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Purpose: To describe patient characteristics, treatment patterns, and the burden of illness among adult migraine patients in Canada prescribed migraine prophylactics. Little is known about the relative persistence of treatments in the real-world setting and the impact of migraine prophylactic therapy on patients. As a result, migraine care in Canada continues to inadequately serve patients suffering from frequent headache days, reflecting a large unmet need. Methods: This retrospective study used Reformulary Group’s longitudinal prescription claims database. Private payer data were analyzed to identify 2007 migraine prophylactic naïve patients, with a prior history of acute therapy, for tracking over 24 months to determine treatment patterns and costs. Patient flow is summarized in a Sankey diagram visualizing persistence and switching across different timepoints. Results: Patient persistence to migraine prophylactic medications was low at 24.9% (n=500); Switching from index medications to another prophylactic medication was common (27%), however 50% of patients discontinued without switching. It was observed that acute treatment and opioid use were much lower when patients established and maintained therapy on migraine prophylactics. Overall, angiotensin receptor blockers and CGRP antagonists had high persistence but were underutilized therapies while the inverse was true for antidepressants and anticonvulsants. Conclusion: In a real-word setting, recognizing that many patients may discontinue preventative treatment completely after their first therapy, there is a need to employ migraine-specific prophylactics and/or tolerable medications early. Treatment guidelines aligned to costs savings and/or requiring step therapy may be inadvertently failing patients. Further, the impact of migraine on the day-to-day lives of patients and high societal costs such as its impact on productivity should be weighed in considering migraine’s burden of illness and the benefits of treatment.

Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3′ untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.Significance:No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Background Suspension of cancer screening and treatment programs were instituted to preserve medical resources and protect vulnerable populations. This research aims to investigate the implications of COVID-19 on cancer management and clinical outcomes for patients with prostate and colorectal cancer in Canada. Methods We examined hospital cancer screening, diagnosis, treatment, length of stay, and mortality data among prostate and colorectal cancer patients between April 2017 and March 2021. Baseline trends were established with data between April 2017 and March 2020 for comparison with data collected between April 2020 and March 2021. Scenario analyses were performed to assess the incremental capacity requirements needed to restore hospital cancer care capacities to the pre-pandemic levels. Results For prostate cancer, A 12% decrease in diagnoses and 5.3% decrease in treatment activities were observed during COVID-19 between April 2020 and March 2021. Similarly, a 43% reduction in colonoscopies, 11% decrease in diagnoses and 10% decrease in treatment activities were observed for colorectal cancers. An estimated 1,438 prostate and 2,494 colorectal cancer cases were undiagnosed, resulting in a total of 620 and 1,487 unperformed treatment activities for prostate and colorectal cancers, respectively, across nine provinces in Canada. To clear the backlogs of unperformed treatment procedures will require an estimated 3%-6% monthly capacity increase over the next 6 months. Interpretation. A concerted effort from all stakeholders is required to immediately ameliorate the backlogs of cancer detection and treatment activities. Mitigation measures should be implemented to minimize future interruptions to cancer care in Canada.

Chronic kidney disease (CKD) is an important health issue that affects ~ 9.1% of the world adult population. Serum creatinine is the most commonly used biomarker for assessing kidney function and is utilized in different equations for estimating creatinine clearance or glomerular filtration rate (GFR). The Cockcroft-Gault formula for adults and "original" Schwartz formula for children have been the most commonly used equations for estimating kidney function during the last 3-4 decades. Introduction of standardized serum creatinine bioanalytical methodology has reduced interlaboratory variability but is not intended to be used with Cockcroft-Gault or original Schwartz equations. More accurate equations (for instance, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for adults and bedside Schwartz or Chronic Kidney Disease in Children Schwartz equation for children) based on standardized serum creatinine values (and another biomarker-cystatin C) have been introduced and validated in recent years. Recently, the CKD-EPI equation refitted without a race variable was introduced. Clinical practice guidance in nephrology advocates a shift to these equations for managing health care of patients with CKD. The guidance also recommends use of albuminuria in addition to GFR for CKD diagnosis and management. Significant research with large data sets would be necessary to evaluate whether this paradigm would also be valuable in drug dose adjustments. This article attempts to highlight some important advancements in the field from a clinical pharmacology perspective and is a call to action to industry, regulators, and academia to rethink the current paradigm for assessing kidney function to enable dose recommendation in patients with CKD.

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum-based chemotherapy. These exposure-response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum-pretreated patients with EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in a pivotal phase I/II study. A statistically significant relationship between the independent review committee-assessed objective response rate and molar sum exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not discernable using a longitudinal model of clinical response driven by normalized dynamic molar sum exposure or a static model of best clinical response based on time-averaged molar sum exposure. However, the longitudinal model suggested a trend for decreased probability of response with the change in mobocertinib molar sum exposure between the 160- and 120-mg doses (odds ratio: 0.78; 95% confidence interval: 0.55-1.10; P = 0.156). Time-averaged molar sum exposure was a significant predictor of the rate of grade ≥ 3 treatment-emergent adverse events (AEs). Taken together, these exposure-efficacy and exposure-safety results support a favorable benefit-risk profile for the approved mobocertinib 160-mg q.d. dose and dose modification guidelines for patients experiencing AEs.

Study Design Retrospective Objective To compare the rate of positive pathology on thoracic MRI ordered by surgical spine specialists to those ordered by nonsurgical spine specialists. Methods Outpatient thoracic MRIs from January–March 2019 were evaluated from a single academic health care system. Studies without a known ordering provider, imaging report, or patients with known presence of malignancy, multiple sclerosis, recent trauma, or surgery were excluded (n = 320). Imaging studies were categorized by type of provider placing the order (resident, attending, or advanced practice practitioner) and department. MRIs were deemed positive if they showed relevant pathology that correlated with indication for exam as determined by a radiologist. One-sided chi-squared analysis was performed to determine statistical significance. Results Overall, our data demonstrated 17.2% of studies with positive pathology. Compared to nonspecialty clinicians, subspecialists showed 35/184 (19.0%) positivity rate versus the non-specialist with 20/136 (14.7%) positivity rate (P = .156). Posthoc analysis demonstrated that surgical specialists who order thoracic MRIs yield significantly higher positivity rates at 19/79 (24.0%) compared to nonsurgical specialists at 36/241 (14.9%) (P < .05). Overall, neurosurgery demonstrated the highest rate of positive thoracic MRIs at 14/40 (35.0%). Comparison between the rate of positivity between physicians and advanced practitioners was insignificant (P > .05). Conclusions Clinical diagnosis of symptomatic thoracic spine degenerative disease requires an expert physical exam combined with careful attention to radiology findings. Although the percent of relevant pathology on thoracic MRI is low, our data suggests evaluation by a surgical specialist should precede ordering a thoracic spine MRI.

INTRODUCTION The molecular mechanisms that drive leptomeningeal dissemination (LD) of medulloblastoma (MB) are largely unknown. The Abelson (ABL) family kinases, originally identified as oncogenes in leukemia, play an important role in lung cancer cell migration, invasion, cell adhesion, and chemotherapy resistance. The objective of this work was to elucidate the role of ABL kinases in MB LD. METHODS ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of MB LD. RESULTS ABL1 and ABL2 levels were significantly higher in MB patients with LD than without (p=2.6x10-10 and 7.2x10-7, respectively) and overall survival was significantly reduced in patients with high ABL1 and 2 expression (p=0.019 and 0.00027, respectively). In vitro pharmacologic inhibition and genetic knockdown of ABL1 and ABL2 in Group 3/4 MB resulted in statistically significant cell death, decreased adhesion to vitronectin (a key leptomeningeal extracellular matrix [ECM] protein), decreased migration through ECM extract, and decreased c-myc expression in multiple MB cell types. In mouse models of MB LD, ABL1/2 knockdown significantly decreased LD as determined by bioluminescence and improved overall survival (p=0.0044). Pharmacologic inhibition of ABL1/2 using nilotinib resulted in improved median overall survival (64 vs. 76.5 days). CONCLUSIONS ABL1 and ABL2 are preferentially expressed in patients with MB LD at diagnosis and are associated with poor survival. Both genetic inactivation and pharmacologic inhibition of ABL1 and 2 decreased MB LD in vitro and in vivo, likely via reduction of c-myc signaling. This preliminary work suggests a key role for ABL1/2 in driving MB LD.

Background Cystic fibrosis (CF) is an autosomal recessive disease that can present with multisystem manifestations based on mutations in the CF transmembrane regulator (CFTR) gene. Screening for CF was added to the Newborn Screening Ontario (NSO) program in 2008 using immunoreactive trypsinogen and genetic testing with a panel of 39 + 3 polymorphisms. From 2008-2020, our centre had all referred screen positive individuals undergo confirmatory genetic testing with an expanded panel of 70 + 4 polymorphisms, occasionally identifying a second mutation of varying clinical consequence. If an individual had a second mutation identified on our panel, prospective follow-up was offered. Objectives The aim of the study is to evaluate the utility of our expanded panel and subsequent identification of individuals with possible CFTR dysfunction. Design/Methods We conducted a retrospective descriptive analysis of our database of screen positive individuals, focusing on the subset who had a second mutation identified through expanded panel and whom we have offered clinical follow-up for 12 years. Results From 2008 to 2020, 718 screen positive individuals were referred to our CF Canada-accredited centre. 566 had one mutation identified by NSO. 94 of these had a second mutation identified on expanded panel. Of these, 13 had a sweat chloride between 30-60 mmol/L and 7 had a positive sweat test. Of those with borderline or negative sweats, 9 individuals continued to be followed. Two have converted to positive sweats, with 1 of these individuals requiring antibiotics for pulmonary exacerbations and the other remaining asymptomatic. Another 2 individuals are trending toward positive sweats (> 50 mmol/L). All spirometry values (FEV1, FVC) have been normal to date, and none have grown Pseudomonas aeruginosa. Conclusion Use of a confirmatory expanded panel identified a second mutation in 94 newborns referred with a positive screen. Offering follow-up has allowed us to monitor clinical progression, including conversion to positive sweats in 2 individuals. While spirometry and cultures have been unremarkable, more sensitive measures such as lung clearance index could be considered for future study. As of 2020, NSO moved to the use of extended sequencing and analysis of this change is ongoing.