A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients.

Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

Response to OKN-007 and NAC in a Patient with Unilateral Hearing Loss and Chronic Tinnitus from Vestibular Schwannoma.

BACKGROUND: Tinnitus is the perception of sound in the absence of external acoustic stimulation. Being one of the most common diseases of the ear, it has a global prevalence ranging from 4.1 to 37.2%. To date, it has been difficult to treat tinnitus as its pathophysiology is poorly understood and there are limited treatment options. OBJECTIVE: To investigate the effect of OKN-007 (also known as HPN-07), a nitrone-based investigational drug, in combination with oral N-acetylcycsteine (NAC), for the treatment of hearing loss and chronic tinnitus under an individual expanded access protocol. PATIENT CASE: We report the case of a patient who presented with left-sided ear fullness, mild tinnitus, and mild high frequency sensorineural hearing loss with 100% word recognition. A large enhancing mass seen on MRI revealed a vestibular schwannoma. He underwent subtotal resection of the tumor resulting in a moderate-to-profound sensorineural hearing loss and catastrophic tinnitus. The patient was treated with intravenous OKN-007 at 60 mg/kg dosed three times per week and oral NAC 2500 mg twice daily. RESULTS: Post-treatment audiometric testing revealed an average of 16.66 dB in hearing threshold improvement in three frequencies (125, 250 and 500 Hz) with residual hearing in the affected left ear. His tinnitus loudness matching improved from 90 dB to 19 dB post-treatment. His Tinnitus Handicap Inventory improved from 86/100 (Catastrophic) to 40/100 (Moderate). He also experienced improvements in sleep, concentration, hearing, and emotional well-being, and reported significantly decreased levels of tinnitusrelated distress. CONCLUSIONS: This case report highlights the feasibility and therapeutic potential of the combination of OKN-007 and NAC in treating hearing loss and tinnitus that warrants further investigation.

Tertiary drug information sources for treatment and prevention of COVID-19.

Objective: To evaluate tertiary drug information databases in terms of scope, consistency of content, and completeness of COVID-19 drug information. Methods: Five electronic drug information databases: Clinical Pharmacology, Lexi-Drugs, AHFS DI (American Hospital Formulary Service Drug Information), eFacts and Comparisons, and Micromedex In-Depth Answers, were evaluated in this cross-sectional evaluation study, with data gathered from October 2021 through February 2022. Two study investigators independently extracted data (parallel extraction) from each resource. Descriptive statistics were primarily used to evaluate scope (i.e., whether the resource addresses use of the medication for treatment or prevention of COVID-19) and completeness of content (i.e., whether full information is provided related to the use of the medication for treatment or prevention of COVID-19) based on a 10-point scale. To analyze consistency among resources for scope, the Fleiss multi-rater kappa was used. To analyze consistency among resources for type of recommendation (i.e., in favor, insufficient evidence, against), a two-way mixed effects intraclass coefficient was calculated. Results: A total of 46 drug monographs, including 3 vaccination monographs, were evaluated. Use of the agents for treatment of COVID-19 was most frequently addressed in Lexi-Drugs (73.9%), followed by eFacts and Comparisons (71.7%), and Micromedex (54.3%). The highest overall median completeness score was held by AHFS DI followed by Micromedex, and Clinical Pharmacology. There was moderate consistency in terms of scope (kappa 0.490, 95% CI 0.399-0.581, p<0.001) and recommendations (intraclass correlation coefficient 0.518, 95% CI 0.385-0.651, p<0.001). Conclusion: Scope and completeness results varied by resource, with moderate consistency of content among resources.

Activity of pemetrexed in pre-clinical chordoma models and humans.

Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).

Advocacy in community-based service learning: perspectives of community partner organizations.

Background: Health advocacy is a core competency for physicians, which can be developed through community-based service-learning (CBSL). This exploratory study investigated the experiences of community partner organizations (CPOs) participating in CBSL in the context of health advocacy. Methods: A qualitative study was conducted. Nine CPOs at a medical school participated in interviews on topics pertaining to CBSL and health advocacy. Interviews were recorded, transcribed, and coded. Major themes were identified. Results: CPOs perceived a positive impact from CBSL through student activities and connecting with the medical community. There was no unifying definition of health advocacy. Advocacy activities varied depending on the individual's role (i.e., CPO, physician, and student), which encompassed providing patient care or services, raising awareness of healthcare issues, and influencing policy changes. CPOs had different perceptions of their role in CBSL from facilitating service-learning opportunities to teaching students in CBSL, while a few desired to be involved in curriculum development. Conclusion: This study provides further insight into health advocacy from the lens of CPOs, which may inform changes to health advocacy training and the CanMEDS Health Advocate Role to better align with the values of community organizations. Engaging CPOs in the broader medical education system may improve health advocacy training and ensure a positive bidirectional impact.

Contexte: La promotion de la santé est une compétence fondamentale pour les médecins, qui peux être développée dans le cadre de l'apprentissage par le service communautaire (ASC). Cette étude exploratoire examine les expériences des organismes communautaires partenaires (OCP) participant à l'ASC en ce qui concerne le volet promotion de la santé. Méthodes: Dans le cadre d'une étude qualitative, neuf OCP d'une faculté de médecine ont participé à des entretiens sur des sujets liés à l'ASC et à la promotion de la santé. Les entretiens ont été enregistrés, transcrits et codés, et les thèmes principaux en ont été extraits. Résultats: Les OCP ont perçu un effet positif de l'ASC, notamment par le biais des activités étudiantes et des liens établis avec la communauté médicale. Nous n'avons pas relevé de définition commune de la promotion de la santé. Les activités s'y rapportant varient selon le rôle de la personne (OCP, médecin ou étudiant) et comprennent la prestation de soins ou de services aux patients, la sensibilisation aux enjeux de santé et la promotion de changements d'orientations politiques. Les divers OCP avaient des perceptions différentes de leur rôle dans l'ASC, allant d'offrir des activités d'apprentissages aux étudiants en ASC, au désir de participer à l'élaboration des programmes d'études. Conclusion: Cette étude permet de mieux saisir le point de vue des OCP sur la promotion de la santé. Elle peut ainsi éclairer les révisions du rôle CanMEDS de promoteur de la santé et de la formation en la matière de façon à les aligner davantage sur les valeurs des organismes communautaires. L'intégration des OCP à la formation médicale au sens large pourrait contribuer à améliorer le volet promotion de la santé de cette dernière et profiter aux partenaires de part et d'autre.

A systematic review of fear, stigma, and mental health outcomes of pandemics.

BACKGROUND: The COVID-19 pandemic has negatively affected the mental health of people globally. Despite substantial research on the short-term psychological impact of COVID-19, its long-term consequences on mental health remain relatively unexplored. AIMS: We aimed to examine mental health literature on prior outbreaks to provide recommendations for developing effective strategies to mitigate the short- and long-term psychological impact of the current pandemic. METHODS: We conducted a narrative review of 41 studies to analyze the adverse impact of the following epidemics and pandemics on the mental health of individuals, groups, and communities: Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome, Influenza A/H1N1, and Ebola Virus Disease. RESULTS: We noted that these past epidemics and pandemics escalated stress, distress, anxiety, fear, and stigma that persisted in countries and communities. We also identified the role of misinformation in propagating discrimination and prejudice towards certain groups. CONCLUSIONS: We discuss how the mental health outcomes of previous pandemics differed from the COVID-19 outbreak. We believe that strategies that reduce misinformation, educational initiatives, and mental health programs when introduced at the individual and community level have the potential to effectively diminish the negative psychological impact of COVID-19. PRISMA: This study followed the PRISMA guidance and was not registered in PROSPERO. This is a narrative review that used qualitative thematic analysis. Publishing a protocol on a protocol repository for such reviews is not the standard of practice.

What factors promote vaccine hesitancy or acceptance during pandemics? A systematic review and thematic analysis.

Examine the factors that promote vaccine hesitancy or acceptance during pandemics, major epidemics and global outbreaks. A systematic review and thematic analysis of 28 studies on the Influenza A/H1N1 pandemic and the global spread of Ebola Virus Disease. We found seven major factors that promote vaccine hesitancy or acceptance: demographic factors influencing vaccination (ethnicity, age, sex, pregnancy, education, and employment), accessibility and cost, personal responsibility and risk perceptions, precautionary measures taken based on the decision to vaccinate, trust in health authorities and vaccines, the safety and efficacy of a new vaccine, and lack of information or vaccine misinformation. An understanding of participant experiences and perspectives toward vaccines from previous pandemics will greatly inform the development of strategies to address the present situation with the COVID-19 pandemic. We discuss the impact vaccine hesitancy might have for the introduction and effectiveness of a potential COVID-19 vaccine. In particular, we believe that skepticism toward vaccines can still exist when there are no vaccines available, which is contrary to contemporary conceptualizations of vaccine hesitancy. We recommend conducting further research assessing the relationship between the accessibility and cost of vaccines, and vaccine hesitancy.

Molecularly targeted treatment of recurrent anaplastic astrocytoma - a case report.

High-grade astrocytomas are malignant and aggressive, with limited treatment options. Treatment is geared not only toward increasing patient's overall survival but also in delaying or preventing neurological disability, a cause of significant morbidity. Increasingly, targeted and customized treatment approaches, especially for recurrent disease, are being explored. Here we present a successful outcome in a young patient with rapidly progressive disease who responded to targeted treatment based on genetic sequencing and circulating tumor DNA markers, given the inaccessibility of the tissue to biopsy. Molecular testing on tissue, serum or CSF may be helpful in identifying unique targets in these complex patients.

Characterization of molecular pathways for targeting therapy in glioblastoma.

Glioblastoma remains the most common malignant brain neoplasm in adults. The available therapies for treatment have only modestly extended survival. Traditional chemotherapy agents have shown only slight effectiveness in controlling this disease. The use of molecular profiling has allowed personalized medicine options to be explored for the care of these individuals. Targeted therapies have shown significant benefit in numerous other cancer types with survival being extended significantly. In glioblastoma, several promising markers have been identified including vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). These targets have been shown to play a critical role in glioblastoma formation and proliferation. The pathways of these receptors have been elucidated in detail. This level of understanding has led to the a more robust understanding of possible mechanism of pathway modification. The targeting of these specific markers has led to the development of several selective therapies with additional therapies being evaluated. The clinical trials validating these markers have been promising but have yet to show a clear benefit in brain tumors. This identification of alternative methods to address these markers or identify additional targets may be the key to the fight against this disease. The molecular targeting of glioblastoma pathways may have significant impact on disease control and patient survival.

Knowledge, (mis-)conceptions, risk perception, and behavior change during pandemics: A scoping review of 149 studies.

The severe acute respiratory syndrome-coronavirus-2 pandemic has spread rapidly and has a growing impact on individuals, communities, and healthcare systems worldwide. At the core of any pandemic response is the ability of authorities and other stakeholders to react appropriately by promoting hygiene and social distancing behaviors. Successfully reaching this goal requires both individual and collective efforts to drastically modify daily routines and activities. There is a need to clarify how knowledge and awareness of disease influence risk perception, and subsequent behavior in the context of pandemics and global outbreaks. We conducted a scoping review of 149 studies spanning different regions and populations to examine the relationships between knowledge, risk perceptions, and behavior change. We analyzed studies on five major pandemics or outbreaks in the twenty-first century: severe acute respiratory syndrome, influenza A/H1N1, Middle East respiratory syndrome, Ebola virus disease, and coronavirus disease 2019.

Sustaining Social Distancing and Mass Quarantine in the COVID-19 Era: Lessons Learned.

A new decade often begins with new life, new relationships and new purposes. Unfortunately, the start of this decade has been anything but, thanks to the rather unprecedented global crisis that has rapidly taken over our lives. COVID-19 - which seemed to be just a flu-like infection spreading modestly in mainland China - has suddenly became a pandemic that has crashed economies and broken health systems worldwide.

The impact of pricing strategy on the costs of oral anti-cancer drugs.

BACKGROUND: The soaring costs of anti-cancer drugs pose a threat to the sustainability of cancer care. The pricing strategy chosen by manufacturers can impact the costs of oral anti-cancer drugs during dose modifications, but this issue remains under-recognized in the literature. In general, with the flat pricing strategy, there is a single fixed price for each tablet regardless of dosage strength, whereas with linear pricing, the price of each tablet increases with its dose. We hypothesize that flat pricing will have increased drug costs compared to linear pricing during dose reductions since the cost remains fixed despite decreased dose requirements. This practice may have significant financial implications considering the high costs, extensive utilization, and frequent occurence of dose reductions with anti-cancer drugs.  METHODS: Oral anti-cancer drugs reviewed by the pan-Canadian Oncology Drug Review program between 2011 and 2018 were identified. The cost per mg and cost per 28-day cycle were calculated for dose levels -2 to +2. The percent change in cost per mg and cost per cycle during dose modifications from the standard dose were calculated. We conducted Mann-Whitney U and Fisher-exact tests to compare the association between drug costs during dose reductions and pricing strategy. RESULTS: In this study, 30 oral anti-cancer drugs for use in 41 indications were analyzed; 44% of drugs used linear pricing and 56% used flat pricing. Dose reductions increased the mean cost per mg for drugs with linear pricing by 14.7% (range: 0%-50%) at dose level -1 and 17.2% (range: 0%-50%) at dose level -2 and flat pricing by 60.8% (range: 19%-100%) at dose level -1 and 99.1% (range: 0%-300%) at dose level -2. The cost per mg was significantly increased in drugs using flat pricing compared to linear pricing when dose reduction to either level -1 (P = 0.010) or level -2 (P = 0.006) occurred. The mean cost per cycle was decreased for drugs using linear pricing by 20.9% (range: -40% to 0%) at dose level -1 and 48.7% (range: -60% to -25%) at dose level -2 and flat pricing by 0.8% (range -6% to 0%) at dose level -1 and 11.0% (range: -50% to 100%) at dose level -2. The cost per cycle was significantly decreased in drugs with linear pricing compared to flat pricing when the standard dose is reduced to either dose level -1 (P = 0.005) or dose level -2 (P = 0.026). CONCLUSIONS: Overall, flat pricing had significantly greater costs compared to linear pricing during dose reductions of anti-cancer drugs. While there is a general expectation that the cost of drugs should decrease with dose reduction, drugs with flat pricing were generally found to have increased cost per mg and no change in the cost per cycle. The resultant increased spending on drug acquisition (despite purchasing lower doses) lead to financial wastage, which has significant implications on cost-effectiveness considerations and budgets. Future economic evaluations should take into consideration the hidden costs associated with dose reductions of flat priced drugs.

Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors.

Aim: Genomically matched trials in primary brain tumors (PBTs) require recent tumor sequencing. We evaluated whether circulating tumor DNA (ctDNA) could facilitate genomic interrogation in these patients. Methods: Data from 419 PBT patients tested clinically with a ctDNA NGS panel at a CLIA-certified laboratory were analyzed. Results: A total of 211 patients (50%) had ≥1 somatic alteration detected. Detection was highest in meningioma (59%) and gliobastoma (55%). Single nucleotide variants were detected in 61 genes, with amplifications detected in ERBB2, MET, EGFR and others. Conclusion: Contrary to previous studies with very low yields, we found half of PBT patients had detectable ctDNA with genomically targetable off-label or clinical trial options for almost 50%. For those PBT patients with detectable ctDNA, plasma cfDNA genomic analysis is a clinically viable option for identifying genomically driven therapy options.

The impact of cancer drug wastage on economic evaluations.

BACKGROUND: The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area- or weight-based dosing. METHODS: Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum-wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. RESULTS: Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost-effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost-effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. CONCLUSIONS: Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017;123:3583-90. © 2017 American Cancer Society.

Chemotherapy-induced cardiotoxicity: detection, prevention, and management.

Chemotherapy-induced cardiotoxicity is a major cause of morbidity and mortality in cancer survivors. It might manifest as arrhythmia, hypertension, myocardial ischemia, thromboembolism, heart failure, systolic dysfunction, or other adverse events. Anthracyclines and trastuzumab are the chemotherapeutic agents with the most documented cardiac side effects; however, the array of novel molecular targeting therapies available is concerning because their side effects are not yet well understood. Nevertheless, there are potential strategies to mitigate the risks of cardiac complications for cancer patients. In this article, the common systemic drugs with cardiotoxic potential and the monitoring and diagnostic tools, including the role of biomarkers for early detection, are reviewed. We will also review the use of cardioprotectant agents as pharmacological interventions in prophylactic and treatment settings. Our aim is to provide a concise and up-to-date summary of the detection, management, and prevention of chemotherapy-induced cardiotoxicity for the busy clinician.