Faculty Bibliography

Non-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Here, we conducted an in vivo CRISPR screen that identified HDAC1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients.

INTRODUCTION/BACKGROUND:AR selectivity and enhances detrusor relaxation without compromising voiding function. This review summarises the clinical and real-world evidence supporting the efficacy, safety and patient-reported benefits of vibegron in OAB. METHODS:A comprehensive search of the PubMed database was conducted in December 2024 using the keyword "vibegron". This search yielded 123 entries, which were subsequently screened by title for relevance to the objectives of this narrative review. All relevant articles identified through this process were included. RESULTS:AR selectivity and lack of cytochrome P450 interactions offer advantages in specific patient groups. Ongoing research, including real-world phase IV studies, aims to further define the long-term effectiveness and safety of vibegron in clinical practice. CONCLUSION/CONCLUSIONS:Vibegron represents an important advance in the pharmacologic management of OAB, providing a well-tolerated and effective alternative to existing therapies.

OBJECTIVE:KEYNOTE-775 defined lenvatinib/pembrolizumab as the new standard-of-care for patients with proficient mismatch repair (pMMR) recurrent EC. However, the regimen required dose reductions in 66.5 % of participants and the generalizability of these results was uncertain. We conducted an observational study to determine the prescribing patterns, outcomes and side effects in a real-world setting. METHODS:A national multidisciplinary consortium was utilized to study treatment patterns of patients with advanced/recurrent EC treated with lenvatinib/pembrolizumab from 2019 through 2022. Treatment decisions were based on the physician's recommendation. RESULTS:188 patients across 14 institutions were included. Histologic subtypes were 33 % endometrioid, 41 % serous, 9.6 % mixed, 10.1 % carcinosarcoma, and 2.1 % clear cell. 85.6 % were pMMR and 5.3 % were dMMR. Lenvatinib starting dose was 20 mg in 19.7 %, 18 mg in 14.9 %, 14 mg in 47.3 %, and 10 mg in 18.1 %. Median dose intensity of lenvatinib was 14 mg. Pembrolizumab dosing was 200 mg Q3W in 94.1 %. Grade ≥ 3 adverse events (AE) rates related to lenvatinib were similar across starting doses: 20 mg (13.5 %), 18 mg (17.9 %), 14 mg (7.9 %), 10 mg (17.6 %) (p = 0.31). Response rates in relation to lenvatinib starting dose were 20 mg (27 %), 18 mg (35.7 %), 14 mg (39.3 %), 10 mg (44.1 %) (p = 0.50). In relation to lenvatinib starting dose, PFS, OS and duration of therapy were not statistically different. Response rates (p = 0.24), PFS (p = 0.66) & OS (p = 0.22) were similar in White and Black patients. CONCLUSIONS:In a real-world analysis, the predominant starting dose was 14 mg lenvatinib and 200 mg pembrolizumab. Starting at varying doses does not appear to compromise response rates or survival and no new severe adverse events emerged.

Adolescents and young adults with a cancer diagnosis face unique challenges during treatment and into survivorship related to fertility and family building. This review provides an updated overview of the impact of cancer and its associated treatments, including novel treatments in male and female fertility. An overview of fertility preservation and family building options, including experimental options, is also provided.

A clinical trial of a multi-strain vaginal synbiotic (NCT05659745, registered 12/19/2022 at clinicaltrials.gov) led to an optimal vaginal microbiome dominated by L. crispatus (CST I). The synbiotic led to a significant increase in L. crispatus compared to placebo (p < 0.05), and conversion to CST I was significantly higher with the vaginal synbiotic than with placebo (90 vs 11%; p < 0.002). Mechanistically, the synbiotic reduced Gardnerella vaginalis and Candida, clinically important microbes.

OBJECTIVE:To propose a model of international meetings of minimally invasive gynecologic surgery to decrease the carbon footprint while preserving personal interactions and the financial stability of meetings and of medical societies. WHAT WE KNOW/UNASSIGNED:International medical society meetings create a substantial carbon footprint, with 95% generated by air travel. Meetings may be organized virtually or in-person with distinct benefits and drawbacks of each format. In-person meetings encourage personal interactions, sensitive discussions, and social exchanges which are important for learning and mental well-being. WHAT WE PROPOSE/UNASSIGNED:A collaborative effort of international societies to organize annual scientific meetings at one main venue per continent and regional hubs where participants, can come together in person. Presentations and session moderations will be possible from main venues and distant hubs. Carbon footprint from air travel would decrease, while the scientific contents would be improved by the collaboration between the societies. We theorize that local hubs, easier and less expensive to reach, will increase the number of participants who face economic, geopolitical, ecological and familial barriers to travel. Regional and time differences would allow each society to preserve the specific characteristics and sessions of its conference. The preservation of one main venue on each continent, will enable a gradual transition, allowing medical societies and corporate sponsors to take advantage of the enlarged audience, while measuring the desired outcomes and being able to adjust their management. Hubs participants will be actively involved reducing the burden of travel, transitioning to a preference of joining the main venue only every second or third year. CONCLUSION/CONCLUSIONS:An economically sustainable approach towards low carbon footprint, scientifically improved and more accessible meetings needs to be considered.

OBJECTIVE:To evaluate the performance of an artificial intelligence (AI)-based software to identify second-trimester fetal ultrasound examinations suspicious for congenital heart defects. METHODS:The software analyzes all grayscale two-dimensional ultrasound cine clips of an examination to evaluate eight morphologic findings associated with severe congenital heart defects. A data set of 877 examinations was retrospectively collected from 11 centers. The presence of suspicious findings was determined by a panel of expert pediatric cardiologists, who determined that 311 examinations had at least one of the eight suspicious findings. The AI software processed each examination, labeling each finding as present, absent, or inconclusive. RESULTS:Of the 280 examinations with known severe congenital heart defects, 278 (sensitivity 0.993, 95% CI, 0.974-0.998) had at least one of the eight suspicious findings present as determined by the fetal cardiologists, highlighting the relevance of these eight findings. We then evaluated the performance of the AI software, which identified at least one finding as present in 271 examinations, that all eight findings were absent in five examinations, and was inconclusive in four of the 280 examinations with severe congenital heart defects, yielding a sensitivity of 0.968 (95% CI, 0.940-0.983) for severe congenital heart defects. When comparing the AI to the determination of findings by fetal cardiologists, the detection of any finding by the AI had a sensitivity of 0.987 (95% CI, 0.967-0.995) and a specificity of 0.977 (95% CI, 0.961-0.986) after exclusion of inconclusive examinations. The AI rendered a decision for any finding (either present or absent) in 98.7% of examinations. CONCLUSION/CONCLUSIONS:The AI-based software demonstrated high accuracy in identification of suspicious findings associated with severe congenital heart defects, yielding a high sensitivity for detecting severe congenital heart defects. These results show that AI has potential to improve antenatal congenital heart defect detection.

OBJECTIVE:Trastuzumab deruxtecan, a HER2 antibody drug conjugate (ADC), is active in HER2 expressing gynecologic cancers. This study aims to determine the proportion of endometrial cancers (EC) that are HER2 expressing and eligible for these ADCs. METHODS:This was a retrospective, single-institution study of patients who underwent surgery for EC over 18 months. Clinical HER2 testing consisted of HER2 IHC and reflex FISH for select 2+ IHC. The outcome of interest was the proportion of patients with HER2 expressing tumors by IHC (1+, 2+, 3+). Chi-square tests of independence were performed to examine relationships between categorical variables and HER2 expression. RESULTS:(2, N = 217) = 6.7, p = 0.035) than HER2 0 tumors. CONCLUSION/CONCLUSIONS:In this retrospective study, 60 % of newly diagnosed EC patients were HER2 expressing by IHC. One-third of unselected EC were HER2 2+ or 3+ and would potentially qualify for current NCCN listed HER2 directed ADCs. HER2 expression was distributed across all histologic and molecular EC subtype suggesting that all endometrial tumors should undergo HER2 IHC testing.

PURPOSE/OBJECTIVE:Tumor next generation sequencing (NGS) may identify potential germline DNA mutations associated with cancer susceptibility. We describe the frequency of tumor NGS results in patients meeting ESMO 2019 recommendations for germline genetic testing (GT) and reasons for not undergoing germline GT. METHODS:A retrospective study (Sept. 2019-Feb. 2022) in a large, urban healthcare system identified patients meeting ESMO guidelines for potentially actionable germline mutations on NGS. RESULTS:Of 3470 patients who underwent tumor NGS, 326 (9.4 %) had at least one potential actionable germline mutation. Of eligible patients, 189 (58.0 %) did not receive germline GT. Reasons for not undergoing GT include: 127 (67.2 %), not referred for GT; 30 (15.9 %), referred but did not attend genetic counseling; 32 (16.9 %), declined, died before GT, had insufficient samples, lacked insurance or lost to follow-up. Among 127 patients not referred for germline GT (39.0 % of the total eligible cohort), the most common cancer types were lung (33.0 %), colorectal (9.4 %), and cancer of unknown primary (9.4 %). Overall, 64 (50.4 %) patients not referred for germline GT had mutations in BRCA1/2 and/or Lynch syndrome genes. Of 137 patients who underwent germline GT, 86 (62.8 %) had positive GT. CONCLUSIONS:In this cohort, 60 % of the eligible population by ESMO criteria did not receive GT, most commonly due to lack of referral (over 2/3 of patients). Further, 50 % of patients not referred for GT had mutations in commonly known genes (i.e., BRCA1/2). Education on germline eligibility and reflex clinical protocols are needed to ensure patients receive germline GT.

OBJECTIVE:Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. This case study aims to assess current PPH at our study site hospital, identify strategies to enhance management based on audit findings, and pilot test the feasibility and acceptability of these strategies. METHODS:A criteria-based audit (CBA) was conducted at La Maternidad Renee Klang Viuda Guzman Hospital in Santiago, Dominican Republic from November 2021 to September 2022. The audit assessed current practice through surveys of 59 healthcare workers and a retrospective review of 10 PPH cases, using eight evidence-based criteria. Audit findings informed the development of a PPH toolkit, protocol, and simulation-based training program (SBT). The toolkit's impact was evaluated through surveys, and SBT effectiveness was assess through post-training feedback from participants. RESULTS:The baseline audit revealed 25% compliance with evidence-based criteria. Key gaps included maternal risk assessment, provider training, and protocol use. Targeted strategies, including a PPH toolkit, protocol and SBT, were implemented. Of the 13 toolkit users, 92% felt it improved timely management. Post-SBT surveys showed that participants rated the training highly, with significant improvements in communication, teamwork, and self-reported competence in PPH management. CONCLUSION/CONCLUSIONS:CBAs are effective in identifying care barriers in middle-income settings. The PPH toolkit and SBT were well received and improved both technical and non-technical skills, offering a scalable model for improving PPH management in low-resource settings.