Michael Fralick

Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design.

BACKGROUND Clinical experience suggests that many women with triple-negative metastatic breast cancer (MBC) relapse quickly. This has implications for clinical practice and trial design. We evaluated the duration of first-, second-, and third-line chemotherapy as a surrogate for duration of treatment response. PATIENTS AND METHODS We performed a retrospective multicenter chart review of patients with triple-negative MBC receiving palliative chemotherapy. Primary outcome was duration of palliative chemotherapy, and secondary outcome was to identify prognostic variables. RESULTS A total of 111 patients were analyzed. Median age at diagnosis was 51 years (range, 26-82 years). Fourteen percent of patients presented with MBC. Twenty-seven percent received neoadjuvant chemotherapy, and 48% received adjuvant chemotherapy. Median distant disease-free interval (DDFI) was 18 months (range, 0-172 months). At presentation of MBC, 68% had visceral and 71% had multiple sites of disease. Median survival with MBC was 13.3 months (range, 0.8-99.8 months). Median duration of first-line palliative therapy was 11.9 weeks (range, 0-73.1 weeks). Eighty-seven patients (78%) went on to receive second-line therapy with a median duration of 9 weeks (range, 0-120.9 weeks), and 55 (49%) received third-line therapy with a median duration of 4 weeks (range, 0-59 weeks). Multivariate analysis revealed that age < 50 years, ALP > 120 U/L, history of previous chemotherapy, DDFI < 12 months, and visceral presentation were all independently associated with a poor prognosis. CONCLUSION Despite the poorer overall prognosis of patients with triple-negative disease, there remains considerable heterogeneity in individual outcomes. Many women with recurrent triple-negative disease will progress quickly on first-, second-, and third-line palliative treatment. Future clinical trials in this population must take into account their shorter time to progression when determining optimal trial design.

Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor

A study that assessed the risk of diabetic ketoacidosis after the initiation of SGLT2 inhibitor therapy showed nearly twice the risk as with a DPP4 inhibitor.

Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study

Objective To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. Design Population based nested case-control study. Setting Ontario, Canada, from 1 April 1994 to 1 January 2012. Participants Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Main outcome measure Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index. Results Of 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin. Conclusions In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.

Risk of suicide after a concussion

Background: Head injuries have been associated with subsequent suicide among military personnel, but outcomes after a concussion in the community are uncertain. We assessed the long-term risk of suicide after concussions occurring on weekends or weekdays in the community. Methods: We performed a longitudinal cohort analysis of adults with diagnosis of a concussion in Ontario, Canada, from Apr. 1, 1992, to Mar. 31, 2012 (a 20-yr period), excluding severe cases that resulted in hospital admission. The primary outcome was the long-term risk of suicide after a weekend or weekday concussion. Results: We identified 235 110 patients with a concussion. Their mean age was 41 years, 52% were men, and most (86%) lived in an urban location. A total of 667 subsequent suicides occurred over a median follow-up of 9.3 years, equivalent to 31 deaths per 100 000 patients annually or 3 times the population norm. Weekend concussions were associated with a one-third further increased risk of suicide compared with weekday concussions (relative risk 1.36, 95% confidence interval 1.14–1.64). The increased risk applied regardless of patients’ demographic characteristics, was independent of past psychiatric conditions, became accentuated with time and exceeded the risk among military personnel. Half of these patients had visited a physician in the last week of life. Interpretation: Adults with a diagnosis of concussion had an increased long-term risk of suicide, particularly after concussions on weekends. Greater attention to the long-term care of patients after a concussion in the community might save lives because deaths from suicide can be prevented.

In search of evidence-based treatment for concussion: characteristics of current clinical trials

Abstract Objective: To assess the characteristics of current clinical trials investigating the treatment of concussion. Background: Recent systematic literature reviews have concluded that there is minimal evidence to support any specific treatment for concussion, including the principles of return-to-activity protocols such as type or duration of rest. Design/methods: Clinical trial data was extracted from Clinicaltrials.gov and seven additional World Health Organization primary registries. The trial databases were accessed up until 3 October 2013. This study used search terms of ‘concussion’ or ‘mild traumatic brain injury’ (mTBI) and filtered for interventional trials. Trials that were terminated, already published or not interventional trials of concussion/mTBI were excluded. Results: Of the 142 concussion/mTBI interventional clinical trials identified, 71 met inclusion criteria. Trials had a median estimated enrolment of 60 participants. There was a wide-range of treatments studied, including cognitive/behavioural therapies (28.2%), medications (28.2%), devices (11.3%), dietary supplements (8.5%), return-to-activity/rest (1.4%) and others (22.4%). Heterogeneity among trials for concussion identification/diagnosis and primary outcomes utilized was evident. Symptom-based questionnaires (39.4%) and neuropsychological tests (28.2%) were the most common outcome measures. Conclusions: Diverse, potentially promising therapeutics are currently being studied for the treatment of concussion. However, several deficiencies were identified including a paucity of trials addressing return-to-activity principles. Also, small sample size and trial heterogeneity may threaten scientific evaluation and subsequent clinical application.

External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

BackgroundSetting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer.MethodsA comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario.ResultsDuring the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14–46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56).ConclusionPriority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting.

FDA Approval of Desmopressin for Nocturia

On March 3, 2017, the US Food and Drug Administration (FDA) approved desmopressin nasal spray (Noctiva) for the “treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void.”1 According to the product manufacturer, Serenity Pharmaceuticals, nocturia is a common condition affecting “over 89 million adults in the U.S.”

Drowning and the influence of hot weather

Background Drowning deaths are devastating and preventable. Public perception does not regard hot weather as a common scenario for drowning deaths. The objective of our study was to test the association between hot weather and drowning risk. Materials and Methods We conducted a retrospective case-crossover analysis of all unintentional drowning deaths in Ontario, Canada from 1999 to 2009. Demographic data were obtained from the Office of the Chief Coroner. Weather data were obtained from Environment Canada. We used the pair-matched analytic approach for the case-crossover design to contrast the weather on the date of the drowning with the weather at the same location one week prior (control period). Results We identified 1243 drowning deaths. The mean age was 40 years, 82% were male, and most events (71%) occurred in open water. The pair-matched analytic approach indicated that temperatures exceeding 30°C were associated with a 69% increase in the risk of outdoor drowning (OR = 1.69, 95% CI 1.23–2.25, p = 0.001). For indoor drowning, however, temperatures exceeding 30°C were not associated with a statistically significant increase in the risk of drowning (OR = 1.50, 95% CI 0.53–4.21, p = 0.442). Adult men were specifically prone to drown in hot weather (OR 1.67, 95% CI 1.19–2.34, p = 0.003) yet an apparent increase in risk extended to both genders and all age groups. Conclusion Contrary to popular belief, hot weather rather than cold stormy weather increases the risk of drowning. An awareness of this risk might encourage greater use of drowning prevention strategies known to save lives.

Bleeding associated with coadministration of rivaroxaban and clarithromycin

A 65-year-old man presented to hospital with hemoptysis, epistaxis, headache and syncope. His medical history included antiphospholipid antibody syndrome with recurrent deep vein thrombosis, most recently 10 years earlier. He also had mixed restrictive–obstructive lung disease, myasthenia gravis,

Physician burnout: Who will protect us from ourselves?

See related analysis on page [761][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.131053][2], and infographic, [www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140588/-/DC2][3] When the workday ends at Volkswagen, so does an employee’s access to company email. Atos, an information technology company