Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

INTRODUCTION: Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. MATERIALS AND METHODS: We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. RESULTS: Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. CONCLUSIONS: Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up.

Continuing Professional Development Needs Amongst University of Toronto's Department of Radiation Oncology Faculty.

Continuing professional development (CPD) and lifelong learning are core tenets of most healthcare disciplines. Where undergraduate coursework lays the foundation for entry into practice, CPD courses and offerings are designed to aid clinicians in maintaining these competencies. CPD offerings need to be frequently revised and updated to ensure their continued utility. The purpose of this qualitative study was to better understand the CPD needs of members of the University of Toronto's Department of Radiation Oncology (UTDRO) and determine how these needs could be generalized to other CPD programs. Given that UTDRO consists of members of various health disciplines (radiation therapist, medical physicists, radiation oncologists, etc.), eleven semi-structured interviews were conducted with various health professionals from UTDRO. Inductive thematic analysis using qualitative data processing with NVivo® was undertaken. The data was coded, sorted into categories, and subsequently reviewed for emergent themes. Participants noted that a general lack of awareness and lack of access made participation in CPD programs difficult. Members also noted that topics were often impractical, irrelevant, or not inclusive of different professions. Some participants did not feel motivated to engage in CPD offerings due to a general lack of time and lack of incentive. To address the deficiencies of CPD programs, a formal needs assessment that engages stakeholders from different centers and health professions is required. Needs assessments of CPD programs should include analyzing elements related to access, how to utilize technology-enhanced learning (TEL), determine barriers to participation, and understand how to better engage members.

Nivolumab in Squamous Cell Carcinomas of the Head and Neck (SCCHN): A Real-world Outcome Study in Ontario, Canada.

The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic/advanced squamous cell carcinomas of the head and neck (SCCHN). We evaluated the outcomes of SCCHN patients in Ontario, Canada, treated with nivolumab through retrospective review of the provincial treatment registry. Kaplan-Meier method was used to estimate overall survival (OS) and Cox regression to evaluate the prognostic effect of selected factors. Nivolumab was used as second-line therapy after disease relapse for curative-intent platinum chemotherapy (PC) (indication 1-I1), as second-line therapy post-PC in noncurative intent (indication 2-I2), and as first-line therapy in noncurative intent due to contraindication for PC (indication 3-I3). The median OS for patients treated with nivolumab was 5.8 months (95% CI: 4.5-7.3), and the 1-year OS was 28.4% (CI: 2.10-36.1). When patients with I3 were excluded to match inclusion criteria for CheckMate-141, median OS was 4.8 months (CI: 3.6-6.7) with 1-year OS of 21.8% (14.4-30.1). Patients with lower body surface area (BSA) (<1.81) had a median OS of 3.9 months (CI: 3.1-6.7) versus 9.0 months (CI: 6.5-14.8) in those with higher BSA, hazard ratio (HR)=0.12 (CI: 0.04-0.39, P <0.001). Patients receiving nivolumab for I1 had a median OS of 7.2 months (CI 3.8-9.8) versus 11.9 months (CI: 6.2-not reached) for I3, HR=1.73 (CI: 0.94-3.16). Patients receiving nivolumab for I2 had a median OS of 3.9 months (CI: 2.9-5.4) as compared with I3, HR=3.27 (CI: 1.80-5.94). Real-world analysis of patients with advanced/metastatic SCCHN in Ontario, Canada, treated with nivolumab demonstrates poorer median OS compared with CheckMate-141 trial. Lower BSA was a predictor of poorer median OS.

Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review.

Immune-related adverse events (irAEs) are toxicities resulting from use of immune checkpoint inhibitors (ICIs). These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents. Little is known about chronic irAEs and they are felt to be rare. We performed a systematic review to characterize non-endocrine chronic irAEs reported in the literature and describe their management. Ovid MEDLINE and Embase databases were searched for reports of adult patients with solid cancers treated with ICIs who experienced chronic (>12 weeks) non-endocrine irAEs. Patient, treatment and toxicity data were collected. Of 6843 articles identified, 229 studies including 323 patients met our inclusion criteria. The median age was 65 (IQR 56-72) and 58% were male. Most patients (75%) had metastatic disease and the primary cancer site was melanoma in 43% and non-small cell lung cancer in 31% of patients. The most common ICIs delivered were pembrolizumab (24%) and nivolumab (37%). The chronic irAEs experienced were rheumatological in 20% of patients, followed by neurological in 19%, gastrointestinal in 16% and dermatological in 14%. The irAE persisted for a median (range) of 180 (84-2370) days and 30% of patients had ongoing symptoms or treatment. More than half (52%) of patients had chronic irAEs that persisted for >6 months. The ICI was permanently discontinued in 60% of patients and 76% required oral and/or intravenous steroids. This is the first systematic review to assess and report on moderate/severe chronic non-endocrine irAEs after treatment with ICI in the literature. These toxicities persisted for months-years and the majority required discontinuation of therapy and initiation of immunosuppression. Further research is needed to better understand chronic irAEs, which hold potential substantial clinical significance considering the expanded use of ICIs and their integration into the (neo)adjuvant settings.

EGFR Targeting TKI-Related Skin Toxicities in a Patient with Darker Skin: A Case Report.

Epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) can result in significant skin toxicities that may impact patients' quality of life. While these skin reactions are well documented in patients with lighter skin, there is a paucity of literature and images to guide clinicians in their assessment in patients with darker skin tones. Given that dermatological reactions in patients with darker skin are not well represented, this can result in the undertreatment or mistreatment of these otherwise common toxicities. Herein, we present a case of a female patient with a darker skin tone with metastatic non-small cell lung carcinoma (NSCLC) with EGFR-TKI-related skin toxicity and her clinical course.

Retrospective analysis of VES-13 questionnaires in the Senior Women's Breast Cancer Clinic at Sunnybrook Health Sciences, Toronto, Ontario, Canada.

PURPOSE: Vulnerable Elder Survey (VES-13) is a screening tool used in assessing older vulnerable patients at risk of functional decline. We sought to evaluate how VES-13 tool would impact oncologist referral pattern to geriatricians as our primary outcome. We also sought to better understand how VES-13 scores impacted referral to additional services (allied healthcare), and modification to oncological treatment. METHODS: A retrospective review of VES-13 questionnaires completed by older women (age 70 or older) with breast cancer referred to the Senior Women's Breast Cancer Clinic (SWBCC) was undertaken. Patients with a VES-13 score of three or greater, who were at significantly higher risk of functional decline, had further retrospective chart review for risk factors that would contribute to functional decline such as Eastern Cooperative Oncology Group (ECOG) score, social supports, and current living situation. The primary and secondary endpoints described above were analyzed through bivariate comparisons and multivariable logistical regression to determine if there was any statistical significance (p < 0.05). RESULTS: 701 patients completed VES-13 form, of which 235 (33.5%) had a VES-13 score of three or greater. Less than 5% of oncologists documented VES-13 scores in their notes, with less than 5% of patients being referred for geriatric services. Neither VES-13 (p= 0.900) nor ECOG (p= 0.424) were associated with referral for geriatrics assessment. Referral to allied healthcare services was significantly associated with (ECOG) score (OR 2.24 [1.49-3.37], p < 0.0001), while not significantly associated with VES-13 score (OR 0.89 [0.78-1.02], p= 0.102). VES-13 (OR 1.23 [1.04-1.45], p=0.014) and ECOG (OR 2.37 [1.29-4.37), p=0.005) were both associated with modification in oncology treatment (chemotherapy or radiation). CONCLUSION: Approximately one third of our population was at risk of functional decline. VES-13 scores were infrequently mentioned in oncologists notes from their clinical assessments, with very few patients being referred for geriatric assessment. By not collecting and analyzing VES-13 scores, and relying on performance status alone, there is a missed opportunity in assessing for functional decline and reducing potential complications from treatment for our patients.

Liver enzyme elevation and eosinophilia with atorvastatin: a case of probable DRESS without cutaneous symptoms.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening hypersensitivity reaction to medication. While a relatively rare phenomenon, early identification and discontinuation of the offending agent is pivotal to patient management. To our knowledge this is the first reported case of probable atorvastatin induced DRESS syndrome without rash. CASE PRESENTATION: An adult female presented with 4 days of persistent fevers, abdominal and flank pain, malaise, and generalized muscle weakness without any cutaneous reaction following 20 days of therapy with atorvastatin. She was febrile (38.5 °C), at presentation with a heart rate of 72, and blood pressure of 93/51 mmHg. Her laboratory investigations at their peak demonstrated an Alkaline Phosphatase (ALP) of 792 U/L, Alanine aminotransferase (ALT) of 265 U/L, gamma glutamyl transferase (GGT) of 236 U/L, total bilirubin at 21 mg/dL, eosinophils 3100 cells/µL, leukocytes 20.2 K/µL, hemoglobin of 12.5 gm/dL. During her admission she had normal creatinine and troponin. Her serology for Hepatitis A, B and C were negative. Cytomegalovirus, Epstein-Barr viral serologies were negative. Antinuclear Antibody (ANA), rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA), mitochondrial antibody, and smooth muscle antibody were negative. The patient was initially diagnosed as having pyelonephritis due to nonspecific bilateral flank pain but given ongoing fevers and lack of clinical and laboratory improvement with antibiotics, a diagnosis of atorvastatin induced DRESS syndrome was considered probable, and atorvastatin was discontinued. The patients' clinical status improved gradually without any further therapy and her liver enzymes and eosinophils normalized over the course of a month. CONCLUSION: In patients who present with systemic organ involvement and eosinophilia, even without cutaneous manifestations, clinicians should apply the RegiSCAR criteria for DRESS syndrome. This can then help guide treatment with discontinuation of offending agent, or treatment with systemic corticosteroids.

Evaluation of the effectiveness of the Global Medical Student Partnership program in undergraduate medical education.

BACKGROUND: The Global Medical Student Partnership (GMSP) is a medical student-led international initiative to promote accessible global health learning. This study aims to evaluate the effectiveness of the GMSP program in meeting its learning objectives. METHODS: Canadian and international medical student pairs met online monthly (January-May 2018) to discuss global health-related medical cases. Students then reviewed cases with local GMSP peers and faculty experts. A mixed-methods study was performed to evaluate whether the objectives of the program had been achieved. 26 of 32 (81.3%) students completed a questionnaire, and 13 (40.6%) also participated in one-on-one semi-structured interviews. Descriptive statistics and thematic analysis were used to analyze students' perspectives on skill development through GMSP. RESULTS: GMSP students agreed or strongly agreed that international collaboration and communication skills were more important to them following program participation (92.3%, 92.3% respectively). Many expressed that after GMSP, they knew more about their healthcare system, practices abroad and how to solve complex health issues (92.3%, 84.6%, 61.5% respectively). Qualitative data showed GMSP improved students' communication and presentation skills, provided a foundation for international relationships, fostered appraisal of diverse health systems, and furthered students' understanding of health advocacy. CONCLUSIONS: Our findings demonstrate that GMSP met its original objectives by providing students with opportunities to engage in international collaborations and to further develop their skills in advocacy, communication, and health-systems research. This program may be an important addition to medical education as it makes use of technology and peer-to-peer exchange to enable global health learning.

CONTEXTE: Le Global Medical Student Partnership (GMSP) est une initiative d'envergure internationale menée par des étudiants en médecine qui vise à favoriser la formation en santé mondiale. La présente étude consiste à évaluer l'efficacité du programme GMSP pour atteindre ses objectifs d'apprentissage. MÉTHODOLOGIE: Des paires d'étudiants en médecine canadiens et étrangers se sont rencontrés en ligne tous les mois, entre janvier et mai 2018, pour discuter de situations cliniques en santé mondiale. Après la rencontre, ces situations cliniques ont été revues par des pairs locaux du programme GMSP et des experts du corps professoral. On a effectué une étude à devis mixte pour déterminer si les objectifs du programme avaient été atteints. 26 des 32 (81,3 %) étudiants ont répondu à un questionnaire et 13 (40,6 %) ont aussi pris part à des entrevues individuelles semi-dirigées. Des statistiques descriptives et une analyse thématique ont été utilisées analyser les perceptions des étudiants sur le développement d'habiletés par le programme GMSP. RÉSULTATS: Les étudiants participant au programme GMSP étaient d'accord ou très en accord pour dire que les habiletés à la collaboration internationale et à la communication étaient plus importantes à leurs yeux après la participation au programme (92.3%, 92,3%, respectivement). Bon nombre ont affirmé qu'après le programme GMSP, ils en connaissaient plus sur leur système de soins de santé, les pratiques à l'étranger et les façons de résoudre des problèmes de santé complexes (92,3 %, 84,6 %, 61,5 % respectivement). Des données qualitatives ont montré que le programme GMSP a amélioré les aptitudes à la communication et des techniques de présentation. Elles ont servi à établir des relations à l'international, à évaluer divers systèmes de soins de santé et à mieux comprendre la promotion de la santé et à militer en faveur de celle-ci. CONCLUSIONS: Nos résultats montrent que le programme GMSP a atteint ses objectifs de départ puisqu'il a donné aux étudiants des occasions de collaboration internationale et leur a permis de développer davantage leurs habiletés en matière de défense des droits, de communication, et de recherche sur les systèmes de soins de santé. Ce programme pourrait s'avérer un important complément à la formation médicale parce qu'il utilise la technologie et des échanges pairs-pairs pour l'apprentissage des enjeux de santé mondiaux.

Do Canadian Radiation Oncologists Consider Geriatric Assessment in the Decision-Making Process for Treatment of Patients 80 years and Older with Non-Metastatic Prostate Cancer? - National Survey.

PURPOSE: Clinical judgement may not be sufficient to detect relevant problems in older cancer patients. We investigated what Geriatric Assessment tools (GA) are used by Canadian radiation oncologists (CROs) to treat non-metastatic prostate cancer patients aged 80 years and older. METHODS: A 27-item cross-sectional survey was developed with input from a multidisciplinary team and distributed electronically to Genitourinary (GU) CROs via LimeSurvey. Survey contents included: demographics, treatment choice based on components of GA, and how GA tools are used in clinic. Descriptive statistics were used to analyze multiple-choice data, with Open-ended question being coded and analyzed for emerging themes. RESULTS: 154 GU CRO's were contacted, 44 responded (29%). Active surveillance was the choice of therapy in older low risk prostate cancer patients regardless of factors used in a GA assessment (97%). Results in intermediate and high-risk older prostate cancer patients were more heterogenous. Functional status and comorbidities were the most important factor in the decision-making-process (94%, 91%). Sixty-six percent of CROs did not use any GA tools; yet 77% felt comfortable to very comfortable treating older patients. Eighty-eight percent felt there were some to very few guidelines in helping them to treat older patients. Barriers to using GA included lack of knowledge, time, support, and resources. CONCLUSIONS: GAs are not commonly utilized by CROs. Majority of CROs felt comfortable treating older patients with prostate cancer, regardless of guidelines/evidence in this population. This may have negative implications on patient care. CROs are however open to referring patients for a formal GA.

Paradoxical effects of Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates on hCD45(+) cells in the bone marrow and spleen of leukemia-engrafted NOD/SCID or NRG mice.

INTRODUCTION: (111)In-DTPA-NLS-CSL360 radioimmunoconjugates (RIC) recognize the overexpression of the interleukin-3 receptor α-subchain (CD123) relative to the ß-subchain (CD131) on leukemia stem cells (LSC). Our aim was to study Auger electron radioimmunotherapy (RIT) of acute myeloid leukemia (AML) with (111)In-DTPA-NLS-CSL360 in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice or NOD-Rag1(null)IL2rγ(null) (NRG) mice engrafted with CD123(+) human AML-5 cells. METHODS: The toxicity of three doses of (111)In-DTPA-NLS-CSL360 (3.3-4.8MBq; 11-15µg each) injected i.v. every two weeks was studied in non-engrafted NOD/SCID or NRG mice pre-treated with 200cGy of γ-radiation required for AML engraftment. Engraftment efficiency of (1-5)×10(6) cells AML-5 cells inoculated i.v. into NOD/SCID or NRG mice was assessed by flow cytometric analysis for human CD45(+) (hCD45(+)) cells in the bone marrow (BM) and spleen. AML-5 engrafted mice were treated with two or three doses (3.7MBq; 10µg each) every two weeks of (111)In-DTPA-NLS-CSL360, non-specific (111)In-DTPA-NLS-hIgG, unlabeled CSL360 (10µg) or normal saline. The percentage of hCD45(+) cells in the BM and spleen were measured at one week after completion of treatment. RESULTS: (111)In-DTPA-NLS-CSL360 in combination with 200cGy of γ-radiation caused an initial transient decrease in body weight in NOD/SCID but not in NRG mice. There were no hematological, liver or kidney toxicities. The spleen exhibited 13-fold lower engraftment efficiency than the BM in NOD/SCID mice inoculated with 1×10(6) cells but both organs were highly (>85%) engrafted in NRG mice. Unexpectedly, (111)In-DTPA-NLS-CSL360 or non-specific (111)In-DTPA-NLS-hIgG caused a paradoxical 1.5-fold increase (P<0.0001) in the proportion of hCD45(+) cells in the BM of NOD/SCID mice compared to normal saline treated mice. (111)In-DTPA-NLS-CSL360 reduced hCD45(+) cells in the spleen by 3.0-fold compared to (111)In-DTPA-NLS-hIgG (P=0.0015) but the proportion of hCD45(+) cells was not significantly different than in normal saline treated mice. Unlabeled CSL360 decreased the percentage of hCD45(+) cells in the BM (P=0.004) or spleen (P=0.007) in NOD/SCID mice by 1.6-fold and 2.5-fold, respectively. (111)In-DTPA-NLS-CSL360 or unlabeled CSL360 did not decrease the proportion of hCD45(+) cells in the BM or spleen of NRG mice, due to a much higher leukemic burden. CONCLUSION: (111)In-DTPA-NLS-CSL360 and (111)In-DTPA-NLS-hIgG caused a paradoxical increase in the proportion of hCD45(+) cells in the BM of NOD/SCID mice. This may be due to a priming effect on the BM niche that promotes expansion of engrafted hCD45(+) cells, analogous to γ-radiation required for AML engraftment. There appears to be a competition between this effect and the cytotoxic effects of the Auger electrons on leukemia cells. The effectiveness of (111)In-DTPA-NLS-CSL360 on reducing hCD45(+) cells in the BM or spleen of NOD/SCID and NRG mice was dependent on the leukemic burden. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This study demonstrates for the first time a paradoxical radiation priming effect of RIT on enhancing the hCD45(+) cell population in the BM and spleen of NOD/SCID or NRG mice. Our results have important implications for preclinical evaluation of radioimmunotherapies for patients with AML.

The human polynucleotide kinase/phosphatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 ¹¹¹In-NLS-7G3 radioimmunoconjugates.

INTRODUCTION: Leukemia stem cells (LSCs) are believed to be responsible for initiating and propagating acute myeloid leukemia (AML) and for causing relapse after treatment. Radioimmunotherapy (RIT) targeting these cells may improve the treatment of AML, but is limited by the low density of target epitopes. Our objective was to study a human polynucleotide kinase/phosphatase (hPNKP) inhibitor that interferes with DNA repair as a radiosensitizer for the Auger electron RIT agent, ¹¹¹In-NLS-7G3, which recognizes the CD123⁺/CD131⁻ phenotype uniquely displayed by LSCs. METHODS: The surviving fraction (SF) of CD123⁺/CD131⁻ AML-5 cells exposed to ¹¹¹In-NLS-7G3 (33-266 nmols/L; 0.74MBq/µg) or to γ-radiation (0.25-5Gy) was determined by clonogenic assays. The effect of A12B4C3 (25 µmols/L) combined with ¹¹¹In-NLS-7G3 (16-66 nmols/L) or with γ-radiation (0.25-2Gy) on the SF of AML-5 cells was assessed. The density of DNA double-strand breaks (DSBs) in the nucleus was measured using the γ-H2AX assay. Cellular dosimetry was estimated based on the subcellular distribution of ¹¹¹In-NLS-7G3 measured by cell fractionation. RESULTS: Binding of (111)In-NLS-7G3 to AML-5 cells was reduced by 2.2-fold in the presence of an excess (1µM) of unlabeled NLS-7G3, demonstrating specific binding to the CD123⁺/CD131⁻ epitope. ¹¹¹In-NLS-7G3 reduced the SF of AML-5 cells from 86.1 ± 11.0% at 33 nmols/L to 10.5 ± 3.6% at 266 nmols/L. Unlabeled NLS-7G3 had no significant effect on the SF. Treatment of AML-5 cells with γ-radiation reduced the SF from 98.9 ± 14.9% at 0.25Gy to 0.03 ± 0.1% at 5 Gy. A12B4C3 combined with ¹¹¹In-NLS-7G3 (16-66 nmols/L) enhanced the cytotoxicity up to 1.7-fold compared to treatment with radioimmunoconjugates alone and was associated with a 1.6-fold increase in DNA DSBs in the nucleus. A12B4C3 enhanced the cytotoxicity of γ-radiation (0.25-0.5Gy) on AML-5 cells by up to 1.5-fold, and DNA DSBs were increased by 1.7-fold. Exposure to ¹¹¹In-NLS-7G3 (66 nmols/L) delivered up to 0.6Gy to AML-5 cells. CONCLUSIONS: We conclude that A12B4C3 radiosensitized AML cells to the DNA damaging effects of ¹¹¹In-NLS-7G3. Combination treatment may increase the effectiveness for Auger electron RIT of AML targeting the LSC subpopulation.