Successful Trastuzumab-Deruxtecan Rechallenge After Interstitial Lung Disease: A Case Report.

Trastuzumab deruxtecan (T-DXd) is used to treat human epidermal growth factor receptor 2-positive advanced breast cancer. Interstitial lung disease (ILD) is a severe adverse event associated with T-DXd. Current guidelines recommend permanent discontinuation of T-DXd after Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 ILD. Here, we describe a case of successful rechallenge with T-DXd after CTCAE grade 2 treatment-induced ILD. After discontinuation of T-DXd, ILD was treated with steroids until complete resolution. Given the initial beneficial antitumor response, retreatment was discussed during disease progression. In a shared decision with the patient, T-DXd was restarted at the lowest registered dose, along with low-dose steroids. ILD did not reoccur. Importantly, both clinical and radiological responses to the treatment were observed, with an improvement in the patient's quality of life. This case demonstrates that retreatment with T-DXd after a grade 2 ILD event is feasible and yields clinical benefit.

The reporting of ethical review and ethical considerations in articles published in medical education journals: A literature review.

BACKGROUND: Health professions education research (HPE-R) must be ethically sound. Ethical review decisions and other ethical considerations should be clearly reported in journal articles to allow readers to assess the ethical soundness of the research. We explored and evaluated how ethical review decisions and ethical considerations for HPE-R are reported in health professions education (HPE) journal articles. METHODS: We identified a 1-year sample, for 2020, of eight HPE journals. We systematically assessed the reporting of ethical review and key ethical considerations in the articles in the sample. RESULTS: The search yielded 2004 articles, of which 955 articles (47.7%) were eligible and were thus assessed. Most (83.4%) of the assessed articles mentioned a review by an ethical review board (ERB). In the category 'research articles', 92% articles reported the outcome of the ethical review. In the category 'other articles' (e.g. educational case reports), reporting of ethical processes was less common (32%). Overall, the reporting of key ethical considerations was limited, although these considerations were more reported in 'research articles' compared with 'other articles'. CONCLUSIONS: ERB assessments and HPE-R approval was reported in most research articles. This finding is an improvement compared with previous evaluations of ethical research practice in HPE-R. All studies, particularly those that are exempted or not fully reviewed, should describe their key ethical considerations clearly to enable the HPE community to assess the ethical soundness. Our review revealed that the reporting of ethical considerations was limited and deserves attention from the research community.

Beyond Skin Rash: Alpelisib-Induced Anaphylactic Reactions.

Alpelisib is a specific oral PI3K inhibitor used combined with fulvestrant for the treatment of patients with HR+/HER2-/PIK3CA-mutated metastatic breast cancer. Adverse drug reactions with alpelisib are common, including hyperglycemia and rash. Here we describe extraordinary and life-threatening reactions beyond skin rash in two patients with progressive PIK3CA-mutated metastatic cancer in whom alpelisib was initiated. Case-A (vaginal cancer): After 10 days on treatment, she developed dry eyes, generalized rash and itching. Alpelisib was interrupted and symptomatic treatment initiated. Because of an initial tumor response, a rechallenge was done. Ninety minutes after a reduced dose of alpelisib, she developed an anaphylactic reaction with angioedema, hypotension, and skin rash. Case-B (breast cancer): After 11 days on treatment, she developed skin rash and alpelisib was interrupted. At re-initiation, she felt tingles in her face and ears and some skin erythema. Given the mild rash, a second rechallenge with premedication was performed. Ninety minutes after a reduced dose of alpelisib, she developed a type-1 allergic reaction with angioedema, tingles, and skin rash. In both cases, a type-1 allergic reaction was diagnosed and symptomatic treatment was initiated, alpelisib was permanently discontinued and the patients fully recovered the next week(s). This report underlines the critical importance to consider type-I allergic reactions in the differential diagnosis in cases of rash associated with alpelisib. Even if a reaction develops after days on treatment, a type-I allergic reaction cannot be excluded. A rechallenge can be dangerous and should always be well contemplated or even avoided.

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review.

INTRODUCTION: The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group. METHODS: Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response. RESULTS: 26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response. CONCLUSION: This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates.

Short-term fasting and fasting mimicking diets combined with chemotherapy: a narrative review.

Many patients with cancer search for and use alternative and complementary treatments, aiming to improve the effectiveness of their anticancer treatment and a reduction in treatment-associated side effects. Short-term fasting (STF) and fasting mimicking diets (FMDs) are among the most commonly used dietary interventions. In recent years, different trials have reported the promising results of dietary interventions in combination with chemotherapy, in terms of slowing down tumor growth and reduction in chemotherapy-related side effects. In this narrative review, we identify and describe the current evidence about feasibility and effects of STF and FMDs in cancer patients receiving chemotherapy. The studies that examined the effects of STF when combined with chemotherapy suggest potential benefits regarding reduction in side effects and improved quality of life. We also conclude with a list of well-designed studies that are still recruiting patients, examining the long-term effects of STF.

Topiramate intoxications & hemodialysis - Literature review and the first case report of a massive suicidal intoxication treated with hemodialysis.

Background: Topiramate is an anticonvulsant from sulfamate-substituted monosaccharides that is increasingly used to treat migraines. Serious topiramate intoxications have been described. Unfortunately, indications for and the effect of interventions, including hemodialysis, in severe intoxications seem expert-based and lack empirical evidence. We aim to review the literature on topiramate intoxication cases and to describe the first topiramate intoxication with toxicokinetic data following treatment with hemodialysis. Methods: A literature review was conducted using the PubMed database. Included articles were reviewed for symptoms; management, including acute hemodialysis; toxicokinetic data; and outcomes. Results: We found 61 hits in the PubMed database and checked 392 references in the snowball search; 22 were included for data extraction, reporting 29 cases. The majority of the patients were female (n = 23/29, 79%), ranging in age from 2 to 44 years (median 21). The ingested topiramate amount ranged from 175 to 40,000 mg (usual maintenance dose of 50 mg BID and a general maximum of 500 mg BID). Topiramate concentrations were reported in eight cases, ranging from 3.7 to 356.6 mg/L (for reference, the therapeutic range is 2-30 mg/L). Serious topiramate intoxications can result in seizures, coma, hemodynamic instability and severe metabolic acidosis. In no single case was hemodialysis used. Conclusion: Serious symptoms of topiramate intoxications exist, and hemodialysis is used infrequently. If symptoms are refractory to symptomatic treatment, hemodialysis can reduce topiramate concentrations and symptomatology.

Roses and Balances: A Paradigm for Constructive Ethical Review of Health Professions Education Research.

Recently, the balance between value and necessity of ethical review of health professions education research has been debated. At present, there are large differences in how ethical review of research proposals for health professions education is organized. We present a framework that describes the organization of ethical review in health professions education research, based on the interpersonal circumplex model, also known as Leary's Rose. The framework is based on the two main balances in ethical review of health professions education research, being the protectiveness for the subjects and how ethical review is organized and responsibilities are shared. The axis/balance of protectiveness ranges between the extremes "paternalistic protective" to "liberal permissive". The axis/balance of organization and responsibility ranges between the extremes of "centralized" to "local/decentralized". This model offers insight in the position of an ethical review board and shows the dynamics of the decisions for ethical approval and the consequences of the different approaches to the organization of ethical review of health professions education research.

[Chest pain after angiography without anomalies]. / Pijn op de borst na angiografie zonder afwijkingen.

BACKGROUND: Myocardial infarction can be categorized based on ECG-findings (presence or absence of ST-elevations on STEMI/NSTEMI) or on the results from coronary angiography (CAG) (presence or absence of obstructive atherosclerosis). Myocardial infarction without significant obstruction on CAG (Myocardial Infarction with Non-Obstructive Coronary Arteries/Atherosclerosis; MINOCA) occurs in up to a quarter of patients with myocardial infarcts. These patients have a higher risk of future heart diseases; up to a quarter of MINOCA patients suffer from heart diseases during a median follow-up of four years. CASE DESCRIPTION: We describe a 55-year old woman, who suffered from two myocardial infarctions in one week. The first time, no ST-elevation was detected with ECG and CAG was without abnormalities (MINOCA). Five days later, she experienced the same symptoms; ECG showed ST-elevations and CAG revealed a coronary dissection. CONCLUSION: Patients with a myocardial infarction without coronary obstruction (MINOCA) have a higher risk of future heart diseases. In this case, a coronary dissection.

[An unexpected cause of nausea]. / Een onverwachte oorzaak van misselijkheid.

An 88-year old woman had a sudden onset of nausea and vomiting. She had an end colostomy following a curative resection of rectal cancer six years earlier. As we suspected a high gastrointestinal obstruction, an abdominal CT scan was made. This showed a paracolostomic herniation, including herniation of the stomach.

Clarifying learning experiences in student-run clinics: a qualitative study.

BACKGROUND: Student-run clinics (SRCs) are outpatient clinics run and organized by undergraduate medical students. While these clinics offer participating students multiple learning opportunities, little is known about how participation in an SRC contributes to learning and how this learning is influenced. METHODS: In this qualitative clarification study, we conducted semi-structured interviews with a purposive sample of 20 students and student-coordinators participating in our learner-centred SRC (LC-SRC), to gain in-depth insight into their experiences and learning. These interviews were analysed using Glaser's approach to grounded theory. RESULTS: Analysis revealed that responsibility, authenticity, and collaboration described how SRC participation contribute to learning. Responsibility encompassed the responsibility students had for their patients and the responsibility that the student coordinators had for the students. Authenticity reflected the context and tasks in the LC-SRC. Collaboration covered collaboration with other students, with student coordinators, and with clinical supervisors. These three themes are interrelated, and together enhanced motivation and promoted patient-centred learning in both the LC-SRC and the regular curriculum. CONCLUSIONS: Learning in an LC-SRC is highly dependent on students' feelings of responsibility for real authentic tasks and is stimulated by extensive collaboration with fellow students and supervising doctors.

What Future Healthcare Professionals Need to Know About Pharmacovigilance: Introduction of the WHO PV Core Curriculum for University Teaching with Focus on Clinical Aspects.

Adverse drug reactions (ADRs) can cause serious health problems, as shown in studies about drug-related hospitalizations. To build knowledge of and raise awareness about ADRs among healthcare professionals, more education in the field of ADRs and pharmacovigilance (PV) is needed. No standard exists for teaching PV at universities for medical, pharmacy, dentistry and nursing students, so a core curriculum needs to be developed to teach important aspects of PV to students. In September 2016, a stakeholders' meeting was initiated on behalf of the World Health Organization (WHO) and organized by the Netherlands Pharmacovigilance Centre Lareb. This meeting addressed and agreed on the PV competencies students need to develop and what key aspects of the subject should be taught. Five key aspects were identified: understanding the importance of PV in the context of pharmacotherapy, and preventing, recognizing, managing and reporting ADRs. Since time and resources for PV education are limited, elements of the WHO PV core curriculum for university teaching were designed to be integrated into existing courses but can be used as a stand-alone programme. The basis of and outline for the WHO PV core curriculum for university teaching are addressed in this paper. It is expected that PV competencies for students are vital for their contribution to safe use of medicines in the future. In addition, this article aims to stimulate discussion on this subject and promote collaboration between universities, national PV centres and other stakeholders to integrate key aspects of PV in their educational programmes.

Improving antibiotic prescribing skills in medical students: the effect of e-learning after 6 months.

Background: Antimicrobial prescribing behaviour is first established during medical study, but teachers often cite lack of time as an important problem in the implementation of antimicrobial stewardship in the medical curriculum. The use of electronic learning (e-learning) is a potentially time-efficient solution, but its effectiveness in changing long-term prescribing behaviour in medical students is as yet unknown. Methods: We performed a prospective controlled intervention study of the long-term effects of a short interactive e-learning course among fourth year medical students in a Dutch university. The e-learning was temporarily implemented as a non-compulsory course during a 6 week period. Six months later, all students underwent an infectious disease-based objective structured clinical examination (OSCE) aimed at simulating postgraduate prescribing. If they passed, each student did the OSCE only once. We created a control group of students from a period when the e-learning was not implemented. Main outcomes were the OSCE pass percentage and knowledge, drug choice and overall scores. We used propensity scores to create equal comparisons. Results: We included 71 students in the intervention group and 285 students in the control group. E-learning participation in the intervention group was 81%. The OSCE pass percentage was 86% in the control group versus 97% in the intervention group (+11%, OR 5.9, 95% CI 1.7-20.0). OSCE overall, knowledge and drug choice grades (1-10) were also significantly higher in the intervention group (differences +0.31, +0.31 and +0.51, respectively). Conclusions: E-learning during a limited period can significantly improve medical students' performance of an antimicrobial therapeutic consultation in a situation simulating clinical practice 6 months later.

Opportunities for Students to Prescribe: An Evaluation of 185 Consultations in the Student-run Cardiovascular Risk Management Programme.

Involving students in cardiovascular risk management (CVRM) could offer patients a structured CVRM programme and students a valuable learning opportunity. We describe and evaluate a student-run CVRM programme that was set up to offer primary prevention to patients with known risk factors in a general practitioner's practice. During a consultation, two undergraduate medical students assessed the patients' actual risk and formulated a CVRM plan, which they discussed with the patient after approval by a GP. After the consultations, patients were asked to complete evaluation/feedback questionnaires. From December 2014 to December 2015, 185 consultations were carried out by 46 students. Feedback questionnaires of 153 consultations were returned, in which patient satisfaction was 8.43 (1-10, min-max). The cardiovascular risk of 95 patients was determined, and in >50% patients, it was 'high'. Participating students and GPs were enthusiastic about the (pharmacotherapy) learning opportunities and improved CVRM care while contributing to real patient care in this CVRM programme.

The adverse drug reaction reporting assignment for specialist oncology nurses: a preliminary evaluation of quality, relevance and educational value in a prospective cohort study.

In a new prescribing qualification course for specialist oncology nurses, we thought that it is important to emphasize pharmacovigilance and adverse drug reaction (ADR) reporting. We aimed to develop and evaluate an ADR reporting assignment for specialist oncology nurses. The quality of report documentation was assessed with the "Clinical Documentation tool to assess Individual Case Safety Reports" (ClinDoc). The relevance of the reports was evaluated in terms of ADR seriousness, the listing for additional monitoring of the drug by European Medicines Agency (EMA), and lack of labelling information about the ADR. Nurses' opinions of the assignment were evaluated using an E-survey. Thirty-three ADRs were reported, 32 (97%) of which were well documented according to ClinDoc. Thirteen ADRs (39%) were "serious" according to CIOMS criteria. In five cases (15%), the suspect drugs were listed for additional monitoring by EMA and in seven cases (21%), the ADR was not mentioned in the Summary of Product Characteristics. Twenty-five (78.1%) of the 32 enrolled nurses completed the E-survey. Most were > 45 years of age (68%), female (92%) and had extensive clinical experience (6-33 years). All agreed or completely agreed that the reporting assignment was useful, that it fitted in daily practice and that it increased their attention for medication/patient safety. A large majority (84.0%) agreed the assignment changed how they dealt with ADRs. Specialist oncology nurses are capable of reporting ADRs, and they considered the assignment useful. The assignment yielded valuable, relevant, and well-documented ADR reports for pharmacovigilance practice.

Feasibility and Educational Value of a Student-Run Pharmacovigilance Programme: A Prospective Cohort Study.

INTRODUCTION: Pharmacovigilance, the monitoring of drug safety after marketing approval, highly depends on the adequate reporting of adverse drug reactions (ADRs). To improve pharmacovigilance awareness and future ADR reporting among medical students, we developed and evaluated a student-run pharmacovigilance programme. METHODS: In this project, teams of medical students (first- to fifth-year) assessed real ADR reports, as submitted to the national pharmacovigilance centre. After assessment of causality, including identification of a potential pharmacological explanation for the ADR, the students wrote a personalized feedback letter to the reporter, as well as a summary for the European Medicines Agency (EMA) and World Health Organization (WHO) pharmacovigilance databases. This student assessment was then verified and evaluated by staff from The Netherlands Pharmacovigilance Centre Lareb (Lareb), using an e-questionnaire. Student attitudes, intentions, skills, and knowledge of ADR reporting were evaluated using the e-questionnaire, before and after participation in the programme. RESULTS: From May 2014 to January 2015, a total of 43 students assessed 100 different ADR reports selected by Lareb staff (n = 3). Student assessments were rated as useful (93%), scientifically substantiated (90%), accurate (92%), and complete (92%), and, on average, did not cost Lareb staff extra time. Medical students were positive about ADR reporting, and their awareness of ADR reporting increased significantly following participation in the programme (p < 0.05). After participation in the programme, the students intended to report serious ADRs in their future practice, and their knowledge of pharmacovigilance and ADR reporting showed they had a high overall level of pharmacological understanding. CONCLUSION: The student-run pharmacovigilance programme is a win-win venture. It offers students a valuable 'pharmacovigilance experience', creates awareness in future doctors, and has the potential to increase pharmacovigilance skills and knowledge.