TP53 mutations and the association with platinum resistance in high grade serous ovarian carcinoma.

OBJECTIVES: Alterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance. METHODS: Next generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed. RESULTS: 209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance. CONCLUSIONS: TP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.

An online alternative: a qualitative study of virtual abortion values clarification workshops.

BACKGROUND: Following the U.S. Supreme Court Dobbs decision, access to abortion education is increasingly regionally dependent. Participation in values clarification workshops on abortion can improve abortion knowledge and reduce stigma. Traditionally, values clarification workshops occur in person, yet medical education increasingly utilizes online learning. We sought to understand how a virtual platform impacted medical students and Obstetrics and Gynecology (ObGyn) residents' experience with a values clarification workshop on abortion. METHODS: We conducted values clarification workshops over Zoom with medical students and ObGyn residents at four midwestern teaching hospitals from January 2021-December 2021 during the COVID-19 pandemic. We held semi-structured interviews with participants and facilitators to learn about how the virtual format impacted their experience with the workshop. Four researchers analyzed transcripts using an inductive approach to generate codes then themes. RESULTS: We interviewed 24 medical students, 13 ObGyn residents, and five workshop facilitators. Participants and facilitators found the virtual platform to have both unique advantages and disadvantages. Four central themes were identified: 1) Screen as a barrier: participants noted obstacles to conversation and intimacy. 2) Emotional safety: participants felt comfortable discussing sensitive topics. 3) Ease of access: participants could access virtual workshops regardless of location. 4) Technology-specific features: Zoom features streamlined aspects of the workshop and allowed for anonymous contributions to discussion. CONCLUSIONS: Our findings suggest that a virtual platform can be a convenient and effective way to deliver values clarification workshops on abortion, and this technology could be leveraged to expand access to this training in areas without trained facilitators.

"We had to put ourselves in their shoes": Experiences of Medical Students and ObGyn Residents with a Values Clarification Workshop on Abortion.

Purpose: Values clarification workshops on abortion have been shown to increase support for abortion among healthcare workers. However, few studies have examined the impact of values clarification workshops on abortion among medical trainees. This study aimed to understand medical student and obstetrics and gynecology (ObGyn) residents' experiences with a virtual values clarification workshop on abortion. Methods: Clerkship year medical students and ObGyn residents at four midwestern teaching hospitals were invited to be interviewed about their experiences in a virtual values clarification workshop on abortion from January 2021 through December 2021. A single interviewer conducted interviews via Zoom using a standardized interview guide. Participants were asked to provide feedback and discuss their experiences in the workshop. Four qualitatively trained evaluators coded the interview transcripts in NVivo, using an inductive approach to establish consensus codes then themes. Results: This study interviewed 37 trainees, including 24 medical students and 13 ObGyn residents, as well as five facilitators, between November 2021 and February 2022. Three themes emerged in both trainee groups. First, participants found the workshops helped trainees clarify and understand their own views on abortion through thought exploration, peer validation, and reflection on their views' potential societal impacts. Second, through the workshop, participants reflected on others' opinions on abortion and better understood the spectrum of beliefs their peers held. Finally, participants found the workshops helped them explore and develop their professional identity as physicians-in-training, through practicing communication skills and building trust and mutual respect among peers. Conclusions: Medical trainees found values clarification workshops on abortion to be valuable, helping them establish their own beliefs about abortion, contextualize these beliefs among their peers', and practice professionalism. These findings indicate that values clarification workshops can play a key role in helping medical trainees discuss abortion and prepare for their professional future.

Pre-Treatment Left Ventricular Ejection Fraction Assessment and Long-Term Cardiovascular Outcomes in Adolescent and Young Adult Lymphoma Survivors.

Purpose: Anthracyclines can cause long-term cardiovascular (CV) morbidity, especially in long-term Adolescent and Young Adult (AYA) lymphoma survivors. Pre-treatment left ventricular ejection fraction (LVEF) evaluation is recommended, although its utility in AYA is not established. We sought to determine the pre-treatment LVEF assessment practices in AYA lymphoma survivors treated with anthracyclines and factors associated with long-term cardiotoxicity. Methods: Through an electronic health records review, we retrospectively identified AYA lymphoma survivors with ≥5 years of follow-up postanthracycline treatment. Pre-treatment and follow-up data were abstracted. CV health conditions were defined as risk factors for CV disease and confirmed CV diagnoses. Survivors who had new CV health conditions at follow-up were compared to those who were not using descriptive statistics and logistic regression. Results: One hundred fifteen AYA lymphoma survivors met the study criteria. Pre-treatment LVEF assessment did not affect chemotherapy decisions. Survivors with pre-treatment CV evaluation had mean follow-up since diagnosis of 8 ± 3.3 years, while survivors without it had 10.3 ± 4.2 years, p < 0.05. Survivors with pre-treatment LVEF assessment received lower cumulative anthracycline dose (240.4 mg/m2 vs. 280.1 mg/m2, p < 0.05) and fewer cycles of chemotherapy (4.8 ± 1.5 vs. 5.6 ± 1.2, p < 0.05). Body mass index (BMI) category at diagnosis and follow-up, in addition to age were associated with development of new CV health conditions, pre-treatment LVEF evaluation was not. Conclusion: Pre-treatment LVEF assessment for AYA lymphoma survivors does not impact oncologic treatment decisions or development of CV health conditions. It may be more valuable to assess and modify CV risk factors such as BMI for CV disease prevention.

Pimavanserin for Psychosis in Parkinson's Disease-Related Disorders: A Retrospective Chart Review.

BACKGROUND: Psychosis is common in Parkinson's disease-related disorders and is associated with significant morbidity. Pimavanserin is a newly approved treatment for Parkinson's disease psychosis, but real-world experience with pimavanserin has been limited by small sample sizes and limited assessment of longitudinal outcomes. OBJECTIVE: The aim was to summarize the clinical experience with pimavanserin in a large cohort of patients with Parkinson's disease-related psychosis. METHODS: We conducted a retrospective chart review of patients who were prescribed pimavanserin at Vanderbilt University Medical Center in the southeast United States between May 2016 and July 2018. We used Chi-squared analyses to compare efficacy and tolerability of pimavanserin, considering patient diagnosis, presence of dementia or delusions, use of deep brain stimulation, and prior antipsychotic failure. Additionally, we compared the clinical characteristics of patients who started treatment and those who did not, to evaluate safety outcomes. RESULTS: We identified 107 patients prescribed pimavanserin, and 91 began treatment. Clinical improvement in psychosis was documented in 76% of patients (69/91) and did not differ based on diagnosis, presence of dementia, delusions, use of deep brain stimulation, or prior antipsychotic failure. Adverse effects were reported in 20 patients (22%), the most common of which was worsening gait instability (5/91, 5%). Side effects led to cessation of therapy in 11 of the 91 patients (12%). At current follow-up, 50 (65%) of 77 living patients remain on treatment, with a mean treatment duration of 14.6 months. Although most of these patients are on pimavanserin monotherapy (33/50, 66%), 17 patients (34%) are on a dual-antipsychotic regimen. The living patients no longer on treatment stopped pimavanserin primarily because of a lack of perceived benefit (11/77, 14%), side effects (9/77, 12%), or both (1/77, 1%), though six patients (8%) stopped for reasons unrelated to medication effects, including the desire to reduce overall medication burden and negative media reporting on pimavanserin. CONCLUSIONS: Study results emphasize long-term efficacy and tolerability of pimavanserin for psychosis in Parkinson's disease-related disorders, including patients with dementia, delusions, deep brain stimulation use, or prior antipsychotic failure.

Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma.

Glaucoma, a common cause of blindness, is currently treated by intraocular pressure (IOP)-lowering interventions. However, this approach is insufficient to completely prevent vision loss. Here, we evaluate an IOP-independent gene therapy strategy using a modified erythropoietin, EPO-R76E, which has reduced erythropoietic function. We used two models of glaucoma, the murine microbead occlusion model and the DBA/2J mouse. Systemic recombinant adeno-associated virus-mediated gene delivery of EpoR76E (rAAV.EpoR76E) was performed concurrent with elevation of IOP. Axon structure and active anterograde transport were preserved in both models. Vision, as determined by the flash visual evoked potential, was preserved in the DBA/2J. These results show that systemic EpoR76E gene therapy protects retinal ganglion cells from glaucomatous degeneration in two different models. This suggests that EPO targets a component of the neurodegenerative pathway that is common to both models. The efficacy of rAAV.EpoR76E delivered at onset of IOP elevation supports clinical relevance of this treatment.