Clinical efficacy and safety of first-line treatments in patients with mantle cell lymphoma: A systematic literature review.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin's lymphoma (NHL) with a median overall survival (OS) of approximately 3-5 years. Systematic literature reviews (SLRs) identified efficacy and safety data for first-line therapies, reported in randomised controlled trials (RCTs) and non-randomised interventional studies (NRISs). Nine and 20 independent studies were included in the RCT and NRISs SLRs, respectively. Differences in the regimens and patient outcomes varied according to patient age and suitability for autologous stem cell transplantation (ASCT). In elderly patients ineligible for transplant, OS ranged from 40 months to 69.6 months. In young transplant-eligible patients, OS ranged from 53 months to 152.4 months. Despite the paucity of directly comparable evidence on the efficacy and safety of MCL therapies, these SLRs highlight that MCL remains a difficult NHL subtype to treat, with short survival highlighting the unmet need for newer treatments that improve patient outcomes.

Systematic Literature Review of Economic Evaluations, Costs/Resource Use, and Quality of Life in Patients with Mantle Cell Lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. While treatment of patients with MCL and their outcomes are previously published, the availability of heath economics evidence is unclear. OBJECTIVE: The aim of this paper was to conduct a comprehensive review of studies relating to economic evaluations, costs and resource use, and health-related quality of life (HRQoL) in patients with MCL. METHODS: Search strategies were designed to capture studies reporting economic or HRQoL outcomes published in the previous 11 years (2007-2018). The following electronic databases were searched: MEDLINE, Embase, NHS Economic Evaluation Database (NHS EED), and EconLit. In addition, we reviewed congress abstracts presented over the previous 2 years (2015 and 2016; where 2017 proceedings had occurred, these were searched instead of 2015). Publications were screened in duplicate by two reviewers and supplementary searches were carried out on health technology assessment websites. Searches were first conducted in October 2017 and updated in March 2018. FINDINGS: The systematic literature review identified 11 economic evaluations (in 16 publications), seven studies reporting data relating to costs or resource use, and five relating to HRQoL. Four economic evaluations presented results for patients with MCL modelled in the first-line setting, while seven modelled patients in the relapsed/refractory setting. The majority of economic evaluations were conducted using a Markov model with three to five health states. Seven studies assessed resource use and reported adverse events as key drivers of increased costs and resource use. Across the five studies reporting HRQoL, disparate measures were used. Two studies reported improvement in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) total scores following treatment and found that clinical response to treatment was associated with improvement in overall HRQoL. CONCLUSIONS AND RELEVANCE: The published economic and HRQoL evidence in MCL, although scarce, reveals that the economic and HRQoL burden associated with MCL is substantial. In highlighting this evidence, this analysis underlines a critical unmet need for more effective treatments with improved outcomes in MCL.

Cost-Effectiveness Analyses, Costs and Resource Use, and Health-Related Quality of Life in Patients with Follicular or Marginal Zone Lymphoma: Systematic Reviews.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are types of indolent non-Hodgkin lymphoma (NHL) that develop in the B lymphocytes (also known as B cells). OBJECTIVE: The aim of this study was to conduct a comprehensive review of studies relating to cost effectiveness, costs and resource use, and health-related quality of life (HRQoL) in patients with FL or MZL. METHODS: Three separate systematic reviews were conducted to identify all published evidence on cost effectiveness, costs and resource use, and HRQoL between 2007 and March 2017 using the MEDLINE®, MEDLINE in-process, E-pubs ahead of print (Ovid SP®), Embase (Ovid SP®), NHS EED, and EconLit databases. Select congress proceedings were also searched. Two systematic reviewers independently reviewed titles, abstracts, and full papers against eligibility criteria. Relevant data were extracted into bespoke data extraction templates (DETs) by a single systematic reviewer; these data were then validated for accuracy by a second reviewer against clean copies of the relevant publications. RESULTS: A total of 25 cost-effectiveness studies (24 in FL; 1 in FL and MZL) met the eligibility criteria. Markov models were the most utilised cost-effectiveness model. US FL studies reported an incremental cost-effectiveness ratio (ICER) of $28,565/QALY for first-line rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP) versus CVP, and $43,000/QALY for second-line obinutuzumab plus bendamustine (G + B) followed by G maintenance versus B. In the UK, ICERs were £1529-10,834/quality-adjusted life-year (QALY) for first-line rituximab + chemotherapy versus chemotherapy, £27,988/QALY for second-line G + B + G-maintenance versus B, and £62,653/QALY for second-line idelalisib versus chemotherapy and/or rituximab. Five costs/resource use and four HRQoL studies were identified in FL, and none in MZL. US mean lifetime costs in first-line patients ranged from $108,000 (rituximab) to $130,300 (rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone [CHOP]), and from £2185 (watch-and-wait) to £17,054 (chemotherapy) in the UK. In a multinational study, more rituximab-refractory patients receiving G + B + G-maintenance reported a meaningful improvement in total FACT-Lym scores compared with patients receiving B. In the UK, total FACT-Lym scores were meaningfully higher for newly diagnosed patients compared with patients with progression (136.04 vs. 109.7). CONCLUSIONS AND RELEVANCE: We found a small body of evidence of quality of life, and potentially cost-effective treatment options for FL; however, no evidence was reported on MZL specifically. The significant data gaps in knowledge in these diseases demonstrate a marked need for further studies.

Systematic literature review of the global burden of illness of mantle cell lymphoma.

Background: Mantle cell lymphoma (MCL), a rare and aggressive disease, accounts for approximately 5% of all B-cell non-Hodgkin's lymphomas. Evidence on the burden of this disease, for patients and healthcare providers, is scarce.Methods: Four systematic literature reviews were developed to identify epidemiological, real-world clinical, economic and humanistic burden data on patients with MCL. Electronic databases searched included MEDLINE and Embase, NHS EED and Econlit.Results: Eight epidemiological studies, 19 clinical burden, 2 economic impact and 0 quality of life studies were identified. The range of standardized MCL incidence rates was 0.1-1.27/100,000. Overall survival rates of patients at 3 years differed by age at diagnosis (≤65 years: 76-81%, >65 years: 46-64%) and disease stage (stage I: 73-80%, stage IV: 48-53%). Outcomes were poorer in previously treated patients, and those with later stage or blastoid disease, and improved with more recent diagnosis/treatment. Hospitalization is a major contributor to healthcare cost and differs by therapy toxicity.Conclusions: We identified significant data gaps for many G20 countries for epidemiology, real-world clinical, economic and humanistic burden. These literature reviews demonstrate the ongoing unmet need for MCL patients globally. Future research to further understand the real-world impact of MCL is needed along with new therapeutic options to improve patient outcomes.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Naive and Treatment-Experienced Patients in Canada.

INTRODUCTION: The Antiretroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to evaluate the cost-effectiveness of dolutegravir (DTG) in Canada in treatment-naive (TN) and treatment-experienced (TE) human immunodeficiency virus (HIV)-1 patients. METHODS: The ARAMIS-DTG model is a microsimulation model with a lifetime analytic time horizon and a monthly cycle length. Markov health states were defined by HIV health state (with or without opportunistic infection). DTG was compared to efavirenz (EFV), raltegravir (RAL), darunavir/ritonavir, rilpivirine (RPV), elvitegravir/cobicistat, atazanavir/ritonavir and lopinavir/ritonavir in TN patients and to RAL in TE patients. The initial cohort, the main efficacy data and safety data were derived from phase III clinical trials. Treatment algorithms were based on expert opinion. Costs normalized to the year 2013 included antiretroviral treatment cost, testing, adverse event, HIV and cardiovascular disease care and were derived from the literature. RESULTS: Dolutegravir was estimated to be the dominant strategy compared with all comparators in both TN and TE patients. Treatment with DTG was associated with additional quality-adjusted life-years that ranged from 0.17 (vs. RAL) to 0.47 (vs. EFV) in TN patients and was 0.60 in TE patients over a lifetime. Cost savings ranged from Can$1393 (vs. RPV) to Can$28,572 (vs. RAL) in TN patients and amounted to Can$3745 in TE patients. Sensitivity analyses demonstrated the robustness of the model. CONCLUSIONS: Dolutegravir is a dominant strategy in the management of TN and TE patients when compared to recommended comparators. This is mainly related to the high efficacy and high barrier to resistance. FUNDING: ViiV Healthcare.

Intravenous Immunoglobulin (IVIg) Utilization in Immune Thrombocytopenia (ITP): A Multi-Center, Retrospective Review.

INTRODUCTION: Intravenous immunoglobulin (IVIg) is an immune thrombocytopenia (ITP) therapy, which is associated with toxicities, limited availability, increasing utilization, and high cost. This study aimed to assess short- and long-term IVIg utilization in patients with ITP at two tertiary care centers in Ontario, Canada, to determine the proportion of IVIg used in ITP compared with all usage, and to forecast IVIg demand in ITP. METHODS: Records from all adult ITP patients who received IVIg between January 1, 2003, and September 30, 2012, at Hamilton Health Sciences and London Health Sciences Centre were reviewed retrospectively. RESULTS: During the study period, 383 adult ITP patients (mean age 51.3 years) received a total of 2,098 IVIg infusions (London 547 infusions in 150 patients; Hamilton 1,551 infusions in 233 patients). ITP accounted for 5.6 and 9.1 % of all IVIg usage in London and Hamilton, respectively. The treatments included 264 (53.7 %) acute, 172 (35.0 %) short-term, and 56 (11.4 %) long-term treatments. The amounts of IVIg used for short- and long-term treatment of ITP are forecasted to be approximately 5,000 and 11,000 g per year, respectively, up to 2018. Together, these two centers represent 19.9 % of the provincial IVIg utilization. Assuming similar patient populations and practice patterns in Ontario, the overall provincial cost of IVIg use in ITP may be as high as $5 million annually. CONCLUSION: Short- and long-term IVIg utilization for ITP will remain an expensive resource within the Ontario provincial health care system. Physicians and policy makers should reflect on the impact of treating ITP with IVIg and should consider alternatives, where appropriate, to improve patient quality of life and decrease economic costs.

Costs associated with severe and nonsevere systemic lupus erythematosus in Canada.

OBJECTIVE: To evaluate the annual direct medical cost of systemic lupus erythematosus (SLE) in Canada by disease severity and to estimate the incremental cost associated with disease severity and flares. METHODS: Medical charts of consecutive patients seen in 3 SLE-specialized treatment centers between July 2007 and June 2008 were retrospectively assessed for disease severity at baseline and for disease activity and health care resource utilization over the following 2 years (±6 months). Annual cost was stratified by disease severity at baseline. Two-year cost was compared for patients with and without flares over 2 years. Multiple linear regression was used to determine the associations between annual cost and SLE severity, and between 2-year cost and the number and type of flare (mild/moderate versus severe). RESULTS: A total of 109 active SLE patients (94% women, mean age 41.4 years, mean disease duration 11.3 years, 56 patients with severe disease) were studied. The average annual direct medical cost was $10,608 Canadian (2010 dollars) and was higher for patients with severe disease, $15,048 versus $5,917 (P < 0.001). The 2-year direct cost for patients with at least 1 flare was $22,633 versus $11,113 (P = 0.028) for patients without flares. The mean incremental annual cost was $7,007 (95% confidence interval [95% CI] $3,487, $13,048) for an SLE patient with severe disease, and the 2-year mean incremental cost was $5,848 (95% CI $2,919, $8,777) for each additional severe flare. CONCLUSION: The direct health care cost of SLE patients in Canada is influenced by disease severity and the type and frequency of flares.

The effect of dutasteride on the detection of prostate cancer: A set of meta-analyses.

BACKGROUND: Dutasteride has been shown to significantly improve symptoms of benign prostatic hyperplasia (BPH) and reduce clinical progression. Recent data from studies evaluating 5-alpha reductase inhibitors (5-ARIs) for the prevention of prostate cancer, however, suggest 5ARIs, including dutasteride, may be associated with increased incidence of Gleason 8-10 prostate tumours. This meta-analysis was undertaken to quantify the effect of dutasteride on detection of prostate cancer and high-grade prostate cancer. METHODS: Our meta-analysis includes data from GlaxoSmithKline-sponsored phase III randomized clinical trials (with a study duration of ≥2 years) evaluating the effect of dutasteride, alone or in combination with tamsulosin, to treat BPH or to reduce the risk of prostate cancer. The incidence of prostate cancer, including Gleason 7-10 and Gleason 8-10, for patients taking either dutasteride, dutasteride plus tamsulosin, tamsulosin alone, or placebo, were evaluated using the Mantel-Haenszel Risk Ratio (MHRR) method of conducting meta-analyses. RESULTS: The meta-analysis demonstrated that in a population with symptomatic BPH and/or at increased risk of prostate cancer, a statistically significant lower number of detectable prostate cancers was found in men taking dutasteride compared to control groups (MHRR: 0.66, 95% CI 0.52-0.85). In our analysis, there was no increased risk for Gleason 7-10 (MHRR: 0.83, 95% CI 0.56-1.21) or Gleason 8-10 prostate cancers (MHRR: 0.99, 95% CI 0.39-2.53) in men taking dutasteride over control groups. There were several limitations that need to be considered when interpreting these results. CONCLUSION: These data provide support for the continued use of dutasteride in the treatment of symptomatic BPH patients.

Antipsychotic switching: results from a one-year prospective, observational study of patients with schizophrenia.

OBJECTIVE: The Health Outcomes of a Canadian Community Cohort (HOCCC) study is a 1-year prospective observational study of outpatients with schizophrenia or related psychotic disorders. The purpose of the study was to compare effectiveness of antipsychotic treatment as measured by 1-year treatment completion rates. DESIGN AND METHODS: Patients (N = 929) were enrolled if in the course of usual clinical practice they switched to a second-generation antipsychotic (SGA). Observational data were collected for up to 1 year. The primary analysis compared 1-year treatment-completion rates for the olanzapine cohort with the other SGA cohort (quetiapine, risperidone, clozapine), using a chi-squared test. RESULTS: Of 929 patients enrolled, 64.8% (516/796) of evaluable patients completed 1 year of treatment. There was no statistically significant difference in the proportion of treatment completers between the olanzapine cohort (67.4%, 256/380) and the other SGA cohort (62.5%, 260/416). Treatment-completion rates were risperidone 62.0% (127/205), quetiapine 63.7% (123/193) and clozapine 55.6% (10/18). Antipsychotic polypharmacy was common. Patients treated with olanzapine or risperidone had significantly higher increases in BMI than quetiapine-treated patients. There were no major differences between olanzapine monotherapy and pooled other SGA monotherapy groups in status of extrapyramidal symptoms from baseline to endpoint. CONCLUSIONS: Olanzapine and other SGAs exhibited similar rates of 1-year treatment completion. Further study of medication combinations is needed, given their perceived clinical value, and the high frequency of antipsychotic polypharmacy in clinical practice. LIMITATIONS: As most patients received several psychotropics and power was reduced in monotherapy analyses, comparisons between cohorts must be interpreted cautiously. Comparisons between individual antipsychotics were post hoc and not powered a priori. Accuracy and completeness of adverse event information for drugs other than olanzapine is limited.

Measuring Integration of Cancer Services to Support Performance Improvement: The CSI Survey.

OBJECTIVE: To develop a measure of cancer services integration (CSI) that can inform clinical and administrative decision-makers in their efforts to monitor and improve cancer system performance. METHODS: We employed a systematic approach to measurement development, including review of existing cancer/health services integration measures, key-informant interviews and focus groups with cancer system leaders. The research team constructed a Web-based survey that was field- and pilot-tested, refined and then formally conducted on a sample of cancer care providers and administrators in Ontario, Canada. We then conducted exploratory factor analysis to identify key dimensions of CSI. RESULTS: A total of 1,769 physicians, other clinicians and administrators participated in the survey, responding to a 67-item questionnaire. The exploratory factor analysis identified 12 factors that were linked to three broader dimensions: clinical, functional and vertical system integration. CONCLUSIONS: The CSI Survey provides important insights on a range of typically unmeasured aspects of the coordination and integration of cancer services, representing a new tool to inform performance improvement efforts.

MSH2 118T>C and MSH6 159C>T promoter polymorphisms and the risk of colorectal cancer.

The most important indicator of colorectal cancer (CRC) risk is the presence of family history of the disease. Inherited genetic changes, such as single nucleotide polymorphisms, in key candidate genes may contribute to CRC risk. We investigated whether promoter polymorphisms in DNA mismatch repair (MMR) genes MSH2 and MSH6 are associated with the risk of CRC. We genotyped 929 CRC patients and 1098 control subjects from Ontario, and 467 patients and 344 controls from Newfoundland and Labrador, for two promoter polymorphisms in the MMR genes MSH2 and MSH6 using the fluorogenic 5' nuclease assay. We used unconditional logistic regression to evaluate the association between each polymorphism and CRC after adjusting for age and sex. The associations between polymorphisms and tumor clinicopathological features were evaluated with a Pearson's chi-squared test or Fisher's exact test. All statistical tests were two sided. We observed strong associations between the MSH2 -118T>C polymorphism and family history of CRC based on the Amsterdam criteria I (P = 0.005) and Amsterdam criteria I and II (P = 0.036) among cases from Ontario. This association was especially evident among female CRC patients in Ontario (for Amsterdam criteria I, and I and II combined, P = 0.003 and P = 0.0001, respectively). The MSH2 -118T>C polymorphism was associated with strong family history of CRC in Ontario patients.

Does early colectomy increase desmoid risk in familial adenomatous polyposis?

BACKGROUND & AIMS: Desmoid tumors are non-metastasizing fibromatoses that occur in 10%-20% of subjects with familial adenomatous polyposis (FAP). Intra-abdominal desmoid tumors are a major cause of mortality in FAP. FAP-associated desmoid tumors are linked to trauma, particularly abdominal surgery, family history of desmoids, hormonal factors, and the location of the APC mutation. We hypothesized that prophylactic colectomy at an early age might increase the risk of developing desmoids. The aim of this study was to determine whether colectomy earlier in life is a risk factor for the development of desmoid tumors. METHODS: An analysis was made of the association between development of desmoid and age at colectomy, family history of desmoids, gender, and APC mutation in FAP patients in the Registry (1980-2005) at Mount Sinai Hospital, Toronto, Ontario, Canada. RESULTS: FAP patients (n = 930) from 365 kindreds were identified. Desmoid prevalence was 14% (n = 121). Female patients were more likely to develop desmoids than male patients (17% vs 11%, P = .03). Female patients who had an early colectomy were more than 2 times more likely to develop a desmoid, compared with women who had a colectomy at >18 years (P = .01). Early colectomy did not increase risk of developing a desmoid in male patients (P = .42). Female patients who had an early colectomy (

MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer.

BACKGROUND: Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer. METHODS: We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay. Tumor microsatellite instability (MSI) was determined with a polymerase chain reaction-based method; MSI status was assigned as high (MSI-H, > or = 30% unstable markers among all markers tested), low (MSI-L, <30% markers unstable), or stable (MSS, no unstable markers). We used unconditional logistic regression to evaluate the association between each polymorphism and colorectal cancer after adjusting for age and sex. The associations between polymorphisms and tumor clinicopathologic features were evaluated with a Pearson's chi-square or Fisher's exact test. All statistical tests were two-sided. RESULTS: We observed strong associations between the MLH1 -93G>A polymorphism and MSI-H tumors among case patients from Ontario (P = .001) and Newfoundland (P = .003). When compared with the control populations, homozygosity for the MLH1 -93G>A variant allele was associated with MSI-H tumors among case patients in Ontario (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.65 to 6.30) and in Newfoundland (OR = 8.88, 95% CI = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% CI = 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% CI = 1.14 to 5.75). Genotype frequencies were similar among case patients with MSS and MSI-L tumors and control subjects, and the majority of homozygous variant carriers had MSS tumors. Among case patients from Ontario, an association between the MLH1 -93G>A polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed. CONCLUSION: In two patient populations, the MLH1 -93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.

Using latent class analysis (LCA) to analyze patterns of drug use in a population of illegal opioid users.

BACKGROUND: The objective of this paper is to empirically determine a categorization of illegal opioid users in Canada in order to describe and analyze drug use patterns within this population. METHODS: Drug use patterns of 679 eligible illegal opioid users outside treatment from the OPICAN study, a pan-Canadian cohort (recruited March to December, 2002) involving the cities of Toronto, Montreal, Vancouver, Edmonton and Quebec City, were empirically examined using latent class analysis. These latent classes were then further analyzed for associations using chi-square and t-test statistics. FINDINGS: The opioid and other drug user sample surveyed were categorized into three latent classes. Class 1 (N=256) was characterized by the use of Tylenol 3 and benzodiazepines along with high levels of depression and self-reported pain. Class 2 (N=68) was described by the non-injection use of both heroin and crack while having a high level of homelessness. Class 3 (N=344) was shown to consist of injection drug users of heroin and cocaine exhibiting the highest levels of HIV and Hepatitis C infections amongst the classes. CONCLUSIONS: Using latent class analysis we found distinct patterns of drug use amongst illegal opioid users differing in terms of type of drugs co-used, social context, and co-morbid pathologies. These data may be useful as the empirical basis for the planning of specific prevention and treatment interventions.

Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.

Previous case-control studies have suggested that carriers of monoallelic germline mutations in the MYH gene may be at increased risk of colorectal cancer. We applied a kin-cohort design, using a modified segregation analysis, to estimate the colorectal cancer risk using 300 first-degree relatives of 39 colorectal cancer cases who were monoallelic or biallelic carriers of MYH mutations. We found that monoallelic carriers had a 3-fold increased risk of colorectal cancer (hazard ratio, 2.9; 95% confidence interval, 1.2-7.0; P = 0.02) and biallelic carriers a 50-fold increased risk (hazard ratio, 53; 95% confidence interval, 14-200; P < 0.0001). This analysis illustrates the potential of family analysis to estimate cancer risk for low-frequency mutations and, based on the proportion of relatives predicted to be carriers, we believe that this constitutes the largest study of monoallelic carriers to date.

[Volume and profile of alcohol consumption among students and classmates as predictors of aggression and victimization: a multilevel analysis among Swiss adolescents]. / Volume et profil de consommation d'alcool des élèves et des camarades scolaires comme prédicteurs de l'agression et de la victimisation: une analyse multiniveaux auprès d'adolescents suisses.

OBJECTIVE: To test the effects of the volume of alcohol consumption and drinking patterns on alcohol-related aggression and victimization, both at the individual and class levels. METHODS: Representative sample drawn from the European School Survey Project on Alcohol and Other Drugs (ESPAD) of 6496 Swiss adolescents (13 to 16 years). Hierarchical multi-level models were used to simultaneously estimate individual and environmental influences. In addition to indicators of consumption of alcohol and other substances, age, sex, socioeconomic indicators and satisfaction with the relationship to parents were used as covariates. RESULTS: After controlling for confounding, both volume of alcohol consumption and the frequency of binge drinking occasions were associated independently with alcohol-related problems (aggression/victimization) on the individual level. On the aggregate level, there was colinearity between volume of drinking and frequency of heavy drinking occasions. When entered in the same model, however, only the effect of volume effect stayed in the same direction. CONCLUSIONS: Not only individual volume of drinking, but also the way alcohol is consumed influences individual problem levels. This includes individual patterns of drinking as well as environmental influences at school. These results open up important considerations for theory, research and prevention.

Prescription drug abuse in Canada and the diversion of prescription drugs into the illicit drug market.

Prescription drug abuse has received considerable attention in media reports in recent years. The purpose of this article is to describe the Canadian situation and context with regards to prescription drug abuse and the diversion of psychotropic prescription drugs into the illicit drug market, with a focus on the need for more data and interventions. Canada ranks within the top 10% of countries in the use of benzodiazepines, opioid prescriptions and stimulants. There are many ways that prescription drugs are diverted into the illicit market and varied reasons for use and abuse. Prescription drug abuse is further related to a number of negative consequences, including overdose. While seniors and women have been the primary focus for research in Canada on prescription drug abuse, adolescents and young adults have received less attention. Systematic epidemiological data specifically on prescription drug abuse in the Canada context are lacking and are needed in order to more clearly understand the reasons for the phenomenon and to develop and implement appropriate interventions.

School matters: drinking dimensions and their effects on alcohol-related problems among Ontario secondary school students.

AIMS: To test the hypotheses that average volume of alcohol consumption and patterns of drinking, each influence alcohol-related problems and that both act at individual and aggregate levels. METHODS: The 2003 cycle of the Ontario Student Drug Use Survey obtained self-administered questionnaires from a representative classroom-based survey of 2455 Ontario secondary school students (grades 9-12) from 74 schools, with a student completion rate of 72%. Average volume of alcohol consumption was assessed using a quantity-frequency measure. Heavy drinking occasions were operationalized by four dummy variables indicating less than monthly, monthly, weekly and daily consumption of five or more drinks per occasion, with never having a heavy drinking occasion serving as the reference group. Alcohol-related problems were measured by using seven items of the Alcohol Use Disorders Identification Test. RESULTS: As hypothesized, both the average volume of alcohol consumption and patterns of drinking influenced alcohol-related problems at the student level, independently of each other. At the school level, both determinants significantly influenced the problems, but not when simultaneously entered into the equation. CONCLUSIONS: Future prevention of alcohol-related problems in adolescents should consider both the average volume and patterns of drinking. Both prevention and research should also try to include environmental determination of alcohol-related problems.