, gamma-glutamyltransferase, and high-sensitivity C-reactive protein levels, and the results were categorized as normal or abnormal according to published guidelines where possible. Associations between overweight and obesity and risk factors were explored using logistic regression. Clustering of risk factors within individuals was also explored. RESULTS Insulin (P < .001), alanine aminotransferase (P < .001), gamma-glutamyltransferase (P = .005), high-density lipoprotein cholesterol (P < .001), high-sensitivity C-reactive protein (P < .001), and blood pressure (P < .001) were significantly associated with overweight and obesity in adolescent boys. In adolescent girls, insulin, high-density lipoprotein cholesterol (P < .001), and high-sensitivity C-reactive protein (P < .001) were significantly associated with overweight and obesity. Obese adolescent boys and girls were significantly more likely to have 2 or more risk factors (boys: 73.5% vs 7.6%; girls: 44.4% vs 5.4%; P < .001 for both) than nonoverweight adolescents. CONCLUSIONS Overweight and obese adolescents, especially boys, are at substantial risk for chronic conditions. Waist circumference is not a better predictor of metabolic risk factors than is body mass index.

Preventing depression and anxiety in young people: a review of the joint efficacy of universal, selective and indicated prevention.

Depression and anxiety (internalizing disorders) are the largest contributors to the non-fatal health burden among young people. This is the first meta-analysis to examine the joint efficacy of universal, selective, and indicated preventive interventions upon both depression and anxiety among children and adolescents (5-18 years) while accounting for their co-morbidity. We conducted a systematic review of reviews in Medline, PsycINFO and the Cochrane Library of Systematic Reviews, from 1980 to August 2014. Multivariate meta-analysis examined the efficacy of preventive interventions on depression and anxiety outcomes separately, and the joint efficacy on both disorders combined. Meta-regressions examined heterogeneity of effect according to a range of study variables. Outcomes were relative risks (RR) for disorder, and standardized mean differences (Cohens d) for symptoms. One hundred and forty-six randomized controlled trials (46 072 participants) evaluated universal (children with no identified risk, n = 54) selective (population subgroups of children who have an increased risk of developing internalizing disorders due to shared risk factors, n = 45) and indicated prevention (children with minimal but detectable symptoms of an internalizing disorder, n = 47), mostly using psychological-only strategies (n = 105). Reductions in internalizing disorder onset occurred up to 9 months post-intervention, whether universal [RR 0.47, 95% confidence interval (CI) 0.37-0.60], selective (RR 0.61, 95% CI 0.43-0.85) or indicated (RR 0.48, 95% CI 0.29-0.78). Reductions in internalizing symptoms occurred up to 12 months post-intervention for universal prevention; however, reductions only occurred in the shorter term for selective and indicated prevention. Universal, selective and indicated prevention interventions are efficacious in reducing internalizing disorders and symptoms in the short term. They might be considered as repeated exposures in school settings across childhood and adolescence. (PROSPERO registration: CRD42014013990.).