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Intervention In April 2012, the Manitoba Home Cancer Drug Program (HCDP) was introduced to allow 100% coverage for eligible oral anticancer agents (OAA) and supportive medications for Manitobans with cancer requiring these therapies. Research questions What is the extent of use and cost of OAAs among outpatients in Manitoba from 2003/04 to 2015/16? Did the HCDP change OAA user and prescription patterns? Methods This was a retrospective, population-based study using administrative data to measure the prevalence of drug utilization over time and the impact of HCDP on OAA use and prescriptions using generalized linear models. Manitobans with cancer who filled an OAA or supportive medication covered by HCDP from 2003/04 to 2015/16 were included. Results This study included 22,393 people with cancer who filled an OAA prescription. The prevalence of OAA use increased from 222 per 100,000 to 328 per 100,000 from 2003/04 to 2015/16. Hormone therapy for breast cancer was the most common class of OAA used (increased from 154 per 100,000 to 231 per 100,000). We observed a 2.6-fold decrease in the prevalence of oral alkylating agents and a 10.7-fold increase in the prevalence of protein kinase inhibitors during the study period. The total cost of targeted OAAs per year for all Manitobans with cancer increased from $1.8 million to $19 million. Conclusion We observed an increase in OAA prevalence and the cost of oral targeted chemotherapy is high. Our findings underline the need for addressing these high-cost medications in future developments of a national drug program.

Background Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB). Methods A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan–Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy. Results Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil. Conclusions In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

ObjectiveThe Canadian Real-world Evidence for Value in Cancer (CanREValue) Collaboration was established in response to growing interest in using real-world evidence (RWE) to support health technology assessment (HTA). CanREValue has developed a framework to generate and use RWE to inform cancer drug funding decisions.Design and participantsThe RWE framework was developed using a multistage, multistakeholder approach. First, an environmental scan and qualitative study were conducted to understand the current state and key stakeholder perspectives on RWE. Next, five formal working groups (WGs) were established consisting of stakeholders with cancer drug funding expertise including clinicians, patients, methodologists, payers, regulatory decision-makers and data analysts. Through stakeholder consultations, including modified Delphi exercises and workshops, each WG developed specific framework components and identified facilitators and barriers that may impact the uptake of RWE.SettingThe CanREValue Collaboration consisted of membership and participation from stakeholders and expertise from across Canada. Central research operations were managed from Toronto, Ontario, Canada.OutcomesDevelopment of an RWE framework reflective of the needs and perspectives of stakeholders directly involved and/or impacted by cancer drug funding decisions across Canada.ResultsThrough an iterative process, a comprehensive RWE framework was developed that outlined the end-to-end processes necessary for the generation and use of RWE for HTA reassessment in Canada. The framework consists of four phases that uses various tools, templates and processes, which can be applied as a whole or in part. A diverse range of stakeholders and expertise is involved in the decision-making of each phase of the process: Phase I: identification, selection and prioritisation of RWE questions; phase II: initiating and planning the RWE study; phase III: conducting the RWE study and phase IV: conducting reassessment.ConclusionsAs the cancer drug funding landscape continues to evolve, the need for RWE to support evidence-based policy reform, pricing and reallocation of funding from low to high value settings is crucial. We have developed a framework that is adaptable and responsive to the changing landscape. The tools, templates and processes within the framework can be applied by various stakeholder groups in whole or in part to support cancer drug funding decision-making in Canada and can be adapted for use in other jurisdictions.

Background Auto-aggregation is a desired property for probiotic strains because it is suggested to promote colonization of the human intestine, to prevent pathogen infections and to modulate the colonic mucosa. We recently reported the generation of adapted mutants of Lactiplantibacillus plantarum NZ3400, a derivative of the model strain WCFS1, for colonization under adult colonic conditions of PolyFermS continuous intestinal fermentation models. Here we describe and characterize the emerge of an auto-aggregating phenotype in L. plantarum NZ3400 derivatives recovered from the modelled gut microbiota. Results L. plantarum isolates were recovered from reactor effluent of four different adult microbiota and from spontaneously formed reactor biofilms. Auto-aggregation was observed in L. plantarum recovered from all microbiota and at higher percentage when recovered from biofilm than from effluent. Further, auto-aggregation percentage increased over time of cultivation in the microbiota. Starvation of the gut microbiota by interrupting the inflow of nutritive medium enhanced auto-aggregation, suggesting a link to nutrient availability. Auto-aggregation was lost under standard cultivation conditions for lactobacilli in MRS medium. However, it was reestablished during growth on sucrose and maltose and in a medium that simulates the abiotic gut environment. Remarkably, none of these conditions resulted in an auto-aggregation phenotype in the wild type strain NZ3400 nor other non-aggregating L. plantarum , indicating that auto-aggregation depends on the strain history. Whole genome sequencing analysis did not reveal any mutation responsible for the auto-aggregation phenotype. Transcriptome analysis showed highly significant upregulation of LP_RS05225 ( msa ) at 4.1–4.4 log 2 -fold-change and LP_RS05230 ( marR ) at 4.5–5.4 log 2 -fold-change in all auto-aggregating strains compared to non-aggregating. These co-expressed genes encode a mannose-specific adhesin protein and transcriptional regulator, respectively. Mapping of the RNA-sequence reads to the promoter region of the msa - marR operon reveled a DNA inversion in this region that is predominant in auto-aggregating but not in non-aggregating strains. This strongly suggests a role of this inversion in the auto-aggregation phenotype. Conclusions L. plantarum NZ3400 adapts to the in vitro colonic environment by developing an auto-aggregation phenotype. Similar aggregation phenotypes may promote gut colonization and efficacy of other probiotics and should be further investigated by using validated continuous models of gut fermentation such as PolyFermS.

Improvement of bacterial strains in regard to specific abiotic environmental factors is broadly used to enhance strain characteristics for processing and product quality. However, there is currently no multidimensional probiotic strain improvement approach for both abiotic and biotic factors of a colon microbiota. Research and marketing of probiotics demand holistic strain improvement considering both the biotic and abiotic gut environment. Here, we aim to establish the continuous in vitro colonic fermentation model PolyFermS as a tool for adaptive evolutionary engineering. Immobilized fecal microbiota from adult donors were steadily cultivated up to 72 days in PolyFermS reactors, providing a long-term compositional and functional stable ecosystem akin to the donor’s gut. Inoculation of the gut microbiota with immobilized or planktonic Lactiplantibacillus plantarum NZ3400, a derivative of the probiotic model strain WCFS1, led to successful colonization. Whole-genome sequencing of 45 recovered strains revealed mutations in 16 genes involved in signaling, metabolism, transport, and cell surface. Remarkably, mutations in LP_RS14990, LP_RS15205, and intergenic region LP_RS05100

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