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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. Electronic supplementary material The online version of this article (10.1007/s41669-020-00231-w) contains supplementary material, which is available to authorized users.

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 ...

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. Electronic supplementary material The online version of this article (10.1007/s41669-020-00204-z) contains supplementary material, which is available to authorized users.

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.

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.

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

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.

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 incombination 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.

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. Electronic supplementary material The online version of this article (doi:10.1007/s40801-015-0009-6) contains supplementary material, which is available to authorized users.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and fatal disease. The primary aim of this national multicenter non-interventional study known as the INSPIRATION PLUS registry, is to describe the real world effectiveness and safety of pirfenidone and the clinical management practices in Canada. Methods: The patients included had a confirmed diagnosis in accordance with the 2011 international guidelines. Data are collected approximately every 3 to 6 months for a minimum of 2 years. The primary objective is to describe and assess the disease course and outcomes in pirfenidone-treated IPF patients in routine clinical practice. The drug utilization patterns will also be described. A validity assessment of the ATAQ-IPF questionnaire will be done compared to three validated but non-specific to IPF Quality of life measures. Results: Conclusion: The characteristics of this IPF population at the initiation of pirfenidone indicate that pirfenidone is being used in a wide spectrum of IPF patients in Canada. Follow up data will be presented at a later time.

Introduction Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin's lymphoma (NHL) with poor survival outcomes. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended as first-line therapy in younger patients. However the comparative efficacy of such regimens, and of alternative therapy options (for patients unable to tolerate chemotherapy + ASCT), remain unclear. A comprehensive understanding of the current evidence is therefore required. Methods Two systematic reviews (SRs) were developed to identify efficacy and safety data for therapies used in the first-line treatment of MCL. One review identified randomised controlled trials (RCTs) and the other non-randomised studies (NRSs). Searches were carried out in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials electronic databases. Additionally, conference materials were screened from ASH, EHA, ESMO and ASCO proceedings from the last 2 years. All review methodologies were performed according to Cochrane best practice guidelines Results The RCT SR was run in August 2017 and updated in April 2018. Overall, 2,787 abstracts were screened. The SR included 9 full-text articles and data from 2 conference proceedings, together reporting a total of 7 independent studies. Across the RCTs, the most commonly investigated treatment regimens were rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), and bendamustine + rituximab (BR). Frequently reported primary endpoints were response rates and progression-free survival (PFS). Table 1 presents the PFS and overall survival (OS) data reported in the included RCTs. Data from the RCT reporting on intensive induction chemotherapy followed by ASCT are separated from regimens that did not include ASCT. There were notable differences in median PFS rates, between both patients receiving ASCT versus patients not receiving ASCT and also between the two ASCT treatment arms. In pharmacotherapy studies, PFS ranged from 14.4 to 35.4 months, whereas the two arms of the ASCT RCT reported 51.6 and 109.2 months, respectively. Similar trends were observed in OS: the only result for patients undergoing ASCT (117.6 months) was higher than any result reported in patients not receiving transplant (range 40 - 60 months). However, study heterogeneity may affect the appropriateness of directly comparing these results. Frequently reported grade 3-4 adverse events included anemia, infusion-related reactions, nausea, neutropenia and thrombocytopenia (four of seven RCTs reported each event). The NRS SR was run in April 2018. A total of 3,290 abstracts were screened and 75 full papers were assessed. The SR included 25 full-text articles and 6 conference proceedings, together reporting a total of 18 independent single-arm studies. Several of the NRSs investigated treatment regimens that have not been described in RCT studies, including: R-CHOP with alternating or sequential rituximab + cytarabine (maxiCHOP), and cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high dose methotrexate or cytarabine + rituximab (hyperCVAD + R). Across the NRSs, the longest median PFS was 8.5 years (102 months), in patients treated with maxiCHOP (who were young/ASCT-eligible patients). This outcome was reported in a patient population who had responded to induction therapy and were treated with consolidative ASCT. Across all studies there was heterogeneity in the eligible patient population, with some studies focusing on unfit patients and others focusing on high-dose-therapy-eligible patient populations. Many studies also reported maintenance or consolidation treatments, which would influence the long-term outcomes of the patients. Conclusions These SRs highlight the paucity of directly comparable evidence on the efficacy and safety of therapies for patients with MCL. Although there are some marked differences in patient outcomes according to therapy regimen, considerable heterogeneity in study design and patient populations make direct comparison difficult. Despite this, these SRs highlight that MCL remains a difficult subtype of NHL to treat, with short survival highlighting the high unmet need. With new and emerging therapies, additional research is essential to understand optimal regimens for first-line MCL. Table 1. Table 1. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ward:Janssen Pharmaceutica NV: Consultancy. Quigley:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

Introduction Mantle cell lymphoma (MCL) is a rare but often aggressive subtype of non-Hodgkin's lymphoma, with many patients experiencing short survival. While both first and subsequent-line therapies are available, it is unclear what health economic evidence is available for treatments. To provide context for economic evaluations, it is also important to understand the economic burden of MCL and the quality of life which patients experience. Our study aims to comprehensively understand health economic (costs and resource-use, and economic evaluations) and health-related quality of life (HRQoL) evidence base for patients with MCL through three systematic literature reviews (SLRs). Methods Search strategies were designed to capture studies reporting economic or HRQoL outcomes for patients with MCL. Searches were date-limited in order to identify studies published in the last 10 years (2007-current). The following electronic databases were searched: MEDLINE, Embase, NHS Economic Evaluation Database (NHS EED), and EconLit. In addition, we searched congress abstracts (at ASCO, ASH, ISPOR, AMCP, EHA, and ESMO proceedings) presented over the previous 2 years. Potential publications were screened in duplicate by 2 reviewers. Additional online searches were carried out to identify health technology assessment (HTA) submission documents reporting health economic evaluations for patients treated with pharmacological interventions. All searches were conducted in October 2017, and were updated in March 2018. Results The SLR identified 11 economic evaluations reported across 16 publications, and 7 studies reporting data for costs or resource-use. Table 1 presents a summary of the economic evaluations that reported incremental cost effectiveness ratios (ICERs). Four of the 11 economic evaluations presented models for patients in the first-line setting, and 7 presented models for patients in the relapsed/refractory (R/R) setting.. The majority of economic evaluations were conducted using a Markov model with 3-5 health states. R-Chemo was the most common comparator used in both the first line and relapsed/refractory settings. Across the 7 studies reporting costs or resource-use data, all 7 reported data for resource-use and 3 additionally reported costs data. There were a variety of costs and resource use data reported, including treatment-specific and non-treatment-specific data. Studies reported adverse events (AEs) as key drivers of increased costs and resource use. One study specifically reported statistically significant (p≤0.005) increases in emergency room visits were associated with MCL disease related AEs (odds ratio [OR]: 10.571). The following disease-specific HRQoL measures were reported: FACT-Lym, FACT-G, and EORTC QLQ-C30. There was little consistency in the measures used to evaluate HRQoL across studies. Table 2 presents the 2 studies reporting FACT-Lym scores. In both studies, trends for improvement in FACT-Lym total scores following treatment were reported. One phase 3 randomized study in R/R MCL reported 66% of ibrutinib-treated patients and 48% of temsirolimus-treated patients achieving a clinically meaningful improvement in FACT-Lym score. A second study in front line MCL reported improvements in the FACT-Lym total score following treatment with lenalidomide + rituximab. Each of these studies also demonstrated that clinical response to treatment was associated with the improvement in overall HRQoL. Conclusions These SLRs highlight the limited availability of published economic and HRQoL evidence for patients with MCL. The paucity of evidence is even more evident when first-line and R/R data are examined separately. Markov models with 3-5 health states represented the majority of economic evaluations . In both the first line and relapsed/refractory settings, R-Chemo was the most common comparator used. For both settings, AEs may have significant effects on the economic burden MCL places on healthcare payers. Novel agents have shown a clinically meaningful improvement in HRQoL. The noted economic burden of the disease demonstrates a need for newer treatments that decrease the burden MCL places on health care systems globally. There remains a need for future research to further understand the economic and HRQoL burden of MCL. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Surface Oncology: Research Funding. Tam:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ward:Janssen Pharmaceutica NV: Consultancy. Fotheringham:Janssen Pharmaceutica NV: Consultancy. O'Donovan:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

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.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.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.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.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.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common problem associated with significant morbidity and mortality. Previous studies show that immediate endoscopies do not affect outcomes in patients; however, endoscopic interventions have evolved. The present retrospective review of endoscopies performed at a large teaching hospital assessed the timing of endoscopy with respect to the morbidity and mortality of UGIB.METHODS: Diagnostic billing codes were used to assess all inpatients of gastroenterologists at the University Hospital of the London Health Sciences Centre, London, Ontario, from July 2004 to June 2006, using a centralized data recording system. Time to endoscopy (within 6 h, 6 h to 24 h and beyond 24 h) were compared for the outcomes of mortality, need for surgery and transfusion requirements.RESULTS: From July 2004 to June 2006, there were 502 upper endoscopies performed for the indication of suspected UGIB and 375 for overt acute nonvariceal UGIB. Approximately 10% of cases revealed variceal bleeding. When comparing endoscopy within 6 h with endoscopy at 6 h to 24 h, there were no significant differences in mortality, need for surgery (OR 3.6 and 2.8, respectively, compared with endoscopy beyond 24 h) or transfusion requirements. Even when assessing the group that received endoscopic hemostasis, time to endoscopy was not associated with better outcomes. Multivariate analysis did not demonstrate any advantages for early endoscopy (less than 6 h) compared with endoscopy within 24 h.CONCLUSIONS: Most patients with acute gastrointestinal bleeding can be effectively managed with endoscopy within 24 h.

Aims: MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics. Methods and results: Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status (P = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls (P = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls (P = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups. Conclusions: Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.

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.

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.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.We observed strong associations between the MLH1 -93GA 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 -93GA 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 -93GA polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed.In two patient populations, the MLH1 -93GA polymorphism was associated with an increased risk of MSI-H colorectal cancer.

BJECTIVE: 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. Language: fr

Unterschiede zwischen Ko-Gebrauchern von Kokain und Crack bei kanadischen Opioid-Konsumenten Fragestellung: Es wurden Unterschiede zwischen Ko-Gebrauchern von Kokain und Crack in einer kanadischen Kohorte illegaler Opioid-Konsumenten (»OPICAN«) untersucht. Methodik: Kohortenteilnehmer wurden durch Schneeball-Methoden rekrutiert und mittels eines standardisierten Instrumenten-Protokolls befragt. Prävalenzraten verschiedener Substanzen sowie Unterschiede zwischen ausgewählten Indikatoren und den beiden Subgruppen wurden bivariat geprüft. Ergebnisse: Zirka die Hälfte der Studienteilnehmer indizierten Ko-Konsum von Crack beziehungsweise Kokain. Erstere Gruppe zeichnete sich primär durch sozioökonomische Marginalisierung, zweitere durch eine höhere Prävalenz von Depression aus. Schlussfolgerungen: Ko-Gebraucher von Opioiden mit Kokain und Crack in Kanada können als distinkte Subkulturen mit spezifischen Risikofaktoren angesehen werden. Ausgewählte Implikationen für Interventionen werden angesprochen.

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.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).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 (P0.001). 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.The direct health care cost of SLE patients in Canada is influenced by disease severity and the type and frequency of flares.

For more than a decade, health services researchers have focused on the integration of health services as a means to improve performance. Measures have been developed that assess both provider- and patient-derived aspects of the coordination and continuity of health services within and across sectors (Gillies et al. 1993; Burns et al. 2001; Alexander et al. 2001; Fairchild et al. 2002; Ware et al. 2003; Durbin et al. 2004; Dolovich et al. 2004). Cancer systems, representing a microcosm of broader healthcare systems (including health promotion, cancer prevention/screening, surgical interventions, radiation and systemic therapies, supportive and palliative care), present a particularly challenging context for service integration (Sullivan et al. 2008). Cancer patients are often cared for by multiple providers (e.g., surgeons, medical oncologists, radiation oncologists, nurses, radiation therapists, social workers, community healthcare providers, etc.) in multiple care settings (e.g., at specialized/comprehensive cancer centres, teaching and community hospitals, primary care settings and/or at home). In Ontario, Canada, a 2001 review of cancer services highlighted their fragmented nature and recommended “ways to improve the integration of cancer services at the local and regional levels, the quality of patient care, and the productivity and efficiency in the cancer service component of the Ontario health system” (Cancer Services Implementation Committee 2001). While this review led to major reorganization of the Ontario cancer system (Sullivan et al. 2004; Dobrow et al. 2006), a specific measure of cancer services integration (CSI) to guide restructuring and monitor performance improvement did not exist. This paper reports on efforts to develop a measure of integration specific to cancer services as part of a broader undertaking to monitor and improve cancer system performance in Ontario.

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 (≤18 years) were 2.5 times more likely to develop desmoids, compared with male patients who had a late colectomy (P = .05). The prevalence of desmoids in the 5′ and 3′ groups was 13% and 38%, respectively (P = .0005). Patients with a mutation after codon 1399 were found to have 4 times greater chance of developing a desmoid. Conclusions: Female patients with FAP are more likely to develop desmoids than male patients. Female patients who had an early colectomy are at significantly greater risk of developing a desmoid compared with female patients who had a colectomy in adulthood. Patients with APC mutations beyond codon 1399 are more likely to develop desmoids. These results suggest that delayed colectomy might be considered in young female patients with FAP to decrease the chances of developing desmoids.

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.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.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.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.

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. (Cancer Epidemiol Biomarkers Prev 2006;15(2):312–4)

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.

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. ( Received 20 May 2005; first review notified 13 July 2005; accepted in final revised form 17 August 2005)

Objectives To evaluate the annual direct medical costs and the impact of SLE disease severity and flares on incremental costs in autoantibody positive SLE patients (pts) managed by specialists. Methods A retrospective study was conducted in three Canadian academic medical centers with established cohorts of SLE patients. Data on patient characteristics, disease activity and severity, and medical resource utilization were collected through chart review. Consecutive pts seen in clinic between July 2007 and June 2008 were screened for SLE flares and disease severity using predefined decision rules for both. The number and proportion of pts with severe and non-severe SLE was also defined a priori. Patients who met the inclusion criteria were stratified by disease severity (severe and non-severe active SLE) and followed for 2 yrs (±6 mths after the inclusion visit). Severe disease was defined as involvement of renal, neurological, cardiovascular or respiratory systems which required >7.5 mg/day of corticosteroids and/or immunosuppressants or any SLE manifestation that required at least 30mg/day of corticosteroids at the inclusion visit. A modified SELENA-SLEDAI Flare Index was used to identify mild/moderate and severe flares. Costs were calculated by multiplying each health resource utilized (i.e., lab and imaging tests, biopsies, meds, specialist visits, day hospitalizations, emerg visits, inpatient and rehab stays) by its corresponding CAD unit cost. Total unadjusted mean costs and costs associated with flares were assessed over 2 yrs and expressed in CAD dollars. The analyses were primarily performed using appropriate descriptive statistics for continuous and categorical data. Multiple regression analyses was used to identify the association between 2 yr costs and number of mild/moderate flares and number of severe flares, adjusting for age and SLICC/ACR damage index score. Results A total of 109 pts, 93.6% female, with a mean (SD) age of 41.4 (±15.4) yrs and mean disease duration of 11.9 (±12.6) yrs were studied. At enrollment, 56 pts had severe active SLE and 53 had non-severe active SLE. The mean number of flares for severe and non-severe pts over the study period was 2.68 and 1.91 respectively (p=0.005). Patients in the severe patient group had a higher number of severe flares compared to pts with non-severe SLE (1.82 vs. 0.70; p Conclusions Patients with severe active SLE have 2.7 times higher annual costs compared to pts with non-severe disease. Patients experiencing at least one flare incurred 2 times more costs annually than those without flares. Direct healthcare costs in Canada are influenced by SLE disease severity in addition to the type and frequency of SLE flares. Disclosure of Interest A. Clarke Consultant for: the study and received funds from GSK/HGS, is a consultant for MedImmune and Bristol Myers Squibb, and received research grants from GSK and funds from GSK/HGS for the writing of this abstract. M. Urowitz Consultant for: the study and received funds from GSK/HGS, is a consultant for UCB, Merck/Serono, and received funds from GSK/HGS for the writing of this abstract., N. Monga Employee of: GlaxoSmithKline, N. Topors Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, J. Hanly Consultant for: the study and received funds from GSK/HGS, received a grant from GSK, and received funds from GSK/HGS for the writing of this abstract.

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. Electronic supplementary material The online version of this article (doi:10.1007/s40121-015-0071-0) contains supplementary material, which is available to authorized users.