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Background: There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care., Primary Objective: To compare the progression free survival of the combination of avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer., Study Hypothesis: Combination treatment with avutometinib-defactinib will significantly improve progression free survival compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer., Trial Design: GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator's choice of treatment arm may cross over to the avutometinib-defactinib arm., Major Inclusion/exclusion Criteria: Patients must have recurrent low grade serous ovarian cancer ( KRAS mutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor., Primary Endpoint: Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review., Sample Size: Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator's choice of treatment arm (n~135)., Estimated Dates for Completing Accrual and Presenting Results: The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031., Trial Registration: ClinicalTrials.gov NCT06072781., Competing Interests: Competing interests: YCL discloses institutional research grants from BeiGene and honoraria from AstraZeneca. CAA discloses institutional trial funding from Abbvie, Artios Pharma, AstraZeneca, Clovis, and Genentech/Roche. PT discloses advisory board participation with Iovance, AstraZeneca, Clovis, GSK, Seagen, Agenus, Relacorilant, Immunogen, Mersana, Novocurfe, Zentalis, Merck, and Caris. RLC discloses grants from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech, Karyopharm, royalties from Up To Date, and consulting fees or honoraria from Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Karyopharm, Roche/Genentech, Novocure, Merck, and Abbvie. BJM discloses consulting fees or honoraria from Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, CLovis, Eisai, Elevar, EMD Merck, Genmab, GOG Foundation, Gradalis, Heng Rui, Immunogen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, GSK, Sorrento, USO, VBL, Verastem, and Zentalis. DG discloses royalties from UpToDate and Elsevier, consulting fees from Verastem, honoraria from Johns Hopkins, and stock in BMS, J&J, Proctor, and Gamble. RG discloses consulting fees from GSK, AstraZeneca, Myriad, Natera, GOG Foundation, honoraria from PRIME, IDEOlogy, Curio, and funding support by the NIH/NCI cancer center support grant P30 CA 008748. KNM discloses institution research funding from PTC therapeutics, Lilly, Clovis, Genentech, GSK, Verastem, royalties from UpToDate, and consulting fees or honoraria from AstraZeneca, Aravive, Aadi, Blueprint, Clovis, Caris, Duality, Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Iovance, Janssen, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, Onconova, VBL, Verastem, Zentalia, PRIME, RTP, Medscape, Great Debates, and Updates. PH discloses grants or honoraria from AstraZeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, Novartis, Amgen, Mersana, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Daiichi Sankyo, and Karyopharm. MRM discloses consulting fees from GSK, AstraZeneca, Immunogen, Merck, Merck KGA, and stock and leadership position with Karyopharm. AO discloses consulting fees or honoraria from Agenus, AstraZeneca, Clovis, Corcept, Deciphera, Daiichi Sankyo, Debiopharm, Eisai, Exelixis, Roche, Genmab, GSK, Immunogen, Itheos, MSD, Mersana, Myriad, Novocure, OncoXerna, PharmaMar, Regeneron, Shattuck Labs, Seagen, Sutro, TORL, Zentalis, and Zymeworks. DMO discloses institutional research funds from Abbvie, Advaxis, Agenus, Alkermes, Aravive, Arcus, AstraZeneca, BeiGene, Boston Biomedical, BMS, Clovis, Deciphera, Eisai, EMD Serono, Exelixis, Genentech, Genmab, GSK, Roche, Immunogen, Incyte, Iovance, Karyopharm, Leap, Merck, Mersana, NCI, Novartis, Novocure, OncoC4, OncoQuest, Pfizer, Precision Therapeutics, Prelude, Regeneron, RTOG, Seagen, Sutro, and SWOG, consulting fees from Abbvie, Adaptimmune, Agneus, Arquer, Arcus, AstraZeneca, Atossa, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis, Corcept, Duality Bio, Eisai, Elevar, Exelixis, Genetech, Genelux, GSK, Roche, Immunogen, Imvax, Intervenn, InxMed, Iovance, Janssen, Jazz, Laekna, Leap, Luzsana Biotechnology, Merck, Mersana Myriad, Novartis, Novocure, OncoC4, Onconova, Regeneron, RepImmune, RPharm, Roche, SeaGen, Sorrento, Sutro, Tarveda, Toray, Trillium, Umoja, Verastem, VBL, Vincerx Pharma, Xencor, and Zentalis. AMO discloses institutional funding from AstraZeneca, and Amgen. SB discloses consulting fees or honoraria from AstraZeneca, Epsilogen, GSK, Immunogen, ITM Oncologics, MSK, Mersana, Myriad, Novartis, Oncxerna, Seagen, Shattuck, Regeneron, Verastem, Abbvie, Pfizer, Takeda, and Novocure. EVN discloses consulting fees or honoraria from AstraZeneca, Oncoinvent, Regeneron, GSK, and Merck. NC discloses consulting fees or honoraria from Novocure, AstraZeneca, Clovis, Eisai, GSK, Immunogen, Mersana, MSD, Pfizer, Roche/Genentech, Pieris, and Novartis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Background: Social needs screening can help modify care delivery to meet patient needs and address non-medical barriers to optimal health. However, there is a need to understand how factors that exist at multiple levels of the healthcare ecosystem influence the collection of these data in primary care settings., Methods: We conducted 20 semi-structured interviews involving healthcare providers and primary care clinic staff who represented 16 primary care practices. Interviews focused on barriers and facilitators to awareness of and assistance for patients' social needs in primary care settings in Maryland. The interviews were coded to abstract themes highlighting barriers and facilitators to conducting social needs screening. The themes were organized through an inductive approach using the socio-ecological model delineating individual-, clinic-, and system-level barriers and facilitators to identifying and addressing patients' social needs., Results: We identified several individual barriers to awareness, including patient stigma about verbalizing social needs, provider frustration at eliciting needs they were unable to address, and provider unfamiliarity with community-based resources to address social needs. Clinic-level barriers to awareness included limited appointment times and connecting patients to appropriate community-based organizations. System-level barriers to awareness included navigating documentation challenges on the electronic health record., Conclusions: Overcoming barriers to effective screening for social needs in primary care requires not only practice- and provider-level process change but also an alignment of community resources and advocacy of policies to redistribute community assets to address social needs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Kazi, Starling, Milicia, Buckley, Grisham, Gruber, Miller and Arem.)

Background: Health outcomes are strongly impacted by social determinants of health, including social risk factors and patient demographics, due to structural inequities and discrimination. Primary care is viewed as a potential medical setting to assess and address individual health-related social needs and to collect detailed patient demographics to assess and advance health equity, but limited literature evaluates such processes., Methods: We conducted an analysis of cross-sectional survey data collected from n = 507 Maryland Primary Care Program (MDPCP) practices through Care Transformation Requirements (CTR) reporting in 2022. Descriptive statistics were used to summarize practice responses on social needs screening and demographic data collection. A stepwise regression analysis was conducted to determine factors predicting screening of all vs. a targeted subset of beneficiaries for unmet social needs., Results: Almost all practices (99%) reported conducting some form of social needs screening and demographic data collection. Practices reported variation in what screening tools or demographic questions were employed, frequency of screening, and how information was used. More than 75% of practices reported prioritizing transportation, food insecurity, housing instability, financial resource strain, and social isolation., Conclusions: Within the MDPCP program there was widespread implementation of social needs screenings and demographic data collection. However, there was room for additional supports in addressing some challenging social needs and increasing detailed demographics. Further research is needed to understand any adjustments to clinical care in response to identified social needs or application of data for uses such as assessing progress towards health equity and the subsequent impact on clinical care and health outcomes., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Objective: HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment., Methods: We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed., Results: This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated., Conclusions: We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy., Clinicaltrials: govidentifier: NCT04513665., Competing Interests: Declaration of Competing Interest V Makker reports meeting/travel support by Eisai and Merck; participation on Data Safety Monitoring or Advisory Board of Duality, Merck, Karyopharm, Exelexis, Eisai, Karyopharm, BMS, Clovis, Faeth Immunocore, Morphosys, AstraZeneca, Novartis, GSK, Bayer (all unpaid); and study support to the institution by Merck, Eisai, AstraZeneca, Faeth, Karyopharm, Zymeworks, Duality, Clovis, Bayer and Takeda. CF Friedman reports institutional research support from Seagen, Merck, BMS, AstraZeneca, Mersana, and Hotspot Therapeutics; consulting fees from BMS, Seagen, and Aadi Biosciences; honoraria for lectures from Onclive; meeting/travel support by PUMA; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). A Iasonos reports consulting fees from Mylan. MM Rubinstein reports research funding from Merk, Zentalis, and AstraZeneca. C Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. RN Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. C Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). The other authors do not have potential conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences., Competing Interests: Declaration of interests A.A.J., R.G., D.Z., R.T.H., B.C.L., S.L., S.N.W., E.M., M.J.W., S.G., C.A., and K.L. are clinical investigators whose institutions have received clinical trial support from Imunon. This team effort on minimal residual disease in ovarian cancer is supported by funding from Break Through Cancer. N.M.B. and T.P. receive support from Break Through Cancer through their Break Through Cancer Scientist Program., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Maryland Primary Care Program is a statewide advanced primary care program that works directly with practices to transform healthcare delivery by managing chronic disease, preventing unnecessary hospital utilization, and integrating with the public health system. The Maryland Primary Care Program has demonstrated how linking the public health system to primary care practices, paired with strategic financial and resource investments in primary care, can enable the delivery of high-value care and reduce acute hospital utilization. Such a system is especially prudent when responding to crises. Throughout the COVID-19 pandemic, the Maryland Primary Care Program was able to capitalize on existing infrastructure to quickly engage primary care in a robust pandemic response. Successes of this relationship included early and consistent communication channels, as well as coordinated resource distribution. In particular, this partnership allowed primary care providers, the most trusted source of healthcare in patients' lives, to directly provide patients with health information and vaccines. Now comprising more than 500 practices, this vaccine program uses data-driven reports to facilitate intentional vaccine outreach. The program has enabled a more equitable vaccine distribution system, resulting in over 400,000 vaccines administered in Maryland counties. The effectiveness of Maryland's integrated response indicates that partnerships between public health and primary care will result in an effective response in future times of crisis.

Importance: Advanced primary care is a team-based approach to providing higher-quality primary care. The association of advanced primary care and COVID-19 outcomes is unknown., Objective: To evaluate the association of advanced primary care with COVID-19 outcomes, including vaccination, case, hospitalization, and death rates during the first 2 years of the COVID-19 pandemic., Design, Setting, and Participants: This retrospective cohort study used Medicare claims data from January 1, 2020, through January 31, 2022, and Maryland state vaccination data. All Part A and B Medicare claims for Maryland Medicare beneficiaries were included. The study population was divided into beneficiaries attributed to Maryland Primary Care Program (MDPCP) practices and a matched cohort of beneficiaries not attributed to MDPCP practices but who met the eligibility criteria for study participation from January 1, 2020, through December 31, 2021. Eligibility criteria for both groups included fee-for-service Medicare beneficiaries who were eligible for attribution to the MDPCP. A forced-match design was used to match both groups in the study population by age category, sex, race and ethnicity, Medicare-Medicaid dual eligibility status, COVID-19 Vulnerability Index score, Maryland county of residence, and primary care practice participation., Exposures: Primary care practice participation in the MDPCP., Main Outcomes and Measures: Primary outcome variables included rate of vaccination, monoclonal antibody infusion uptake, and telehealth claims. Secondary outcomes included rates of COVID-19 diagnosis, COVID-19 inpatient claims, COVID-19 emergency department claims, COVID-19 deaths, and median COVID-19 inpatient admission length of stay. Claims measures were assessed from January 1, 2020, through October 31, 2021. Vaccination measures were assessed from January 1, 2020, through March 31, 2022., Results: After matching, a total of 208 146 beneficiaries in the MDPCP group and 37 203 beneficiaries in the non-MDPCP group were included in this study, comprising 60.10% women and 39.90% men with a median age of 76 (IQR, 71-82) years. Most participants (78.40% and 78.38%, respectively) were White. There were no significant demographic nor risk measure baseline differences between the 2 groups. The MDPCP beneficiaries had more favorable primary COVID-related outcomes than non-MDPCP beneficiaries: 84.47% of MDPCP beneficiaries were fully vaccinated, compared with 77.93% of nonparticipating beneficiaries (P < .001). COVID-19-positive beneficiaries in MDPCP also received monoclonal antibody treatment more often (8.45% vs 6.11%; P < .001) and received more care via telehealth (62.95% vs 54.53%; P < .001) compared with nonparticipating counterparts. In terms of secondary outcomes, beneficiaries in the MDPCP had lower rates of COVID-19 cases (6.55% vs 7.09%; P < .001), lower rates of COVID-19 inpatient admissions (1.81% vs 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs 0.77%; P < .001) compared with nonparticipating beneficiaries., Conclusions and Relevance: These findings suggest that participation in the MDPCP was associated with lower COVID-19 case, hospitalization, and death rates, and advanced primary care and COVID-19 response strategies within the MDPCP were associated with improved COVID-19 outcomes for attributed beneficiaries.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Objective: Although trials of neoadjuvant chemotherapy in ovarian cancer use 3 neoadjuvant cycles, real-world practice varies. We sought to evaluate the influence of increasing pre-operative cycles on survival, accounting for surgical outcomes., Methods: We identified 199 women with newly diagnosed ovarian cancer recommended for neoadjuvant chemotherapy who underwent interval debulking surgery from July 2015 to December 2018. Non-parametric tests were used to compare clinical characteristics by neoadjuvant cycles. The Kaplan-Meier method was used to estimate differences in progression-free and overall survival. The log-rank test was used to assess the relationship of covariates to outcome., Results: The median number of neoadjuvant cycles was 4 (range 3-8), with 56 (28%) women receiving ≥5 cycles. Compared with those receiving 3 or 4, women with ≥5 neoadjuvant cycles received fewer or no post-operative cycles (p<0.001) but had no other differences in clinical factors (p>0.05). Complete gross resection rates were similar among those receiving 3, 4, and ≥5 neoadjuvant cycles (68.5%, 70%, and 71.4%, respectively, p=0.96). There were no significant differences in progression-free or overall survival when comparing 3 versus 4 neoadjuvant cycles. However, more cycles (≥5 vs 4) were associated with worse progression-free survival, even after adjustment for BRCA status and complete gross resection (HR 2.20, 95% CI 1.45 to 3.33, p<0.001), and worse overall survival, even after adjustment for histology, response on imaging, and complete gross resection rates (HR 2.78, 95% CI 1.37 to 5.63, p=0.016). The most common reason for receiving ≥5 cycles was extent of disease requiring more neoadjuvant chemotherapy., Conclusions: Despite maximal cytoreduction, patients receiving ≥ 5 neoadjuvant cycles have a poorer prognosis than those receiving 3-4 cycles. Future studies should focus on reducing surgical morbidity and optimizing novel therapies in this high-risk group., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Homologous DNA repair-deficient (HRD) ovarian cancers (OCs), including those with BRCA1/2 mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair-proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between BRCA1/2 mutations, HRD, and other genomic parameters and response to ICIs and survival in OC., Methods: This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. BRCA1/2 mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of BRCA1/2 status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models., Results: Of the 143 women treated with ICIs, 134 had known BRCA1/2 mutation status. Deleterious germline or somatic BRCA1/2 mutations were present in 31 women (24%). There was no association between presence of BRCA1/2 mutations and response ( P = .796) or survival. Genomic analysis in 73 women found no association between TMB ( P = .344) or HRD ( P = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS ( P = .014) and OS ( P = .01)., Conclusion: TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Alexia IasonosConsulting or Advisory Role: Mylan, Brightpath, IntelligenciaMargaret CallahanEmployment: Bristol Myers Squibb (I), Celgene (I), Kleo Pharmaceuticals (I) Consulting or Advisory Role: AstraZeneca, Moderna Therapeutics, Merck, Immunocore Research Funding: Bristol Myers Squibb (Inst) Other Relationship: Clinical Care Options, Potomac Center for Medical EducationIgnacio Vazquez-GarciaStock and Other Ownership Interests: CRISPR Therapeutics, Editas MedicineAhmet ZehirHonoraria: IlluminaRobert A. BurgerEmployment: Genentech Stock and Other Ownership Interests: Genentech Consulting or Advisory Role: AstraZeneca, Tesaro, Merck, Genentech, Morphotek, Myriad Genetics Research Funding: Incyte (Inst), Astra Zeneca (Inst), and Genzyme (Inst) Travel, Accommodations, Expenses: Tesaro, GenentechDaniel J. Powell JrStock and Other Ownership Interests: Atara Biotherapeutics, InsTIL Bio Consulting or Advisory Role: Neon Therapeutics, Iovance Biotherapeutics, Tmunity Therapeutics, InsTIL Bio, Bellicum Pharmaceuticals Research Funding: Eli Lilly, Tmunity Therapeutics, Incyte, Monojul, AstraZeneca/MedImmune Patents, Royalties, Other Intellectual Property: I hold patents in the field of chimeric antigen receptor (CAR) T-cell therapy in oncology and have received royalties related to their licensing to Novartis; I hold patents in the field of CAR T cell therapy in Oncology and have received royalties related to their licensing to Tmunity Travel, Accommodations, Expenses: Iovance BiotherapeuticsClaire FriedmanConsulting or Advisory Role: AstraZeneca/MedImmune Research Funding: Bristol Myers Squibb (Inst), Arcus Biosciences (Inst), Genentech (Inst), Merck (Inst) Other Relationship: Guidepoint Global Uncompensated Relationships: Genentech, Merck Open Payments Link: https://openpaymentsdata.cms.gov/physician/477023/summaryKaren CadooHonoraria: OncLive Consulting or Advisory Role: GSK Tesaro Research Funding: AstraZeneca (Inst), Syndax (Inst) Travel, Accommodations, Expenses: AstraZenecaRachel GrishamConsulting or Advisory Role: Mateon Therapeutics, Clovis Oncology, Regeneron Research Funding: Context Therapeutics (Inst) Travel, Accommodations, Expenses: EMD Serono Other Relationship: Prime Oncology, MCM Education, OncLiveJason A. KonnerConsulting or Advisory Role: Immunogen, AstraZeneca, Tesaro, AbbVie Research Funding: Genentech Travel, Accommodations, Expenses: AstraZenecaRoisin E. O'CearbhaillConsulting or Advisory Role: Tesaro, GlaxoSmithKline Research Funding: Juno Therapeutics (Inst), Sellas Life Sciences (Inst), Ludwig Institute for Cancer Research (Inst), Stem CentRx (Inst), TapImmune (Inst), TCR2 Therapeutics (Inst), Regeneron (Inst), Genmab (Inst)Carol AghajanianConsulting or Advisory Role: Tesaro, Mersana, Eisai, Roche Research Funding: Genentech (Inst), AbbVie (Inst), Clovis Oncology (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), AstraZeneca (Inst)Jorge S. Reis-FilhoConsulting or Advisory Role: Genentech, Invicro, Ventana Medical Systems, Volition RX, Paige AI, Goldman Sachs, Novartis, Repare TherapeuticsBritta WeigeltConsulting or Advisory Role: Genentech (I), Invicro (I), Ventana Medical Systems (I), Volition RX (I), Page AI (I), Goldman Sachs (I), Repare Therapeutics (I)Dmitriy ZamarinConsulting or Advisory Role: Merck, Synlogic, Western Oncolytics, Tesaro, Agenus, Trieza Therapeutics, ACM Biolabs Research Funding: Genentech (Inst) Patents, Royalties, Other Intellectual Property: I hold a patent regarding the use of recombinant Newcastle disease virus (NDV) for cancer therapy (Inst) No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Combretastatin A4-phosphate (CA4P) is a vascular-disrupting agent (VDA) in clinical development for the treatment of ovarian and other cancers. In contrast to antiangiogenic agents, such as bevacizumab, which suppress the development of new tumor vasculature, VDAs target established tumor vasculature. These differing but complementary mechanisms of action are currently being explored in clinical trials combining CA4P and bevacizumab. Clinical experience to date has highlighted an important need to better understand the cardiovascular adverse events of CA4P, both alone and in combination with antiangiogenic agents, which can also be associated with cardiovascular adverse events. An acute but transient increase in blood pressure is often the most clinically relevant toxicity associated with CA4P. Increases in CA4P-related blood pressure typically occur 0.5 to 1 h after initiation of the 10-min infusion, peak by 2 h, and return to baseline 3 to 4 h after the infusion. Post-infusion increases in blood pressure are likely to recur in subsequent treatment cycles; however, the severity does not appear to increase with successive cycles. Other cardiovascular adverse events, such as transient, predominantly grade 1-2 tachycardia, bradycardia, QTc prolongation, and in rare cases myocardial ischemia, have also been observed with CA4P but at markedly lower frequencies than hypertension. The clinical trial experience with CA4P suggests that cardiovascular assessment of patients prior to CA4P treatment and careful management of blood pressure during CA4P treatment can largely mitigate the risk of cardiovascular adverse events. Accordingly, we have developed a blood pressure management algorithm for use in the ongoing phase II/III FOCUS study of the triple combination of CA4P with physician's choice chemotherapy and bevacizumab., Competing Interests: The protocols of studies described in this manuscript were approved by institutional review boards and all patients provided written informed consent to participate in these studies.Not applicableRG receives grant funding from Cycle for Survival and the Ovarian Cancer Research Fund Alliance. She has also served as a consultant for Mateon Therapeutics. BK has served as a consultant for Mateon Therapeutics. KT has served on speakers’ bureaus for Astra Zeneca, Clovis, Merck, Roche, and Vermillion. He has served on advisory boards for Caris, Clovis, Genentech, and Mateon Therapeutics. He serves on the scientific steering committee for Mateon Therapeutics. DC is an employee of Mateon Therapeutics. JW has served as a consultant for Mateon Therapeutics.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The tip link protein protocadherin 15 (PCDH15) is a central component of the mechanotransduction complex in auditory and vestibular hair cells. PCDH15 is hypothesized to relay external forces to the mechanically gated channel located near its cytoplasmic C terminus. How PCDH15 is coupled to the transduction machinery is not clear. Using a membrane-based two-hybrid screen to identify proteins that bind to PCDH15, we detected an interaction between zebrafish Pcdh15a and an N-terminal fragment of transmembrane channel-like 2a (Tmc2a). Tmc2a is an ortholog of mammalian TMC2, which along with TMC1 has been implicated in mechanotransduction in mammalian hair cells. Using the above-mentioned two-hybrid assay, we found that zebrafish Tmc1 and Tmc2a can interact with the CD1 or CD3 cytoplasmic domain isoforms of Pcdh15a, and this interaction depends on the common region shared between the two Pcdh15 isoforms. Moreover, an interaction between mouse PCDH15-CD3 and TMC1 or TMC2 was observed in both yeast two-hybrid assays and coimmunoprecipitation experiments. To determine whether the Pcdh15-Tmc interaction is relevant to mechanotransduction in vivo, we overexpressed N-terminal fragments of Tmc2a in zebrafish hair cells. Overexpression of the Tmc2a N terminus results in mislocalization of Pcdh15a within hair bundles, together with a significant decrease in mechanosensitive responses, suggesting that a Pcdh15a-Tmc complex is critical for mechanotransduction. Together, these results identify an evolutionarily conserved association between the fish and mouse orthologs of PCDH15 and TMC1 and TMC2, supporting the notion that TMCs are key components of the transduction complex in hair cells.

The hair cells of the inner ear are polarized epithelial cells with a specialized structure at the apical surface, the mechanosensitive hair bundle. Mechanotransduction occurs within the hair bundle, whereas synaptic transmission takes place at the basolateral membrane. The molecular basis of the development and maintenance of the apical and basal compartments in sensory hair cells is poorly understood. Here we describe auditory/vestibular mutants isolated from forward genetic screens in zebrafish with lesions in the adaptor protein 1 beta subunit 1 (ap1b1) gene. Ap1b1 is a subunit of the adaptor complex AP-1, which has been implicated in the targeting of basolateral membrane proteins. In ap1b1 mutants we observed that although the overall development of the inner ear and lateral-line organ appeared normal, the sensory epithelium showed progressive signs of degeneration. Mechanically-evoked calcium transients were reduced in mutant hair cells, indicating that mechanotransduction was also compromised. To gain insight into the cellular and molecular defects in ap1b1 mutants, we examined the localization of basolateral membrane proteins in hair cells. We observed that the Na(+)/K(+)-ATPase pump (NKA) was less abundant in the basolateral membrane and was mislocalized to apical bundles in ap1b1 mutant hair cells. Accordingly, intracellular Na(+) levels were increased in ap1b1 mutant hair cells. Our results suggest that Ap1b1 is essential for maintaining integrity and ion homeostasis in hair cells.

Pde1c is a calcium/calmodulin-regulated, dual-specificity cyclic nucleotide phosphodiesterase. We have used a transposon insertion line to investigate the physiological function of Pde1c in Drosophila melanogaster and to show that the insertion leads to male sterility and male mating behavior defects that include reduced copulation rates. Sterility appears to be primarily due to elimination of sperm from the female reproductive system. The male mating behavior defects were fully rescued by expression of exogenous Pde1c under the control of either a Pde1c or a pan-neuronal promoter, whereas the sterility could be only partially rescued by expression of exogenous Pde1c under the control of these promoters. We also show that Pde1c has a male-specific expression pattern in the CNS with an increased number of Pde1c-expressing neurons in the abdominal ganglion in males.