Real-world safety of first-line immuno-oncology combination therapies for advanced non-small-cell lung cancer.

Aim: Real-world adverse event (AE) data are limited for first-line (1L) treatments in advanced non-small-cell lung cancer (NSCLC). Methods: Using Flatiron Health Spotlight data, information for a pre-specified list of AEs was abstracted and described among patients with advanced NSCLC receiving 1L nivolumab + ipilimumab (NIVO + IPI), NIVO + IPI + chemotherapy and other approved immuno-oncology (IO) therapy + chemotherapy combination therapies. Results: Fatigue, pain, dyspnea, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash were the most common AEs. Rates of AEs were generally numerically similar across the three cohorts. The majority of patients received treatment for AEs and approximately one fourth of the patients had hospitalization due to their AEs. Conclusion: The real-world safety experiences of patients treated with 1L NIVO + IPI-based regimens were in general similar to those treated with other approved IO + chemotherapy combination therapies.

Immuno-oncology (IO) therapies boost the immune system to fight cancer cells and have been approved to treat non-small-cell lung cancer (NSCLC). The IO combination of nivolumab + ipilimumab (NIVO + IPI) is approved to treat NSCLC that has spread to other parts of the body or come back and at least 1% of the tumor cells express a protein called PD-L1; NIVO + IPI is also approved in combination with a short course chemotherapy, independent of tumor PD-L1 expression. While NIVO + IPI-based regimens are generally safe, some patients experienced side effects during the clinical trial. However, there is limited information on the side effects of these treatments in a real-world setting. This study analyzed data on side effects from a de-identified database of patients with advanced NSCLC who were treated with NIVO + IPI, NIVO + IPI + chemotherapy, or other approved IO + chemotherapy combinations based on information obtained from physicians' notes in clinical practice settings. The most common side effects among patients in all groups were tiredness, pain, shortness of breath, weight loss, decreased appetite, diarrhea, nausea/vomiting, cough, constipation and rash. The rates at which the side effects occurred were numerically similar regardless of the specific treatment that patients received. Approximately one-quarter of patients in each treatment group were hospitalized because of a side effect. These results show that in a real-world setting, NIVO + IPI-based regimens have similar safety to other IO + chemotherapy combinations when used as a first treatment for NSCLC that has spread or come back.

Mechanical versus bioprosthetic valves in chronic dialysis: a systematic review and meta-analysis.

BACKGROUND: Many patients with end-stage kidney disease (ESKD) have valvular heart disease requiring surgery. The optimal prosthetic valve is not established in this population. We performed a systematic review and meta-analysis to assess outcomes of patients with dialysis-dependent ESKD who received mechanical or bioprosthetic valves. METHODS: We searched Cochrane Central, Medline and Embase from inception to January 2020. We performed screening, full-text assessment, risk of bias and data collection, independently and in duplicate. Data were pooled using a random-effects model. RESULTS: We identified 28 observational studies (n = 9857 patients, including 6680 with mechanical valves and 3717 with bioprosthetic valves) with a median follow-up of 3.45 years. Twenty-two studies were at high risk of bias and 1 was at critical risk of bias from confounding. Certainty in evidence was very low for all outcomes except bleeding. Mechanical valves were associated with reduced mortality at 30 days (relative risk [RR] 0.79, 95% confidence interval [CI] 0.65-0.97, I 2 = 0, absolute effect 27 fewer deaths per 1000) and at 6 or more years (mean 9.7 yr, RR 0.83, 95% CI 0.72-0.96, I 2 = 79%, absolute effect 145 fewer deaths per 1000), but increased bleeding (incidence rate ratio [IRR] 2.46, 95% CI 1.41-4.27, I 2 = 59%, absolute effect 91 more events per 1000) and stroke (IRR 1.63, 95% CI 1.21-2.20, I 2 = 0%, absolute effect 25 more events per 1000). CONCLUSION: Mechanical valves were associated with reduced mortality, but increased rate of bleeding and stroke. Given very low certainty for evidence of mortality and stroke outcomes, patients and clinicians may choose prosthetic valves based on factors such as bleeding risk and valve longevity. STUDY REGISTRATION: PROSPERO no. CRD42017081863.

Targeting HDACs for diffuse large B-cell lymphoma therapy.

Histone deacetylases (HDACs) are involved in tumorigenesis and progression, however, their role in diffuse large B-cell lymphoma (DLBCL) is not well understood. In this study, we examined the expression levels, mutations, and clinical significance of HDACs in DLBCL. Additionally, we investigated the therapeutic potential of Chidamide, a novel HDAC inhibitor, to provide scientific evidence for targeting HDACs in DLBCL patients. We extracted transcriptome data of DLBCLs--including 47 lymph node samples and 337 whole-blood-cell controls--from The Cancer Genome Atlas. Bioinformatic analyses of HDAC expression, mutation, and correlation with the clinical significance of DLBCL patients were performed with the Gene Expression Profiling Interactive Analysis, GENEMANIA, and web-based software including cBioPortal and WebGestalt. To examine the therapeutic effect of Chidamide, DLBCL cell lines (WSU-DLCL-2 and DB cells) were employed. Cell proliferation and apoptosis were analyzed with Cell Counting Kit-8 and flow cytometry assays. The impact of Chidamide treatment was also analyzed by RNA sequencing of treated DB cells. Western blot was used to explore the molecular mechanism of the cytotoxicity of Chidamide on DLBCL cell lines. The expression of some HDACs (HDAC1, 2, 3, 4, 6, 7, 8, and 9) were significantly higher in the lymph node samples of DLBCL than that in whole-blood-cell controls. Moreover, we found that the mutation rate of HDACs was also higher in DLBCL tissues, although the overall survival of DLBCL patients was not associated with HDAC expression. Chidamide was found to have a cytotoxic effect on DLBCL cells in a dose-dependent manner, while transcriptome analysis and western blot revealed that using it for treatment impacted several biological processes, including PI3K/AKT signaling, mTOR signaling, the cell cycle, and apoptosis pathways. Alterations of HDAC genes, including enhanced expression and mutations, are positively related to DLBCL. Targeting HDACs with specific inhibitors such as Chidamide may represent a potential therapeutic approach for DLBCL patients.

Comparative effectiveness of erenumab versus rimegepant for migraine prevention using matching-adjusted indirect comparison.

Aim: To compare the efficacy of erenumab versus rimegepant as preventive treatment for patients with episodic and chronic migraine using an anchor-based matching-adjusted indirect comparison. Methods: Patients from two phase II/III trials for erenumab (NCT02066415 and NCT02456740) were pooled and weighted to match on the baseline effect modifiers (age, sex, race, baseline monthly migraine days [MMDs], and history of chronic migraine [CM]) reported in the phase II/III trial for rimegepant (NCT03732638). Four efficacy outcomes were compared between the two erenumab regimens (70 mg and 140 mg) and rimegepant, including changes in MMDs from baseline to month 1 and month 3, changes in Migraine-Specific Quality of Life Questionnaire role function - restrictive domain score from baseline to month 3, and change in disability from baseline to Month 3. Results: Compared with rimegepant, erenumab 70 mg was associated with a statistically significant reduction in MMDs at month 3 (-0.90 [-1.76, -0.03]; p = 0.042) and erenumab 140 mg was associated with statistically significant reductions in MMDs at month 1 (-0.94 [-1.70, -0.19]; p = 0.014) and month 3 (-1.28 [-2.17, -0.40]; p = 0.005). The erenumab regimens also had numerical advantages over rimegepant for other efficacy outcomes. Conclusion: In the present study, we found that erenumab had a more favorable efficacy profile than rimegepant in reducing MMDs at month 1 and month 3 for migraine prevention. These results may help with decision-making in clinical practice and can be further validated in future clinical trials or real-world studies.

Treatment Patterns and Survival Outcomes Among Androgen Receptor Pathway Inhibitor-Experienced Patients With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: There is limited real-world data regarding subsequent treatment utilization and clinical outcomes following initial androgen receptor pathway inhibitor (ARPI) exposure for the treatment of advanced prostate cancer. This study aimed to address this evidence gap. METHODS: Electronic health records during 01/01/2013-07/31/2022 from Flatiron Health were used to identify adults with mCRPC, who had prior exposure to ARPIs (irrespective of the setting) and ≥1 post-ARPI line of therapy (LOT) in the mCRPC setting (index therapy: the first eligible LOT in the mCRPC setting). Treatment patterns and survival outcomes following the initiation of index therapy were reported. RESULTS: Among 804 ARPI-experienced mCRPC patients, 459 patients (57.1%) received another ARPI as their index therapy and 192 (23.9%) received chemotherapy as their index therapy. In the overall population, median time on the index therapy and median time from index therapy to next therapy were 4.1 and 6.2 months, respectively. Median overall survival and radiographic progression-free survival from the initiation of index therapy were 15.1 and 7.0 months, respectively. CONCLUSIONS: In this real-world analysis, more than half of patients attempted at least 1 additional ARPI in the mCRPC setting, despite prior treatment with ARPIs. The short treatment duration and survival time highlight the unmet need for additional, effective therapies that may improve clinical outcomes in this population.

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation.

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small cell lung cancer.

BACKGROUND: First-line (1L) immunotherapy (I-O) has improved outcomes in patients with advanced non-small cell lung cancer (NSCLC) in clinical trials and is now routinely used alone or combined with chemotherapy. Although efficacy and safety of I-O therapies have been established in clinical trials, little is known about their performance and long-term efficacy in the real-world setting. We aimed to characterize real-world outcomes for patients with advanced NSCLC treated with 1L I-O therapy in the United States. METHODS: Patients aged ≥18 years with confirmed advanced (stage III-IV) NSCLC who received either 1L I-O monotherapy or single-agent I-O combined with chemotherapy on or after January 1, 2016 were identified from the Flatiron Health database. Primary objectives were to examine overall survival (OS) and real-world progression-free survival. Index date was defined as date of 1L treatment initiation; data cut-off date was June 30, 2020. RESULTS: Among 4271 patients receiving I-O plus chemotherapy, median OS was 10.6 (95 % confidence interval [CI], 9.3-11.8) months in patients with squamous NSCLC (n=814) and 12.0 (95 % CI, 11.3-12.8) months in those with non-squamous disease (n=3457). Regardless of histology, patients with high (≥50 %) tumor programmed death ligand 1 (PD-L1) expression demonstrated longer median OS vs those with low expression. Among 3041 patients receiving I-O monotherapy, median OS was 11.3 (95 % CI, 9.8-12.8) months in patients with squamous NSCLC (n=875) and 14.1 (95 % CI, 12.4-15.8) months in those with non-squamous disease (n=2166). OS benefit appeared to be greatest in the ≥50 % tumor PD-L1 expression group of the non-squamous cohort. CONCLUSION: Survival estimates were generally lower than those reported in pivotal clinical trials. These findings indicate that there remains room for improvement of real-world survival outcomes in patients with advanced NSCLC who receive 1L I-O-based regimens and for identification of subgroups of patients not benefitting from treatment with current I-O regimens.

Real-world progression-free survival in first-line advanced non-small cell lung cancer treated with immunotherapy-based regimens using a US dataset.

While results from clinical trials are important in determining the efficacy of treatment, restrictive eligibility criteria may limit generalizability to patient populations in the real-world setting. Real-world analyses can therefore identify subgroups of patients who may respond differently to specific therapeutic regimens. This supplementary data is supportive to the research article entitled "Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small cell lung cancer" [1]. Using electronic health records data from a large demographically and geographically diverse oncology database, we present real-world progression-free survival (rwPFS) outcomes for patients with advanced non-small cell lung cancer in the United States treated with either first-line immunotherapy as monotherapy or single-agent immunotherapy combined with chemotherapy. rwPFS was estimated for patients in each treatment group using Kaplan-Meier methods; analyses were conducted separately for patients with squamous and non-squamous histology and stratified by Eastern Cooperative Oncology Group performance status, tumor programmed death ligand-1 expression, and presence of brain metastases.

60 Years After the First Woman Cardiac Surgeon: We Still Need More Women in Cardiac Surgery.

In 1960, Dr Nina Starr Braunwald became the first woman to perform open heart surgery. Sixty years later, despite the fact that women outnumbered men in American medical school in 2017, men still dominate the field of cardiac surgery. Women surgeons remain underrepresented in cardiac surgery; 11% of practicing cardiac surgeons in Canada were women in 2015, and 6% of practicing adult cardiac surgeons in the US were women in 2019. Although women remain a minority in other surgical specialties also, cardiothoracic surgery remains one of the most unevenly-gender distributed specialties. Why are there so few women cardiac surgeons, and why does it matter? Evidence is emerging regarding the benefits of diversity for a variety of industries, including healthcare. In order to attract and retain the best talent, we must make the cardiac surgery environment more diverse, equitable, and inclusive. Some causes of perpetuation of the gender gap have been documented in the literature-these include uneven compensation and career advancement opportunities, outdated views on family dynamics, and disproportionate scrutiny of women surgeons, causing additional workplace frictions for women. Diversity is an organizational strength, and gender-diverse institutions are more likely to outperform their non-gender-diverse counterparts. Modifiable issues perpetuate the gender gap, and mentorship is key in helping attract, develop, and retain the best and brightest within cardiac surgery. Facilitating mentorship opportunities is key to reducing barriers and bridging the gap.

En 1960, la Dre Nina Starr Braunwald est devenue la première femme à pratiquer une chirurgie à cœur ouvert. Soixante ans plus tard, malgré le fait que les femmes étaient plus nombreuses que les hommes dans les facultés de médecine américaines en 2017, les hommes dominent toujours le domaine de la chirurgie cardiaque. Les chirurgiennes restent sous-représentées en chirurgie cardiaque; 11 % des chirurgiens praticiens en cardiologie au Canada étaient des femmes en 2015, et 6% des chirurgiens praticiens en cardiologie pour adultes aux États-Unis étaient des femmes en 2019. Bien que les femmes restent également minoritaires dans d'autres spécialités chirurgicales, la chirurgie cardiothoracique reste l'une des spécialités où la répartition des sexes est la plus inégale. Pourquoi y a-t-il si peu de chirurgiennes en cardiologie, et pourquoi est-ce important? Des données émergent au sujet des avantages de la diversité pour une variété de secteurs, y compris les soins de santé. Afin d'attirer et de retenir les meilleurs talents, nous devons rendre le milieu de la chirurgie cardiaque plus diversifié, équitable et inclusif. Certaines causes expliquant la persistance de l'écart entre les sexes ont été documentées dans la littérature : il s'agit notamment de l'inégalité de la rémunération et des possibilités d'avancement, de points de vue dépassés sur la dynamique familiale et de l'attention disproportionnée portée aux chirurgiennes, ce qui entraîne des frictions supplémentaires pour les femmes en milieu de travail. La diversité est une force au sein d'une organisation, et les établissements où la diversité des genres est présente sont plus susceptibles d'obtenir de bons résultats que les autres. Des problèmes modifiables perpétuent l'écart entre les sexes, et le mentorat est essentiel pour attirer, perfectionner et retenir les meilleurs éléments dans le domaine de la chirurgie cardiaque. Il est essentiel de faciliter les possibilités de mentorat pour réduire les obstacles et combler le fossé.

Infective Endocarditis Secondary to Injection Drug Use: A Survey of Canadian Cardiac Surgeons.

BACKGROUND: Injection drug use-associated infective endocarditis (IDU-IE) is a growing epidemic. The objective of this survey was to identify the beliefs and practice patterns of Canadian cardiac surgeons regarding surgical management of IDU-IE. METHODS: A 30-question survey was developed by a working group and distributed to all practicing adult cardiac surgeons in Canada. Data were analyzed using descriptive statistics. RESULTS: Of 146 surgeons, 94 completed the survey (64%). Half of surgeons (49%) would be less likely to operate on patients with IE if associated with IDU. In the case of prosthetic valve IE owing to continued IDU, 36% were willing to reoperate once and 14% were willing to reoperate twice or more. Most surgeons required commitments from patients before surgery (73%), and most referred patients to addiction services (81%). Some surgeons would offer a Ross procedure (10%) or homograft (8%) for aortic valve IE, and 47% would consider temporary mechanical circulatory support. Whereas only 17% of surgeons worked at an institution with an endocarditis team, 71% agreed that there was a need for one at each institution. Most surgeons supported the development of IDU-IE-specific guidelines (80%). CONCLUSIONS: Practice patterns and surgical management of IDU-IE vary considerably across Canada. Areas of clinical unmet needs include the development of a formal addiction services referral protocol for patients, the development of an interdisciplinary endocarditis team, as well as the creation of IDU-IE clinical practice guidelines.

Global Health Values of a Multidirectional Near Peer Training Program in Surgery, Pathology, Anatomy, Research Methodology, and Medical Education for Haitian, Rwandan, and Canadian Medical Students.

BACKGROUND: As health care delivery increasingly requires providers to cross international borders, medical students at McGill University, Canada, developed a multidirectional exchange program with Haiti and Rwanda. The program integrates surgery, pathology, anatomy, research methodology, and medical education. OBJECTIVE: The aim of the present study was to explore the global health value of this international training program to improve medical education within the environment of developing countries, such as Haiti and Rwanda, while improving sociocultural learning of Canadian students. METHODS: Students from the University of Kigali, Rwanda and Université Quisqueya, Haiti, participated in a 3-week program at McGill University. The students spanned from the first to sixth year of their respective medical training. The program consisted of anatomy dissections, surgical simulations, clinical pathology shadowing, and interactive sessions in research methodology and medical education. To evaluate the program, a survey was administered to students using a mixed methodology approach. FINDINGS: Common benefits pointed out by the participants included personal and professional growth. The exchange improved career development, sense of responsibility toward one's own community, teaching skills, and sociocultural awareness. The participants all agreed that the anatomy dissections improved their knowledge of anatomy and would make them more comfortable teaching the material when the returned to their university. The clinical simulation activities and shadowing experiences allowed them to integrate the different disciplines. However, the students all felt the research component had too little time devoted to it and that the knowledge presented was beyond their educational level. CONCLUSION: The development of an integrated international program in surgery, pathology, anatomy, research methodology, and medical education provided medical students with an opportunity to learn about differences in health care and medical education between the 3 countries. This exchange demonstrated that a crosscultural near-peer teaching environment can be an effective and sustainable method of medical student-centered development in global health.