Publications by authors named "David E Dawe"

32 Publications

The impact of the modified frailty index on clinical outcomes for patients with stage IV non-small cell lung cancer receiving chemotherapy.

J Geriatr Oncol 2022 Mar 3. Epub 2022 Mar 3.

Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada; CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address:

Introduction: Frailty impacts outcomes for patients with lung cancer, but no brief tools have been assessed in patients with metastatic disease. We evaluated the impact of the Modified Frailty Index (mFI) on clinical outcomes for patients with metastatic non-small cell lung cancer (NSCLC).

Methods: We conducted a retrospective cohort study of all patients with Stage IV NSCLC diagnosed in Manitoba between 2011 and 2016 who then received first-line cytotoxic chemotherapy. We assigned mFI scores based on documented comorbidities and collected data on toxicity, progression, and survival. Descriptive statistics characterized the cohort and toxicity experienced. Kaplan-Meier methods were used to evaluate progression-free survival (PFS) and overall survival (OS), followed by multivariable Cox proportional hazards models.

Results: Our cohort of 426 (mFI 0/1-2/3+ = 175/196/55) patients, showed no significant association between higher mFI score and incidence of overall chemotherapy toxicity. Patients with mFI 0 experienced more frequent thromboses (p=0.022) and a trend towards less nausea or vomiting (p = 0.059). There was no significant difference in PFS or OS among frailty groups. Poorer performance status, number of metastatic sites, and the absence of a driver mutation were independently associated with poorer PFS and OS. Male sex and not completing chemotherapy were also associated with worse OS.

Conclusion: This study is the first to investigate the use of the mFI as a frailty tool in patients with metastatic NSCLC receiving cytotoxic chemotherapy. The mFI does not appear to be strongly associated with treatment-related toxicities, PFS, or OS in patients with metastatic NSCLC receiving first-line cytotoxic chemotherapy.
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http://dx.doi.org/10.1016/j.jgo.2022.02.015DOI Listing
March 2022

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia.

BMC Cancer 2022 Feb 6;22(1):148. Epub 2022 Feb 6.

Max Rady College of Medicine, 727 McDermot Ave, Winnipeg, MB, R3E 3P5, Canada.

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.
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http://dx.doi.org/10.1186/s12885-022-09256-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818183PMC
February 2022

Treatment Patterns, Toxicity, and Outcomes of Older Adults With Advanced Pancreatic Cancer Receiving First-line Palliative Chemotherapy.

Am J Clin Oncol 2022 02;45(2):55-60

Departments of Internal Medicine.

Objectives: Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC.

Methods: Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS.

Results: A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival.

Conclusions: FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.
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http://dx.doi.org/10.1097/COC.0000000000000882DOI Listing
February 2022

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma.

Curr Oncol 2021 11 8;28(6):4542-4551. Epub 2021 Nov 8.

CancerCare Manitoba Research Institute, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.

Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.
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http://dx.doi.org/10.3390/curroncol28060385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628656PMC
November 2021

Treatment and Prevention of Brain Metastases in Small Cell Lung Cancer.

Am J Clin Oncol 2021 12;44(12):629-638

Department of Internal Medicine, University of Manitoba.

Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. Development of CNS metastasis poses a particular treatment dilemma due to the accompanied cognitive changes, poor permeability of the blood-brain barrier to systemic therapy and relatively advanced state of disease. Survival of patients with untreated SCLC brain metastases is generally <3 months with whole brain radiotherapy used as first-line management in most SCLC patients. To prevent development of CNS metastasis prophylactic cranial irradiation (PCI) is recommended in limited stage disease, after response to chemotherapy and radiation, while PCI may be considered in extensive stage disease after favorable response to upfront treatment. Neurocognitive toxicity with whole brain radiotherapy and PCI is a concern and remains difficult to predict. The mechanism of toxicity is likely multifactorial, but a potential mechanism of injury to the hippocampus has led to hippocampal sparing radiation techniques. Treatment of established non-small cell lung cancer CNS metastases has increasingly focused on using stereotactic radiotherapy (SRS) and it is tempting to extrapolate these results to SCLC. In this review, we explore the evidence surrounding the prediction, prevention, detection, and treatment of CNS metastases in SCLC. We further review whether existing evidence supports extrapolating less toxic treatments to SCLC patients with CNS metastases and discuss trials that may shed more light on this question.
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http://dx.doi.org/10.1097/COC.0000000000000867DOI Listing
December 2021

A scoping review documenting cancer outcomes and inequities for adults living with intellectual and/or developmental disabilities.

Eur J Oncol Nurs 2021 Oct 2;54:102011. Epub 2021 Aug 2.

Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada; CancerCare Manitoba Research Institute, Winnipeg, Canada. Electronic address:

Introduction: Emerging evidence suggests adults with intellectual and/or developmental disabilities (IDD) may be at risk of inequities in cancer experiences and outcomes. Individuals with IDD may experience multiple barriers that could worsen outcomes and experience. These barriers may be connected to features of IDD or the healthcare system overall. Future research and program planning to support adults with IDD and cancer must be informed by evidence that acknowledges potential disparities, underlying determinants, and knowledge deficits.

Objective: We conducted a scoping review to systematically map the evidence describing and comparing cancer-related outcomes along the cancer continuum from risk to mortality for adults with IDD. We identified specific factors observed to influence those outcomes.

Methods: We followed the expanded Arksey & O'Malley framework for conducting the scoping review. We searched for literature in PubMed and Embase databases. We abstracted cancer-related data, IDD-related data, and data related to physical and social determinants of health.

Results: Of the 2796 studies retrieved, 38 were included for review. Most studies focused on screening outcomes and experiences. Studies reported that adults with IDD experienced inequities at various points along the cancer continuum. Numerous social and physical determinants of health influenced the experiences and outcomes of adults with IDD.

Conclusion: This scoping review identified significant gaps in the literature. Of note was the focus on cancer screening and lack of attention to larger systems of oppression that may influence poor cancer experiences and outcomes for adults with IDD. There is strong need to improve both quality and quantity of research in this area.
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http://dx.doi.org/10.1016/j.ejon.2021.102011DOI Listing
October 2021

Active Surveillance in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Clin Genitourin Cancer 2021 12 15;19(6):521-530. Epub 2021 May 15.

Division of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.

Background: Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC).

Patients And Methods: We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts.

Results: A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.47-0.70; P < .0001) and TTF (HR = 0.72; 95% CI, 0.60-0.85; P = .0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71).

Conclusions: Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.
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http://dx.doi.org/10.1016/j.clgc.2021.05.004DOI Listing
December 2021

Integration of geriatric assessment into clinical oncology practice: A scoping review.

Curr Probl Cancer 2021 06 12;45(3):100699. Epub 2021 Jan 12.

CancerCare Manitoba, Winnipeg, Manitoba, Canada; Section of Hematology/Oncology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada. Electronic address:

Sixty percent of newly diagnosed cancers occur in older adults and more complex planning is required to sustain quality care for older populations. Individualized care incorporating geriatric assessment can predict early mortality and treatment toxicity for older cancer patients. We mapped and summarized the available evidence on the integration of geriatric assessment into clinical oncology practice, and ascertained which domains have been implemented. We systematically searched bibliographic databases and trial registries for reports of clinical studies, clinical practice guidelines, systematic and non-systematic reviews, and grey literature published in English. We gathered data on study characteristics, geriatric domains and strategies evaluated, and relevant study objectives and findings. From a total of 10,124 identified citations, 38 articles met our eligibility criteria, 3 of which were clinical practice guidelines. Nearly half of these articles came from the United States. Domains of the geriatric assessment implemented in studies ranged from 1 to 12, with varied combinations. We identified 27 studies on strategies for implementing geriatric assessment and 24 studies on feasibility of implementing geriatric assessment, into clinical oncology practice. We also identified 3 main geriatric assessment models: 2 from the United States and 1 from Australia. Furthermore, we identified 2 reviews that reported varied components of geriatric assessment models. There is increasingly robust evidence to implement formal geriatric assessment in oncology practice. There remains a great deal of variation in the tools recommended to address each of the domains in a geriatric assessment, with only 1 guideline (American Society of Clinical Oncology guideline) settling on a specific best practice. Protocol registration: Open Science Framework osf.io/mec93.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100699DOI Listing
June 2021

Immunotherapy Benefit in a Patient With Non-Small Cell Lung Cancer and a Rare BRAF Mutation.

Cureus 2020 Oct 28;12(10):e11224. Epub 2020 Oct 28.

Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, CAN.

Immunotherapy is less effective in non-small cell lung cancer (NSCLC) with driver mutations in epidermal growth factor receptor or anaplastic lymphoma kinase and some may extrapolate this trend to other driver mutations. Up to 4% of NSCLC cases contain a mutation. Most mutations are V600E, and little is known about the impact of treatment in rare G469A mutations. We present a case of a patient found to have G469A mutated NSCLC. She was diagnosed with Stage IIIB NSCLC and treated with concurrent chemotherapy and radiation. Post-treatment imaging demonstrated disease progression and she was started on nivolumab, resulting in a dramatic and prolonged response which is ongoing after 76 cycles. Her substantial response and prolonged benefit suggest that -mutated NSCLC may respond better than - or -driven disease to immunotherapy. Due to the rarity of specific mutations, this case adds to the limited current published literature on NSCLC harbouring a G469A mutation and suggests that immunotherapy is a reasonable treatment option.
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http://dx.doi.org/10.7759/cureus.11224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704186PMC
October 2020

Population-based Assessment of Intermittent Androgen Deprivation Therapy Utilization for Relapsed, Nonmetastatic, Hormone-sensitive Adenocarcinoma of the Prostate.

Am J Clin Oncol 2020 12;43(12):865-871

Section of Radiation Oncology.

Objectives: Androgen deprivation therapy (ADT) is the standard of care for men with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) after treatment failure. Although intermittent ADT (iADT) is noninferior to continuous ADT for prostate cancer outcomes, with superior quality of life and cost-to-benefit ratio, little is known regarding its real-world utilization. The authors aimed to determine the utilization of iADT in a Canadian Provincial Cancer Program for relapsed nmHSPC and identified risk factors associated with the nonreceipt of iADT.

Materials And Methods: This retrospective population-based cohort study used linked administrative databases to identify all patients with relapsed nmHSPC from 2012 to 2016 and quantified ADT prescription history. Patients were defined as iADT eligible if prostate-specific antigen (PSA) was <4 ng/mL and trending downwards on ≥2 sequential PSAs after ≥6 months of ADT. Univariable and multivariable logistic regression analyses were performed to determine factors associated with nonreceipt of iADT.

Results: A total of 601 men with relapsed, nmHSPC were included with a median age at relapse of 73 (range, 46 to 96), pre-ADT PSA of 12.2 ng/mL, and a median pre-ADT PSA doubling time of 7.8 months. 80.9% of the cohort were eligible to receive iADT and 74.4% were treated with iADT. On multivariable analysis, patients originally treated with surgery (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.08-0.46) or having a Gleason Score ≥8 (OR, 0.30; 95% CI, 0.12-0.78) had decreased odds of receipt of iADT. Patients with longer PSA doubling times were more likely to receive iADT (OR, 2.71; 95% CI, 1.17-6.31).

Conclusions: The utilization of iADT was relatively common for men in Manitoba during the study period, however, the uptake of iADT can be improved among identified subgroups.
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http://dx.doi.org/10.1097/COC.0000000000000763DOI Listing
December 2020

Utility of the modified frailty index in predicting toxicity and cancer outcomes for older adults with advanced pancreatic cancer receiving first-line palliative chemotherapy.

J Geriatr Oncol 2021 01 11;12(1):112-117. Epub 2020 Aug 11.

Department of Internal Medicine, University of Manitoba, 820 Sherbrook St, R3A 1R9 Winnipeg, MB, Canada; CancerCare Manitoba, Department of Hematology and Medical Oncology, 675 McDermot Ave, R3E 0V9 Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, 675 McDermot Ave, R3E 0V9 Winnipeg, MB, Canada. Electronic address:

Background: Pancreatic cancer primarily affects older adults and is associated with a high morbidity and mortality. Identifying frail patients with advanced pancreatic cancer (APC) helps to mitigate the risks of chemotherapy (CT). The modified Frailty Index (mFI) is an 11-point deficit measure used to identify frail patients. Although validated in surgical fields, it has not been assessed in an APC population.

Methods: A retrospective cohort study evaluated consecutive patients, aged ≥65 years, diagnosed with APC from 2011 to 2016 and treated with first line palliative-intent CT. mFI was categorized as: 0, 1, 2 and ≥ 3. Descriptive analysis was completed comparing patient characteristics, CT toxicity, response to treatment, and overall survival (OS) by mFI score.

Results: 87 patients with APC received palliative CT. Median age was 71 (65-88), 54% male. A mFI score of 0, 1, 2, and ≥ 3 occurred for 20 (23%), 28 (32.2%), 25 (28.7%) and 14 (16.1%) patients respectively. Patients with mFI scores of 0-1 were more likely to receive: 5-fluorouracil, irinotecan and oxaliplatin. CT toxicity, emergency room (ED) and urgent cancer clinic (UCC) presentation, and hospitalization length did not differ by mFI. Longer OS was associated with better ECOG and receipt of combination CT.

Conclusion: This is the first assessment of the mFI in an APC population receiving CT. The mFI score did not correlate with toxicity, ED/UCC visits, hospitalization length or OS. Ongoing assessment of tools that accurately identify frailty in patients with APC is critical to help better select candidates for aggressive CT.
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http://dx.doi.org/10.1016/j.jgo.2020.07.004DOI Listing
January 2021

Effect of Hospitalization During First Chemotherapy and Performance Status on Small-cell Lung Cancer Outcomes.

Clin Lung Cancer 2020 09 26;21(5):e388-e404. Epub 2020 Feb 26.

Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada; Department of Hematology and Medical Oncology, CancerCare Manitoba, Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada. Electronic address:

Introduction: Small-cell lung cancer (SCLC) is highly responsive to chemotherapy (CT) and one of the few malignancies treated in hospitalized patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS). Because of the little current information available on the outcomes experienced by hospitalized patients with SCLC receiving CT, we explored the outcomes for these patients to improve the evidence base for practice.

Materials And Methods: We conducted a retrospective cohort study to evaluate patients with a diagnosis of SCLC and treated with CT during a 10-year period. Progression-free survival (PFS) and overall survival (OS) were evaluated according to site of first CT (inpatient vs. outpatient) and PS. Multivariable analysis was completed to assess for independent survival predictors.

Results: A total of 530 patients with SCLC were treated, with 82 (15%) receiving their first CT in hospital. Inpatients had a greater burden of disease and poorer PS. Neutropenia, thrombocytopenia, nephrotoxicity, and fatigue were all experienced less often by the inpatient cohort (P < .001, P < .001, P < .001, and P = .007, respectively). For inpatients and outpatients, the OS rate at 12, 24, and 60 months was 22%, 9%, and 7% and 43%, 20%, and 9%, respectively (P < .001 for all). The median PFS and OS were longer for outpatients and highly functional patients. On multivariable analysis, ECOG PS was an independent predictor of the outcome and the site of first CT was not (P = .04 and P = .49, respectively).

Conclusion: Patients with SCLC initially treated as inpatients and those with poor functional status had shorter PFS and OS; however, some experienced long-term survival, including 5-year survival of 7% for the inpatient cohort and 5% for the ECOG PS 3-4 cohort. CT toxicities were less common in the inpatient cohort, validating that administration of CT in hospital should be considered for these patients because they could experience a meaningful long-term response to therapy.
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http://dx.doi.org/10.1016/j.cllc.2020.02.013DOI Listing
September 2020

Mitochondrial Respiration Correlates with Prognostic Markers in Chronic Lymphocytic Leukemia and Is Normalized by Ibrutinib Treatment.

Cancers (Basel) 2020 Mar 11;12(3). Epub 2020 Mar 11.

Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB R3V 0V9, Canada.

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70), cluster of differentiation 38 (CD38), and elevated β2-microglobulin (β2-M) predicted increased maximal respiration rates. ZAP-70 CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70 CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70 predicted increased maximal respiration. ZAP-70 is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton's tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells.
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http://dx.doi.org/10.3390/cancers12030650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139649PMC
March 2020

Nivolumab-Induced Secondary Sclerosing Cholangitis with Deterioration Despite Immunosuppression.

J Thorac Oncol 2019 09;14(9):e205-e206

Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.04.023DOI Listing
September 2019

Assessing the learning needs of the multidisciplinary team on geriatric oncology and frailty.

J Geriatr Oncol 2019 09 26;10(5):829-831. Epub 2018 Dec 26.

Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada; Cancer Care Manitoba, Department of Hematology and Medical Oncology, Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, Winnipeg, MB, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jgo.2018.12.002DOI Listing
September 2019

The effect of age on referral to an oncologist and receipt of chemotherapy among small cell lung cancer patients in Ontario, Canada.

J Geriatr Oncol 2019 05 11;10(3):449-458. Epub 2018 Oct 11.

Department of Oncology, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Division of Medical Oncology, Juravinski Cancer Centre, 699 Concession St, Hamilton, ON, Canada, L8V 5C2. Electronic address:

Objectives: Small cell lung cancer (SCLC) represents a significant health burden. There is a lack of information about patterns of referral and treatment for older patients over 70 years of age, in comparison to younger patients with SCLC.

Materials And Methods: A population-based retrospective cohort study was undertaken for patients identified from the Ontario Cancer Registry, Canada. All cases of SCLC diagnosed between January 2000 and December 2010 were eligible. Data were extracted on demographic variables, treatment and outcome. Logistic regression analyses were performed as appropriate.

Results: There were 9021 cases of SCLC, with 10% of cases ≥80 years and 32.8% of cases aged 70-79 years and 53% male. Older patients were less likely to be referred to a medical oncologist (OR 0.28 ≥ 80 years, OR 0.60 70-79 years) and less likely to receive chemotherapy (OR 0.19 ≥ 80 years, OR 0.52 70-79 years) compared to younger patients (age < 70). Age, higher comorbidity and prior receipt of home care services were all prognostic of a lower likelihood of referral to a medical oncologist and receipt of chemotherapy. Local health region was also prognostic for referral to and receipt of chemotherapy, indicative of significant regional variation in practice.

Conclusions: Older patients with SCLC are less likely to be referred for treatment and less likely to receive treatment than younger patients. These data represent a potential gap in knowledge translation.
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http://dx.doi.org/10.1016/j.jgo.2018.10.001DOI Listing
May 2019

Benefit of crizotinib in a lung cancer patient with discordant ALK testing results.

Cancer Treat Res Commun 2018 21;15:13-16. Epub 2018 Feb 21.

Rady Faculty of Health Sciences, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada; Cancer Care Manitoba, Department of Hematology and Medical Oncology, Winnipeg, MB, Canada. Electronic address:

Crizotinib is a first line treatment for patients with non-small cell lung cancer (NSCLC) harboring translocations in anaplastic lymphoma kinase (ALK). The current gold standard for determining ALK status is fluorescence in-situ hybridisation (FISH), but immunohistochemistry (IHC) is becoming increasingly popular due to lower cost. There are currently few reports on clinical outcomes with crizotinib therapy in patients who have tested negative by FISH and positive by IHC. A 53 year old lifelong non-smoking, physically active male with newly diagnosed Stage IV NSCLC presented with shortness of breath on exertion one month prior to referral. Staging CT scan failed to show a discreet lung lesion, but the left lower lobe was collapsed due to pleural effusion. Pleural fluid showed adenocarcinoma and IHC was positive for an ALK mutation, while FISH was negative. Pre-treatment PET-CT showed hypermetabolic, enlarged lymph nodes in the mediastinum and retroperitoneum. Partially due to patient concerns about cytotoxic chemotherapy toxicity, crizotinib therapy was instituted. Repeat CT conducted two months after crizotinib initiation showed a decrease in lymphadenopathy at all sites compared to the PET-CT. Furthermore, the patient showed clinical improvement, with less drainage through his PleurX catheter and stability of his excellent performance status. After 12 months on crizotinib CT showed ongoing improvement in lymphadenopathy. His bloodwork has been stable, and he denies significant drug toxicity. This case illustrates a sustained response to crizotinib therapy in a patient with an ALK translocation identified by IHC, but with negative FISH testing. The literature suggests that the population with these discordant results could be up to 19% of ALK positive NSCLC. Patients in this subgroup who are receiving crizotinib should be identified and outcome data pooled. However, in the interim, oncologists may wish to consider targeted therapy for these discordant patients.
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http://dx.doi.org/10.1016/j.ctarc.2018.02.002DOI Listing
June 2019

The use of chemotherapy in older patients with stage II and III colon cancer: Variation by age and era of diagnosis.

J Geriatr Oncol 2019 01 10;10(1):132-137. Epub 2018 Aug 10.

Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada. Electronic address:

Objective: We aim to examine the use and outcomes of adjuvant chemotherapy in older patients with stage II and III colon cancer.

Material And Methods: Using data from the SEER-Medicare database, we analyzed patients aged 66 or greater, diagnosed with stage II or III colon cancer between 1991 and 2007 who received surgery. Using Medicare claims, receipt of adjuvant chemotherapy was identified, and compared between age bands. Logistic regression modeling was performed to assess predictors of receipt of adjuvant chemotherapy, and Cox proportional hazards modeling was performed to assess predictors of mortality.

Results: A total of 31,990 patients were identified: 4371 aged 66-69, 6922 (70-74), 7673 (75-79), 6807 (80-84), 4266 (85-89), and 1951 (90+). The percent starting adjuvant chemotherapy decreased by age cohort: 57% in the 66-69 age cohort, 48% (70-74), 37% (75-79), 20% (80-84), 8% (85-89), and 1% (90+). Multivariable analysis showed that stage III disease was the strongest positive predictor of chemotherapy receipt. Multivariable analysis for mortality risk showed that adjuvant chemotherapy was associated with an increased risk of mortality in stage II patients. Adjuvant chemotherapy was associated with a decreased risk of mortality in stage III patients, consistent across all age cohorts, with the exception of the 90+ cohort, in whom adjuvant chemotherapy appeared to increase mortality.

Conclusion: Administration of adjuvant chemotherapy for stage II/III colon cancer decreases with advancing age, but improved outcomes are seen in stage III patients under 90 years of age.
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http://dx.doi.org/10.1016/j.jgo.2018.07.012DOI Listing
January 2019

Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer.

Horm Cancer 2018 08 18;9(4):288-294. Epub 2018 Jun 18.

Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30-3.70; HR 1.92, 95% CI 1.07-3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31-4.36 for AR- Ki67+ vs HR 1.54, 95% CI 0.44-5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.
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http://dx.doi.org/10.1007/s12672-018-0336-7DOI Listing
August 2018

The effect of statin use on the incidence of prostate cancer: A population-based nested case-control study.

Int J Cancer 2018 07 16;143(1):190-198. Epub 2018 Feb 16.

Faculty of Health Sciences, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

Preclinical studies suggest statins may help prevent prostate cancer (PC), but epidemiologic results are mixed. Many epidemiological studies have relatively short prediagnosis drug exposure data, which may miss some statin use. We completed a nested case-control study investigating the impact of statin use on PC diagnosis and clinically significant PC using data from men aged ≥40 years in the Canadian province of Saskatchewan between 1990 and 2010. Drug exposure histories were derived from a population-based prescription drug database. We used conditional logistic regression to model use of statins as a class and stratified analyses for groups defined by lipophilicity. Clinically significant PC was defined as Gleason score 8-10 OR stage C or D or III or IV at diagnosis. 12,745 cases of PC were risk-set matched on age and geographic location to 50,979 controls. Greater than 90% of subjects had prediagnosis drug exposure histories >15 years. 2,064 (16.2%) cases and 7,956 (15.6%) controls were dispensed one or more statin prescriptions. In multivariable models, ever prescription of statins was not associated with PC diagnosis (OR 0.97; 95% CI 0.90-1.05). Neither lipophilic statins (OR 0.96, 95% CI 0.88-1.04) nor hydrophilic statins (OR 1.06, 95% CI 0.95-1.20) impacted PC diagnosis. There was no effect of the dose or duration of statin use. Diagnosis of clinically significant PC decreased with statin use (OR 0.84, 95% CI 0.73-0.97). Statin use is not associated with overall PC risk, regardless of duration or dose of statin exposure. Statin use is associated with a decreased risk of clinically significant PC.
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http://dx.doi.org/10.1002/ijc.31295DOI Listing
July 2018

Biologic and epidemiologic evidence assessing if statins prevent prostate cancer.

Can J Urol 2017 Dec;24(6):9081-9088

Department of Hematology and Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.

Introduction: During their lives, 1 in 8 men will be diagnosed with prostate cancer. Several drugs have been shown to decrease prostate cancer risk, but have not been widely used in prostate cancer prevention because of concerns about side-effects and cost-effectiveness. Statins are indicated for prevention of cardiovascular disease, have an excellent benefit to risk profile, and some studies suggest that statins may reduce the risk of prostate cancer.

Materials And Methods: We performed a systematic search of Medline (Ovid), EMBASE (Ovid), and PubMed. This search informed a narrative review of the biological rationale for why statins may reduce prostate cancer risk and an evaluation of the existing epidemiological evidence to determine whether further studies are needed to assess the true impact of statins on prostate cancer risk.

Results: Statins may help prevent the development of prostate cancer through inhibition of sustained proliferative signals (androgen and Ras/Rho), sensitizing potentially malignant cells to programmed cell death, minimizing inflammation, reducing angiogenesis, and impeding invasiveness by blocking adhesion molecules. The epidemiologic literature examining the effect of statin use on overall prostate cancer diagnosis is highly heterogeneous, with relative risks of 0.26 to 2.94. Out of 33 published studies, 5 show an increased risk of prostate cancer with statin use, 10 demonstrate a decreased risk, and 18 suggest no effect.

Conclusion: There is a compelling pre-clinical rationale for statins as potential chemopreventive agents. However, large, population-based studies with long pre-diagnosis drug exposure data are needed to investigate the impact of statin exposure on prostate cancer incidence.
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December 2017

Geographical Variation and Factors Associated with Non-Small Cell Lung Cancer in Manitoba.

Can Respir J 2017 21;2017:7915905. Epub 2017 Jun 21.

Department of Community Health Sciences, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Background: Screening decreases non-small cell lung cancer (NSCLC) deaths and is recommended by the Canadian Task Force on Preventive Health Care. We investigated risk factor prevalence and NSCLC incidence at a small region level to inform resource allocation for lung cancer screening.

Methods: NSCLC diagnoses were obtained from the Canadian Cancer Registry, then geocoded to 283 small geographic areas (SGAs) in Manitoba. Sociodemographic characteristics of SGAs were obtained from the 2006 Canadian Census and Canadian Community Health Survey. Geographical variation was modelled using a Bayesian spatial Poisson model.

Results: NSCLC incidence in SGAs ranged from 1 to 343 cases per 100,000 population per year. The highest incidence rates were in the Southeastern, Southwestern, and Central regions of Manitoba, while most of Northern Manitoba had lower rates. Poisson regression suggested areas with higher proportions of Aboriginal people and higher average income, and immigrants had lower NSCLC incidence whereas areas with higher proportions of smokers had higher incidence.

Conclusion: On an SGA level, smoking rates remain the most significant factor driving NSCLC incidence. Socioeconomic status and proportions of immigrants or Aboriginal peoples independently impact NSCLC rates. We have identified SGAs in Manitoba to target in policy and infrastructure planning for lung cancer screening.
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http://dx.doi.org/10.1155/2017/7915905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499243PMC
May 2018

Immune Signatures of Non-Small Cell Lung Cancer.

J Thorac Oncol 2017 06;12(6):913-915

Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada and Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2017.04.008DOI Listing
June 2017

Assessment of Referral and Chemotherapy Treatment Patterns for Elderly Patients With Non-small-Cell Lung Cancer.

Clin Lung Cancer 2016 11 8;17(6):563-572.e2. Epub 2016 Jun 8.

Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

Background: Physiologic changes of aging in combination with greater comorbidity could lead to treatment nihilism for elderly patients (≥ 70 years old) with non-small-cell lung cancer (NSCLC). Randomized trials have shown improved survival with chemotherapy since 1999, but it remains unclear whether these data have translated into practice.

Patients And Methods: We conducted a retrospective, population-based cohort study of NSCLC cases diagnosed in Ontario, Canada from 2000 to 2010. We compared referral and treatment patterns among patients aged < 70 versus ≥ 70 years. Multivariable analyses evaluated predictors of referral to medical oncology or treatment with chemotherapy.

Results: Of 61,646 patients with NSCLC, 32,131 (52.1%) were ≥ 70 years. Fewer adenocarcinomas were diagnosed in the elderly (29.8% vs. 44%), and more elderly patients lacked microscopic confirmation of malignancy (20.1% vs. 6.2%). Charlson co-morbidity scores ≥ 2 (14.0% vs. 7.4%) were higher in the elderly. Only 59.5% of elderly patients with NSCLC were referred to a medical oncologist, versus 78.5% of younger patients. Elderly patients were less likely to receive chemotherapy (18.3% vs. 46.7%), even among those referred to a medical oncologist (30.1% vs. 58.6%). Neither referral nor treatment changed substantially over time. The elderly also had a shorter median survival (5.8 vs. 9.6 months); however, there was less difference in median survival (13.6 vs. 14.9 months) among patients receiving chemotherapy.

Conclusion: Elderly patients are less likely to be considered for systemic therapy for NSCLC, and evidence of benefit has had minimal impact on practice. We believe this disparity could be improved through systematically using tools to comprehensively assess elderly patients.
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http://dx.doi.org/10.1016/j.cllc.2016.05.012DOI Listing
November 2016

Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis.

Lung Cancer 2016 09 18;99:180-5. Epub 2016 Jul 18.

University of Manitoba, Department of Community Health Sciences, Winnipeg, Manitoba, Canada; University of Manitoba/Winnipeg Regional Health Authority, The George and Fay Yee Centre for Healthcare Innovation, Winnipeg, Manitoba, Canada.

In stage III non-small cell lung cancer (NSCLC), the standard of care in young patients is chemoradiotherapy, but this standard is not as clearly established for older patients. We aimed to determine the efficacy and harm associated with chemoradiotherapy versus radiotherapy alone in elderly (≥70 years), stage III NSCLC patients through a systematic review. We conducted a systematic search of MEDLINE, EMBASE, CENTRAL, Scopus, Web of Science and conference proceedings. Two reviewers independently identified randomized trials (RCT) and extracted trial-level data. Risk of bias was assessed and meta-analysis was conducted looking at survival and safety outcomes. We included three trials and subgroup data from one systematic review. The three RCTs had high risk of bias due primarily to lack of blinding and the systematic review scored 4/11 using the AMSTAR tool. Overall survival (HR 0.66, 95% CI 0.53-0.82; I2 0%; 3 trials; 407 patients) and progression-free survival (HR 0.67, 95% CI 0.53-0.85; I2 0%; 2 trials; 327 patients) both favored chemoradiotherapy. Risk of treatment-related death and grade 3+ pneumonitis were not significantly different between groups. In conclusion, treatment of stage III NSCLC patients 70 years or older with chemotherapy and radiotherapy is associated with improved overall survival compared to radiotherapy alone. With the exception of increased hematological toxicity, CRT appears to be tolerable in fit elderly patients and represents a reasonable standard of clinical care.
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http://dx.doi.org/10.1016/j.lungcan.2016.07.016DOI Listing
September 2016

The treatment of metastatic non-small cell lung cancer in the elderly: an evidence-based approach.

Front Oncol 2014 10;4:178. Epub 2014 Jul 10.

Department of Oncology, McMaster University , Hamilton, ON , Canada.

An increasing proportion of patients with advanced non-small cell lung cancer (NSCLC) are over 70 years old, raising unique challenges for treatment decision-making. While these patients are underrepresented in clinical trials, there is an emerging body of evidence associated with this group. The lesson of comprehensive geriatric assessment is that chronological age does not always correlate with physiological age and a variety of important co-morbidities and geriatric syndromes can go undetected in a typical history and physical. These co-morbidities and expected physiologic changes due to aging complicate decision-making around appropriate treatment. This review discusses geriatric assessment in elderly cancer patients and evaluates the current evidence for chemotherapy and targeted therapy for patients with advanced NSCLC aged ≥70 years.
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http://dx.doi.org/10.3389/fonc.2014.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091126PMC
July 2014

Brain metastases in non-small-cell lung cancer.

Clin Lung Cancer 2014 Jul 13;15(4):249-57. Epub 2014 May 13.

Department of Oncology, McMaster University, Hamilton, Ontario, Canada.

Up to 50% of patients with advanced non-small-cell lung cancer will develop brain metastases at some point during their illness. These metastases cause a substantial burden in morbidity and mortality, which has motivated research and technological innovation over the past 2 decades. Surgery, radiotherapy, and systemic therapies have each played a role in management, with the greatest changes associated with the popularization of stereotactic radiosurgery. In this review, the evidence behind each modality used in the management of brain metastases for non-small-cell lung cancer patients is examined, and recommendations regarding the current standards of care and areas of future research focus are provided.
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http://dx.doi.org/10.1016/j.cllc.2014.04.008DOI Listing
July 2014

Challenges in Implementing Personalized Medicine for Lung Cancer within a National Healthcare System.

J Pers Med 2012 Sep 10;2(3):77-92. Epub 2012 Sep 10.

Department of Medical Oncology, McMaster University, Hamilton, ON, L8S 4L8, Canada.

The traditional approach to the treatment of advanced non-small cell lung cancer (NSCLC) relied on the uniform use of cytotoxic chemotherapy. Over the last eight years, this paradigm of care has been shifting towards the use of molecularly targeted agents. Epidermal growth factor receptor (EGFR) mutations have emerged as an important biomarker for these targeted agents and multiple studies have shown that tyrosine kinase inhibitors (TKI) that inhibit EGFR are superior to traditional chemotherapy in patients possessing an EGFR mutation. Nationally funded health care systems face a number of challenges in implementing these targeted therapies, most related to the need to test for biomarkers that predict likelihood of benefiting from the drug. These obstacles include the challenge of getting a large enough tissue sample, workload of involved specialists, reliability of subtyping in NSCLC, differences in biomarker tests, and the disconnect between the funding of drugs and the related biomarker test. In order to improve patient outcomes, in a national healthcare system, there is a need for governments to accept the changing paradigm, invest in technology and build capacity for molecular testing to facilitate the implementation of improved patient care.
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http://dx.doi.org/10.3390/jpm2030077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251366PMC
September 2012

Is there a role for statins in atrial fibrillation?

Pacing Clin Electrophysiol 2009 Aug;32(8):1063-72

Department of Internal Medicine, St. Boniface General Hospital, University of Manitoba, Winnipeg, Canada.

3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are some of the most commonly prescribed drugs in the world. While lipid modification remains the primary function of statins, there has been increasing interest in its potential pleiotropic effects, particularly as an anti-inflammatory agent in its role as an antiarrhythmic. Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and carries with it a significant burden in both morbidity and mortality. Treatment for AF currently involves either rate or rhythm control where both have demonstrable associated risks. Rate control necessitates anticoagulation, which can cause life-threatening bleeding, while rhythm control has a poor side-effect profile that may lead to greater mortality and may not completely eliminate the need for anticoagulation. Considering this pressing need for novel therapeutic interventions in AF, this long overdue systematic review explores the potential role of statins in the treatment and prevention of AF. Physicians, especially cardiologists, need to be aware of the host of currently available literature and, more importantly, need to be stimulated to generate discussion and formulate studies that will help debate the issues under the most erudite standards.
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http://dx.doi.org/10.1111/j.1540-8159.2009.02440.xDOI Listing
August 2009

Mainstream cigarette smoke exposure attenuates airway immune inflammatory responses to surrogate and common environmental allergens in mice, despite evidence of increased systemic sensitization.

J Immunol 2005 Sep;175(5):2834-42

Department of Pathology, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.

The purpose of this study was to investigate the impact of mainstream cigarette smoke exposure (MTS) on allergic sensitization and the development of allergic inflammatory processes. Using two different experimental murine models of allergic airways inflammation, we present evidence that MTS increased cytokine production by splenocytes in response to OVA and ragweed challenge. Paradoxically, MTS exposure resulted in an overall attenuation of the immune inflammatory response, including a dramatic reduction in the number of eosinophils and activated (CD69+) and Th2-associated (T1ST2+) CD4 T lymphocytes in the lung. Although MTS did not impact circulating levels of OVA-specific IgE and IgG1, we observed a striking reduction in OVA-specific IgG2a production and significantly diminished airway hyperresponsiveness. MTS, therefore, plays a disparate role in the development of allergic responses, inducing a heightened state of allergen-specific sensitization, but dampening local immune inflammatory processes in the lung.
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http://dx.doi.org/10.4049/jimmunol.175.5.2834DOI Listing
September 2005
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