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Cell cycle inhibitors have a long history as cancer treatment. Here, we report that these inhibitors combated cancer partially via the stimulator of IFN genes (STING) signaling pathway. We demonstrated that paclitaxel (microtubule stabilizer), palbociclib (cyclin-dependent kinase 4/6 inhibitor), and AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anticancer functions beyond arresting the cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic hepatocellular carcinoma (HCC) cells more sensitive to the antimitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment with cell cycle inhibitors, especially paclitaxel, extended survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that paclitaxel suppressed Sting wild-type HCC more effectively than Sting-KO HCC, suggesting that STING might contribute to the antitumor effects of paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

This study describes the largest cohort to date (n = 147) of pregnant patients with human immunodeficiency virus (HIV) on bictegravir (BIC). BIC in pregnancy was associated with high levels of viral suppression and perinatal outcomes similar to those in the published literature. These findings support consideration for the use of BIC in managing HIV during pregnancy., Competing Interests: Potential conflicts of interest . The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Since 2019, the World Health Organization has recommended dolutegravir-based antiretroviral therapy (ART) as the preferred regimen for human immunodeficiency virus management. Large-scale programmatic transitioning to dolutegravir-based ART was subsequently implemented across Africa, often in the absence of recent viral load testing and without access to genotypic resistance testing (GRT) in case of viremia., Methods: This study assessed emerging dolutegravir resistance in the routine care of the Viral Load Cohort North-East Lesotho. We included pediatric and adult participants who changed from nonnucleoside reverse transcriptase inhibitor- to dolutegravir-based ART and had at least 1 viral load assessment before and after the change. We sequenced available samples of participants fulfilling the additional virological criteria of having 2 viremic episodes while taking dolutegravir, with at least 1 viral load ≥500 copies/mL taken ≥18 months after changing to dolutegravir., Results: Among 15 349 participants, 157 (1.0%) met the virological criteria, and GRT was successful for 85 (0.6%). Among these 85, 8 (9.4%) had dolutegravir resistance, with 2 (2.4%) and 6 (7.1%) predicted to have intermediate- and high-level dolutegravir resistance, respectively. One participant had 2, 2 had 1, and 5 had 0 active drugs in their regimen. A GRT from before the change to dolutegravir was available for 5 of these 8 participants: 4 had 0 and 1 had 1 active drug in their nonnucleoside transcriptase inhibitor-based regimen., Conclusions: Nine percent of people with persistent or recurring human immunodeficiency virus viremia ≥18 months after changing to dolutegravir-based ART had dolutegravir resistance. Detection and management of emerging dolutegravir resistance must be addressed across Africa., Competing Interests: Potential conflicts of interest. N. D. L. reports having received travel grants to attend scientific conferences from Gilead Sciences and ViiV Healthcare. In 2022 and 2023, his division at the University Hospital Basel has received honoraria from ViiV Healthcare. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Anti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART., Methods and Analysis: B-Free is a multistage, randomised, multicentre, open-label, non-inferiority trial, embedded within the Swiss HIV Cohort Study and conducted in collaboration with cohorts of PWH in the Netherlands and France. Cohort participants with a history of ART change due to virologic failure and who maintain HIV virologic suppression with an ART regimen consisting of a pharmacological booster and at least two drugs from classes other than nucleoside reverse transcriptase inhibitors are included. Patients with major drug resistance mutations against DTG or DOR and individuals with chronic hepatitis B virus infection are not eligible for the study. Individuals are randomised 1:1 to either receiving co-formulated DTG/3TC and DOR once daily or continuing their boosted ART regimen. The primary outcome is the proportion of individuals lacking virologic control (HIV-RNA ≥50 cp/mL) at 48 weeks, according to the Food and Drug Administration snapshot algorithm. Changes in DDI burden (assessed using a DDI score), treatment satisfaction (assessed using the HIV Treatment Satisfaction Questionnaire), quality of life and mental health represent key secondary outcomes. Additional secondary outcomes include the proportion of individuals developing new resistance-associated mutations and changes in quality of life and mental health. In a qualitative substudy, we will conduct semistructured interviews with a subset of participants to assess their expectations and experiences towards HIV treatment and clinical research in general. Enrolling 210 individuals will provide 80% power to demonstrate non-inferiority, defined as less than 8% absolute increase in loss of viral suppression in individuals randomised to DOR/DTG/3TC (one-sided type I error rate of 0.025)., Ethics and Dissemination: The study was approved by the competent ethics committees (reference number BASEC 2023-01060) and the regulatory authority Swissmedic (reference number 701655) in Switzerland before the enrolment of the first participant. Approval by the European Medicines Agency and local ethical committees in the Netherlands and France will be obtained prior to including participants in these countries. Participant's written informed consent is obtained by the investigators before enrolment. The results of all major B-Free study outcomes will be submitted to peer-reviewed journals that enable Open Access publication., Trial Registration Number: Swiss National Clinical Trials Portal (SNCTP000005686, registered on 06 November 2023) and Clinicaltrials.gov (NCT06037564, registered on 07 September 2023)., Competing Interests: Competing interests: BS reports financial support for travel grants from Gilead Sciences and ViiV Healthcare and for advisory boards from Gilead Sciences and MSD, paid to his institution. GW has received research grants from Gilead Sciences and Roche Diagnostics, as well as fees for advisory boards and lectures from ViiV Healthcare, MSD, Roche Diagnostics and Gilead Sciences (all paid to his institution). MC’s institution received research grants and expert opinion fees from Gilead Sciences, MSD and ViiV Healthcare. DLB received money paid to himself outside of the submitted work for advisory boards and lectures from the companies Gilead Sciences, MSD, Pfizer and ViiV Healthcare and money for a research grant from the company ViiV Healthcare. The institution of EB received study grants from Merck and Gilead Sciences; it also received travel grants and fees for EB participation to advisory boards from Gilead Sciences, Merck, ViiV Healthcare, Pfizer AG, Moderna, AstraZeneca, AbbVie and Eli Lilly. DH received fees for consultancies from AstraZeneca, Bavarian Nordic, Gilead Sciences, UCB and ViiV Healthcare, a travel grant from Gilead Sciences, and institutional funding from AstraZeneca, Gilead Sciences, GSK, A. Menarini, MSD and ViiV Healthcare. MvdV has received research grants and fees for participation in advisory boards from Gilead Sciences, MSD and ViiV Healthcare, all paid to his institution. MS reports financial support for travel grants from Gilead Sciences and for advisory boards from Gilead Sciences, MSD and ViiV Healthcare, paid to his institution. AR received research grants from Gilead Sciences, paid to his institution; travel expenses from Gilead Sciences and Pfizer, paid to his institution; and honoraria for advisory board consultations from MSD and Moderna, paid to his institution. PS’s institution has received travel grants, congress and advisory fees from ViiV Healthcare and Gilead Sciences unrelated to this work. All other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Conflicting data exists regarding the baseline determinants of virological nonsuppression outcomes in treatment-experienced people living with human immunodeficiency virus (PWH) switching to antiretroviral treatment (ART) with bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) or dolutegravir/lamivudine (DTG/3TC) in Asia. This retrospective observational study, conducted at a designated HIV-care hospital from October 2019 to January 2023, aimed to address this gap. We assessed the odds of virological nonsuppression (VNS) at weeks 48 using logistic regression. A total of 988 patients were included, 35 patients (3.5%) with VNS at week 48. Pre-existing primary resistance-associated mutations (RAM) to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were identified in 11.0% (51/465) and 14.4% (67/465), respectively. The identified risk factor was a record of virological failure ≥2 times (AOR 5.32, 95% CI 2.04-13.85), while an HIV viral load <50 copies/mL within the past three months before switch (AOR: 0.27, 95% CI 0.11-0.72) was identified as a protective factor. No cases of acquired drug resistance-associated mutations were detected at week 48. Additionally, DTG/3TC was noninferior to BIC/FTC/TAF in achieving or maintaining HIV RNA levels of <50 copies/mL, within a -10% noninferiority margin in the per-protocol analysis (responder proportion: 98.2% vs. 95.0%, respectively; adjusted treatment difference [95% CI], 3.2% [0.7% to 5.3%]). In conclusion, DTG/3TC and BIC/FTC/TAF demonstrated good effectiveness in a real-world cohort, but frequent virological failure before the switch might impact the benefits of these regimens in the short term of follow-up., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA -mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172)., Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability., Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response., Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

Background: In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2010/VESTED study, pregnant women were randomized to initiate dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG + FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF., Methods: We assessed red blood cell (RBC) folate concentrations at maternal study entry and delivery, and infant birth. RBC folate outcomes were (1) maternal change entry to delivery (trajectory), (2) infant, and (3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRTs) of each arm comparison in 340 mothers and 310 infants., Results: Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/μL, and log10 HIV RNA was 3 copies/mL. Entry RBC folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG + FTC/TAF versus EFV/FTC/TDF arm (1.03 [95% confidence interval {CI}, 1.00-1.06]). The DTG + FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92 [95% CI, .78-1.09]) versus EFV/FTC/TDF., Conclusions: Results are consistent, with no clinically meaningful differences between arms for all RBC folate outcomes, and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- versus EFV-based antiretroviral therapy., Clinical Trials Registration: NCT03048422., Competing Interests: Potential conflicts of interest. P. D. and S. B. have received funds from ViiV/GSK that were paid to Harvard. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer., (© 2024. The Author(s).)

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer ® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases., (© 2024. The Author(s).)

Background: Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder., Methods: Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale., Results: Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d)., Conclusions: CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed., Systematic Review Registration: PROSPERO CRD42023485028., (Copyright © 2024 President and Fellows of Harvard College.)

Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors., Objective: The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D)., Patients and Methods: Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle., Results: A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort., Conclusions: Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy., Trial Registration: ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015)., Competing Interests: Declarations Funding This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, who are codeveloping olaparib. Disclosure of Potential Conflicts of Interests Erika P. Hamilton: Institutional funding (AstraZeneca, Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, Hutchinson MediPharma, OncoMed, MedImmune, Stem CentRx, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Millennium, TapImmune, BerGenBio, Medivation, Tesaro, Eisai, H3 Biomedicine, Radius Health, Acerta Pharma, Takeda, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Clovis, CytomX, InventisBio, Novartis, Silverback, Black Diamond, ArQule, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Torque Therapeutics, Harpoon Therapeutics, Fochon Pharmaceuticals, Orinove, Molecular Templates, Unum Therapeutics, Aravive, Dana Farber Cancer Institute, G1 Therapeutics, Karyopharm Therapeutics, and Compugen) and non-financial support (Amgen, Bayer, Bristol-Myers Squibb, Genzyme, Helsinn Therapeutics, HERON, Lexicon, Medivation, Merck, Novartis, Roche, Sysmex, Guardant Health, Foundation Medicine, Deciphera, and NanoString). Gerald S. Falchook: Royalties, self (Wolters Kluwer); advisory role, institution (AbbVie, Fujifilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron, Jubilant, BostonGene, Teon, Merck, Sanofi, and BridgeBio); advisory role, self (EMD Serono); speaker’s honorarium for CME (Total Health Conferencing and Rocky Mountain Oncology Society); travel, self, for work and/or research related to institution [Amgen, Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, Sarah Cannon Research Institute (employer), and Synthorx/Sanofi]; research funding, to institution (3-V Biosciences, Abbisko, Abbvie, ABL Bio, ADC Therapeutics, Accutar, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, Bayer, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celgene, Celldex, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Kolltan, Loxo/Bayer, MedImmune, Merck, Metabomed, Millennium, Mirati, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire/BridgeBio, NGM Bio, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tallac, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor, and Zhuhai Yufan). Judy S. Wang: Consulting fees (Janssen, Stemline/Menarini, BioNTech, and Kanaph Therapeutics); honoraria for speakers’ bureau (AstraZeneca and Eisai); research funding to institution only (Syndax, AstraZeneca, Phoenix, Accutar, Celgene, BMS, Tenebio, LOXO, Nurix, Step Pharma, BioNTech, Moderna, Merck, Compugen, Boehringer Ingelheim, Kymab, Sanofi, Bicycle, Cyteir, Daiichi Sankyo, Xencor, Ribon, Klus Pharma, Artios, Genentech, Treadwell, MabSpace, IGM, Immunogen, PureTech, Erasca, Bayer, 7.8 Pharma, NGMBio, Zymeworks, Immuno-Onc, Astellas, Immunitas, Prelude, Blueprint, Beigene, Pionyr, Agenus, Adagene, Macrogenics, Jazz, StingThera, Coherus, Takeda, Taiho, Jounce, Evelo, Vedanta, Stemline, GSK, Janssen, Black Diamond, Vigeo, Relay, and Jacobio). Siqing Fu: Clinical trial research support/grant funding, institution {National Institutes of Health [NIH]/National Cancer Institute [NCI] P30CA016672 – Core Grant [Cancer Center Support Grant (CCSG) Shared Resources]; Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; CUE Biopharma, Inc.; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; and Virogin Biotech, Ltd}. Amit M. Oza: principal investigator (PI) and steering committees (AstraZeneca, GSK, and Clovis); advisory boards (AstraZeneca, Morphosys); CEO [Ozmosis Research (uncompensated)], institutional support for clinical trials (AstraZeneca, GSK, Esperas Pharm, Clovis, Karyopharm, Ocellaris, Senhwa, Merck, ImmunoGen, Immunovaccine, Pfizer, Aravive, Mersana, Seagen, Alkermes, Verastem, Zentalis, Shuttck Labs, Sutro, NovoCure, Plexxikon, and Amgen). Esteban Rodrigo Imedio: Former employee (AstraZeneca). Sanjeev Kumar: Employee and stock ownership (AstraZeneca). Lone Ottesen: Former employee and stock ownership (AstraZeneca). Ganesh M. Mugundu: Former employee and stock ownership (AstraZeneca). Elza C. de Bruin: Employee and stock ownership (AstraZeneca). Mark J. O’Connor: Employee and stock ownership (AstraZeneca). Suzanne F. Jones: Consulting/advisory role (Amgen) – all payments to institution; stock ownership (HCA Healthcare). David R. Spigel: Institutional funding (AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, Merck, Moderna Therapeutics, Nektar, Takeda, Amgen, University of Texas Southwestern Medical Center – Simmons Cancer Center, G1 Therapeutics, Neon Therapeutics, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Acerta Pharma, Oncogenex, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Tesaro, Ipsen, ARMO BioSciences, and Millennium); consultation (AstraZeneca, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, PharmaMar, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, and Merck); travel and expenses (AstraZeneca, Genzyme, Intuitive Surgical, Purdue Pharma, Spectrum Pharmaceuticals, Sysmex, EMD Serono, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, and Merck). Bob T. Li: Uncompensated advisor and consultant (Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly); research grants, institution (Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly); academic travel support (Jiangsu Hengrui Medicine and MORE Health); inventor on two institutional patents at MSK (US62/685,057 and US62/514,661); intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Ethics Approval and Consent to Participate The institutional review boards of all participating sites approved the study, all patients provided written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. Consent to Publish Not applicable. Availability of Data and Material Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/. Code Availability Not applicable. Author Contributions Writing – original draft; writing – review and editing: E.P. Hamilton, G.S. Falchook, J.S. Wang, S. Fu, A.M. Oza, E.R. Imedio, S. Kumar, L. Ottesen, G.M. Mugundu, E. de Bruin, M. J. O’Connor, S.F. Jones, D.R. Spigel, and B.T. Li. Investigation: E.P. Hamilton, G.S. Falchook, J.S. Wang, S. Fu, A.M. Oza, and B.T. Li. Methodology: E.R. Imedio, S. Kumar, G.M. Mugundu, S.F. Jones, and D.R. Spigel. Conceptualization: E.R. Imedio, S. Kumar, G.M. Mugundu, M. J. O’Connor, S.F. Jones, and D.R. Spigel. Supervision: E.R. Imedio, S. Kumar, and G.M. Mugundu. Project administration: E.R. Imedio, S. Kumar, and G.M. Mugundu., (© 2024. The Author(s).)

Background/aim: Biomarkers indicating sensitivity to poly ADP-ribose polymerase (PARP) inhibitors have not yet been identified in gastric cancer. PARP inhibitors target homologous recombination deficiency (HRD); however, homologous recombination (HR) induces complex changes in gene expression, which makes it difficult to identify reliable biomarkers. In this study, we identified a multi-gene expression signature as a marker of PARP inhibitor sensitivity in gastric cancer., Materials and Methods: Seven gastric cancer cell lines were evaluated for susceptibility to PARP inhibitors using a growth inhibition assay. Gene expression profiling (GEP) was used to identify differentially expressed genes between PARP inhibitor-sensitive and -resistant cell lines. The resulting gene set was subjected to cluster analysis using tumor samples from 250 patients who underwent gastrectomy for primary gastroesophageal junction and gastric adenocarcinoma. HRD was defined as a truncating mutation in one or more of 22 HR-related genes and HRD scores were calculated using whole-exome sequencing data., Results: In the growth inhibition assays, the HGC27 and HSC39 cell lines were sensitive to the PARP inhibitors, olaparib, and rucaparib, and were significantly correlated with the GEP results. Seven (2.8%) patients harbored truncating mutations in HR-related genes. A gene expression signature based on the top 100 high and low differentially expressed genes between sensitive and resistant cell lines revealed a patient cluster with a high prevalence of HR-related gene mutations and high HRD scores., Conclusion: The 100-gene expression signature identified in this study may serve as a valuable predictive biomarker for PARP inhibitor sensitivity in gastric cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Significance: Olaparib, a PARP inhibitor, is effective against various cancers, including prostate cancer. However, resistance to olaparib poses a significant challenge. This study uncovers that mitochondrial alterations and PINK1 gene overexpression contribute to this resistance in prostate cancer cells. Enhanced mitochondrial functionality and increased PINK1 expression in olaparib-resistant cells underscore the importance of targeting mitochondrial dynamics and PINK1 to develop more effective treatments for overcoming olaparib resistance in prostate cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Oral leukoplakia (OLK) is the most representative oral potentially malignant disorder, with a high risk of malignant transformation and unclear mechanisms of occurrence. Recently, photodynamic therapy (PDT) has exhibited great potential in the treatment of OLK. However, the efficacy of PDT is difficult to predict and varies from person to person. Ferroptosis-related pathways are upregulated in many cancers, and ferroptosis induction is considered to be a potential synergistic strategy for various antitumor therapies, but its role in OLK treatment remains unclear. This study aimed to determine whether ferroptosis induction can enhance the efficacy of PDT in OLK treatment. Our study revealed that solute carrier family 7 member 11 (SLC7A11), a component of a crucial amino acid transporter and a key negative regulator of ferroptosis, was found to be highly expressed in OLK patients with no response to PDT. 5-Aminolevulinic acid (ALA)-PDT is known to cause apoptosis and necrosis, but ferroptosis also occurred under ALA-PDT in OLK cells in our study. Using erastin to induce ferroptosis enhanced the efficacy of ALA-PDT on OLK cells by disrupting the antioxidant system and further elevating intracellular reactive oxygen species levels, leading to increased apoptosis. Furthermore, this combined modality also enhanced the efficacy of ALA-PDT on 4-nitroquinoline-1-oxide (4NQO)-induced OLK lesions in mice. In summary, ferroptosis induction may serve as a potential strategy to enhance the efficacy of ALA-PDT for OLK treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. The POLO trial showed that olaparib (PARP inhibitor) improved progression-free survival (PFS) but not overall survival (OS), when used as maintenance therapy after ≥ 16 weeks of disease control with first-line platinum-based chemotherapy in patients with germline (g) BRCA 1 or 2 pathogenic variants (PV) metastatic PDAC. However, real-world data on the effectiveness of olaparib are missing., Methods: Patients with unresectable PDAC associated with somatic (s) or (g)BRCA1/2 and (g)non-BRCA-HRD PV (i.e. other homologous recombination deficiency/HRD genes) who were treated with olaparib between 2020-2023 were included. The primary objective was to describe treatment patterns. Secondary exploratory objectives included OS and PFS in patients treated with olaparib according to the POLO trial or not, OS and PFS in patients with (g)HRD PV-associated PDAC versus (s)PVs, olaparib safety profile and factors associated with olaparib poor outcomes., Results: Among 85 patients, 45.9 % received olaparib as defined by the POLO trial. No difference in OS and PFS was observed between patients who received olaparib according to the POLO trial versus not. Patients with (g)HRD PV-associated PDAC had better OS compared to others (22.3 versus 10.5 months, p = 0.038). Factors associated with olaparib poor outcomes included a high neutrophil-to-lymphocyte ratio and the use of olaparib outside the recommendations of the POLO trial. Few grade ≥ 3 adverse events were reported (9.4 %)., Conclusion: Patients with (g)HRD PV-associated PDAC had longer OS than those with (s)HRD PV. Olaparib use beyond the scope of the POLO trial was associated with poor outcomes., Competing Interests: Declaration of Competing Interest APe declares speaker’s engagement from Servier; consulting/advisory role for Amgen; travel grant from Ipsen, Merk and Servier. DT reports consultancy, advisory fees, honoraria from Servier, Pierre Fabre, Merck Serono, MSD, BMS, AZ, Roche, Sanofi; research funding from Sandoz, Astra Zenenca, Servier, MSD; travel grants from Pierre Fabre, MSD, Servier, Roche. JT has received honoraria as a speaker and/or in an advisory role from: AMGEN, Astellas, Astra Zeneca, BMS, Boehringer Ingelheim, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi, Servier, Takeda. MM reports consultancy, advisory fees, honoraria from Pierre Fabre, Merck Serono, MSD, Takeda; travel grants from Pierre Fabre, Servier. OB reports consultancy, advisory fees, honoraria from Servier, Amgen, Pierre Fabre, Merck Serono, MSD, Takeda, Deciphera; travel grants from Pierre Fabre, Servier, MSD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Identifying cancer therapy resistance is a key time-saving tool for physicians. Part of chemotherapy resistance includes senescence, a persistent state without cell division or cell death. Chemically inducing senescence with the combination of trametinib and palbociclib (TP) yields several tumorigenic and prometastatic factors in pancreatic cancer models with many potential antibody-based targets. In particular, urokinase plasminogen activator receptor (uPAR) has been shown to be a membrane-bound marker of senescence in addition to an oncology target. Methods: Here, 2 antibodies against murine uPAR and human uPAR were developed as immuno-PET agents to noninvasively track uPAR antigen abundance. Results: TP treatment increased cell uptake both in murine KPC cells and in human MiaPaCa2 cells. In vivo, subcutaneously implanted murine KPC tumors had high tumor uptake with the antimurine uPAR antibody independently of TP in young mice, yet uPAR uptake was maintained in aged mice on TP. Mice xenografted with human MiaPaCa2 tumors showed a significant increase in tumor uptake on TP therapy when imaged with the antihuman uPAR antibody. Imaging with either uPAR antibody was found to be more tumor-selective than imaging with [ 18 F]FDG or [ 18 F]F-DPA-714. Conclusion: The use of radiolabeled uPAR-targeting antibodies provides a new antibody-based PET imaging candidate for pancreatic cancer imaging as well as chemotherapy-induced senescence., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A. In contrast to a rapid onset of cyst formation and kidney failure in mice with defective ciliogenesis, both kidney function, cyst formation discerned by magnetic resonance imaging and overall survival were strikingly improved in mice additionally lacking Raptor. However, these mice eventually succumbed to cystic kidney disease despite mTORC1 inactivation. In-depth transcriptome analysis revealed the rapid activation of other growth-promoting signaling pathways, overriding the effects of mTORC1 deletion and identified cyclin-dependent kinase (CDK) 4 as an alternate driver of cyst growth. Additional inhibition of CDK4-dependent signaling by the CDK4/6 inhibitor Palbociclib markedly slowed disease progression in mice and human organoid models of polycystic kidney disease and potentiated the effects of mTORC1 deletion/inhibition. Our findings indicate that cystic kidneys rapidly adopt bypass mechanisms typically observed in drug resistant cancers. Thus, future clinical trials need to consider combinatorial or sequential therapies to improve therapeutic efficacy in patients with cystic kidney disease., (Copyright © 2024 International Society of Nephrology. All rights reserved.)

Purpose: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial)., Methods: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV)., Results: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B., Conclusion: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation., Competing Interests: Declaration of competing interest The authors declare no conflict-of-interest., (Copyright © 2024. Published by Elsevier Inc.)

Objective: In patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV., Methods: We assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS)., Results: PFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects., Conclusions: In summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients., Trial Registration Number: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To report the efficacy and safety of combination therapy with selinexor, palbociclib, pembrolizumab, and umbilical cord blood NK cells for advanced hepatocellular carcinoma (HCC).Advanced HCC has a poor prognosis and limited effective treatment options. Exploring personalized combination treatment strategies is critically important for improving outcomes in patients with advanced HCC. This study aims to provide preliminary evaluation of the clinical effectiveness and safety of this combination regimen in this high-risk population, and lay the groundwork for larger studies to bring more treatment choices to patients with advanced HCC., Methods: A 67-year-old male patient with advanced HCC and multiple metastases was treated with palbociclib 75mg on days 1-14 of a 28-day cycle, pembrolizumab 200mg intravenous infusion, selinexor 40mg weekly, and umbilical cord blood NK cell (12×109 cells) infusion on days 1, 14, 28 and 42. Imaging examinations and tumor marker detection were performed before and after two cycles of treatment to evaluate response., Results: After two cycles of combination treatment, follow-up PET-CT showed partial response with the liver tumors reduced in size by approximately 60%, lung metastases reduced by approximately 90%, and FDG uptake decreased more than 90% in lymph nodes and bone metastases. The AFP level decreased compared to baseline. Liver function tests including albumin, bilirubin and prothrombin time improved. The patient's performance status also improved from ECOG 2 to ECOG 1., Conclusions: This case report describes preliminary signals that the combination of selinexor, palbociclib, pembrolizumab, and umbilical cord blood NK cells may warrant further investigation for the treatment of advanced HCC. Objective response was observed based on standardized response criteria. However, due to the limitations of a single-arm case study design, definitive conclusions cannot be drawn regarding the efficacy or safety profile of this personalized combination approach. Larger and more robust clinical trials are needed to fully validate if this treatment strategy can achieve clinical benefit for advanced HCC. Future studies should aim to elucidate potential biomarkers that may help identify patients most likely to respond to this combination regimen. Exploring optimal patient selection criteria could also help maximize clinical benefit. Further research is warranted to continue exploring precision medicine combinations involving immunotherapy, targeted agents and cellular therapies for advanced HCC.

Objectives: Dolutegravir (DTG) has proved to be more efficacious, tolerable, and safer than efavirenz (EFV) among mothers living with HIV and their infants in Uganda. This study assessed the cost-effectiveness of the DTG-based antiretroviral therapy (ART) compared with the standard of care for preventing perinatal transmissions among pregnant women initiating ART in late pregnancy in Uganda., Methods: We used data from a randomized open-label trial (DolPHIN-2) and a 2-part cost-effectiveness model composed of a short-term decision tree to estimate the perinatal transmission rate and costs and an individual-based 3-state Markov model (HIV, advanced HIV, dead) to estimate the long-term costs and health outcomes from the Ugandan payer perspective using a lifetime horizon and a 1-year Markov cycle. The main outcomes were the mean annual costs in US dollars ($), disability-adjusted life-years (DALYs), and incremental cost-effectiveness ratio. Both the deterministic and probabilistic sensitivity analyses were conducted to assess the effect of parameter uncertainties on the ultimate results and the model's robustness., Results: Compared with the EFV-based ART, the DTG-based ART was associated with fewer mean annual costs ($43.58 vs $68.44) and DALYs (0.33 vs 0.56), leading to cost savings of $110 per DALY averted. In the incremental analysis, the DTG-based ART dominated the EFV-based ART; that is, it was less costly and more effective. These results were robust to deterministic and probabilistic sensitivity analyses., Conclusion: The DTG-based ART is a highly cost-effective strategy compared with the EFV-based ART among women initiating treatment in the third trimester of pregnancy in a low-income setting., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Immuno-hematological abnormalities are common among HIV infected individuals as well as patients with highly active antiretroviral therapy (HAART). However, the immuno-hematological outcome of Dolutegravir based antiretroviral therapy (ART) usage is not well investigated., Objectives: To assess hematological and immunological parameters among adult HIV patients before and after initiation of Dolutegravir based ART regimen at St. Peter Specialized Hospital, Addis Ababa, Ethiopia., Methods: A cross-sectional study was conducted from May to July 2021 at St. Peter Specialized Hospital among adult HIV patients. A total of 422 HIV patients on Dolutegravir based ART (combination of Dolutegravir/lamivudine/tenofovir disoproxil fumarate (DTG/3TC/TDF)) for a minimum of 3 months were selected using convenient sampling methods. Socio-demographic as well as clinical data of the participants was obtained using pre-tested structured questionnaires and a review of medical records. Hematological parameters such as CBC was obtained using Beckman coulter automated hematology analyzer and immunological parameters such as CD4 count were determined using BD FACS presto. Statistical analysis of the data was done using SPSS version 21. Paired t-test was used to compare dependent variables before and after initiation of the new HAART and binary logistic regression was used to determine predictors of immuno-hematological abnormalities. P-value < 0.05 was considered as statistically significant., Results: Of 422 adult HIV patients, about 273(64.7%) were females. The mean age of study participants was 42.2 years (±10.4SD). The mean white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (Hb), platelet distribution width (PDW), CD4 count, as well as lymphocyte percentage, neutrophil percentage, and platelet counts (PLT) were increased significantly(P<0.05) after 3 months of the Dolutegravir based therapy. While, red cell distribution width (RDW) and mean cell hemoglobin (MCH) were decreased (P<0.05) after the treatment. Other hematological parameters such as mean cell volume (MCV), hematocrit (HCT), mean cell hemoglobin concentration (MCHC), mean platelet volume (MPV) and platelet distribution width (PDW) showed no significant change. On the other hand, the most common hematological abnormalities identified after the new HAART were anemia (12.1%); followed by Leucopenia (11.3%), neutropenia (6%), and thrombocytopenia (4%). Anemia was associated with female sex (AOR = 7.8, 95% CI: 1.9-32.2, P<0.005) and WHO clinical stage III/IV (AOR = 16, 95% CI: 10.63-66.46, P<0.01)., Conclusion: There was a significant change in certain immuno-hematological parameters such as WBC count, RBC count, PLT count, Hb, PDW, CD4 count, lymphocyte and neutrophil percentage after initiation of the Dolutegravir based therapy. Anemia was the most common hematological abnormality. Further studies are required to fully comprehend the outcome of the new treatment regimen on immuno-hematological parameters., Competing Interests: The authors have declared that no competing interest exist., (Copyright: © 2024 Gudina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Inavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA ) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials., Methods: In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA -mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator., Results: A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group., Conclusions: In patients with PIK3CA -mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.)., (Copyright © 2024 Massachusetts Medical Society.)

Abstract: Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI-therapy failure in people with chronic-phase CML., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Despite recent advancements in the treatment of metastatic castrate-resistant prostate cancer (mCRPC), this disease remains lethal. A novel family of targeted pharmaceuticals known as poly-ADP-ribose polymerase (PARP) inhibitors has been developed to treat mCRPC patients with homologous recombination repair (HRR) gene alterations. The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Two-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States., Methods: Virologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA ® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined., Results: A total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%)., Conclusions: Among virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH., (© 2024. The Author(s).)

While Resolvin D1 (RvD1) shows promise in resolving inflammation in experimental autoimmune encephalomyelitis (EAE), its pro-resolving roles on dendritic cells (DCs) remain unknown, and the chemical instability of RvD1 poses significant challenges to its drug development. This study aims to investigate whether 4-(2'-methoxyphenyl)-1-[2'-[N-(2″-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-MPPF), a novel chemically stable analogue of RvD1, can play a pro-resolving role in EAE, particularly on DCs, and if p-MPPF could serve as a potential substitute for RvD1. We showed that both RvD1 and p-MPPF mediated the resolution of inflammation in EAE, as evidenced by ameliorated EAE progression, attenuated pathological changes in the spinal cord, altered cytokine expression profile in serum, and reduced proportion of pro-inflammatory immune cells in the spleen. Utilizing DCs derived from both the spleen and bone marrow of EAE, our investigation showed that RvD1 and p-MPPF prevented DC maturation, decreased pro-inflammatory cytokine secretion, shifted DCs away from a pro-inflammatory phenotype, increased the phagocytosis capacity of DCs, and suppressed their ability to induce differentiation of CD4 + T cells into Th1 and Th17 subsets. For underlying intracellular mechanisms, we found that RvD1 and p-MPPF down-regulated the lactate dehydrogenase A signaling pathways. Comparisons between RvD1 and p-MPPF showed that they exerted overlapped pro-resolving effects to a large extent. This study demonstrates that both RvD1 and p-MPPF exert therapeutic effects on EAE by mediating inflammation resolution, which is closely associated with modulating DC immune function towards a tolerogenic phenotype. SPM mimetics may serve as a more promising therapeutic drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and niraparib have shown promise in extending progression-free survival (PFS) in patients with platinum-sensitive recurrent (PSR) epithelial ovarian cancer. In this retrospective study, we aimed to present our own data on the effect of PARP inhibitors on PFS in recurrent epithelial ovarian cancer., Methods: 82 patients diagnosed with PSR epithelial ovarian, tubal, or primary peritoneal cancer between May 2017 and September 2023 were initially enrolled from our hospital. However, 16 patients had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Consequently, the study focused on 55 eligible patients. PFS was compared between patients receiving PARP inhibitor maintenance therapy and those who did not., Results: Among the 55 patients with PSR epithelial ovarian cancer, 18 received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation. PARP inhibitor therapy significantly extended PFS (mean 24.0 months) compared to observation (mean 9.0 months, p = 0.0005), regardless of BRCA mutation status (HR = 0.20, 95% CI: 0.08-0.50). Subgroup analysis showed no statistical difference between olaparib and niraparib. Additionally, there was no PFS difference based on BRCA mutation status within both PARP inhibitor groups., Conclusion: Our retrospective study demonstrates that PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, These findings support the broad utilization of PARP inhibitors as a standard maintenance therapy for PSR epithelial ovarian cancer irrespective of BRCA mutation status., (© 2024. The Author(s).)

Background: Second-generation antipsychotic drugs are increasingly used to treat depressive disorders with psychotic symptoms. In addition to effectively managing psychotic symptoms, second-generation antipsychotics can also result in adverse drug reactions in patients, which should not be underestimated., Case Presentation: We report the case of 14 years old unmarried female patient with depression. At first, she started with moping and gradually developed into self-injury and whispering. After antidepressant treatment combined with the second-generation antipsychotic drug blonanserin, the patient's psychotic and depressive symptoms improved significantly, while the patient developed lactation, which stopped after the medication was changed., Conclusions: Although Blonanserin's clinical trials have reported rare adverse reactions like elevated prolactin levels and even lactation, caution is still needed in clinical application of the drug. This case is expected to improve psychiatrists' choice of antidepressant therapy in combination with antipsychotic drugs., (© 2024. The Author(s).)

Body weight is influenced by an interplay of individual and environmental factors. In people with human immunodeficiency virus (HIV), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy. Weight changes in comparative antiretroviral therapy trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors dolutegravir and bictegravir, particularly when coadministered with tenofovir alafenamide fumarate, compared with regimens that include agents such as tenofovir disoproxil fumarate that attenuate weight gain. We review weight changes in major randomized trials of preexposure prophylaxis and initial and switch HIV therapy, highlighting the challenges to assessing the role of antiretroviral therapy in weight change. This examination forms the basis for a model that questions assumptions regarding an association between integrase strand transfer inhibitors and tenofovir alafenamide fumarate and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions., Competing Interests: Potential conflicts of interest . D. A. W. has received honoraria for consultancy from Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, Merck & Co, Theratechnologies, and EMD Serono. His institution has received grant funding to support his research from Gilead Sciences, ViiV Healthcare, and Merck & Co. J. R. K. has served as a consultant to Gilead, Merck, Theratechnologies, and Janssen Pharmaceuticals and has received research support from Gilead Sciences and Merck. P. E. S. has served as a scientific advisory board member/consultant for Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Merck & Co, and Janssen Pharmaceuticals, He has received research support from Gilead Sciences, and GlaxoSmithKline/ViiV Healthcare. G. A. M. has received consultant fees from Janssen Pharmaceuticals, Gilead Sciences, ViiV Healthcare, Merck, and Theratechnologies. D. R. K. is a consultant to and received honoraria from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen, Pharmaceuticals, Merck & Co, Roche, and ViiV Healthcare. He has received research support from Gilead Sciences, ViiV Healthcare, Merck & Co, and Roche and has provided expert testimony on behalf of Gilead Sciences and Janssen. G. M. has served as an advisor to Novartis and Ipsen Pharmaceuticals and a speaker for Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme UK, and ViiV Healthcare. L. K. is a scientific and/or medical consultant to Altimmune, Boehringer Ingelheim, Gilead Sciences, Glyscend, Intellihealth, Johnson & Johnson, Eli Lilly, Novo Nordisk, Pfizer, Sidekick Health, twenty30.health, and Xeno Biosciences. J. v. W. is employed by ViiV Healthcare. R. E. C. is employed by Merck & Co. C. C. is employed by Gilead Sciences. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: It is previously reported that the Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor score is correlated with scales assessing function in patients with major depressive disorder (MDD)., Methods: This was an analysis of a database including 5 long-term, extension studies of prior controlled trials, which evaluated the effects of open-label, maintenance treatment with vortioxetine (5-20 mg/day over 1-year) in adults with MDD. We assessed the association of changes in MADRS anhedonia factor scores with changes in the Clinical Global Impression of Severity (CGI-S), Sheehan Disability scale (SDS), and the SF-36. A minimal clinically important change (MCIC) for MADRS anhedonia factor scores was determined using the CGI-S as anchor., Results: In patients who had completed the prior controlled studies, MADRS anhedonia factor scores continued to improve over 1-year of maintenance treatment (mean ± SE change from baseline of -6.2 ± 0.2 at Month 12). Change in MADRS anhedonia factors score correlated with change in CGI-S (Week 4, r = 0.71), SDS (Week 24 r = 0.60) and SF-36 domains (Week 24 r = -0.19 to -0.61) scores. Using a 1 level improvement on CGI-S as anchor, the MCIC for MADRS anhedonia factor scores versus baseline were - 4.6 at Week 4, -5.5 at Week 24, and - 5.3 at Week 52., Limitations: Neither the MADRS scale, nor the primary studies, were specifically designed to assess anhedonia., Conclusions: These open-label data suggest that patients treated with vortioxetine continued to show clinically relevant improvements in their anhedonia over 1-year of maintenance therapy. Improvements in anhedonia correlated with improvements in measures of functioning and quality of life., Competing Interests: Declaration of competing interest Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Simon Nitschky Schmidt, and Elin Reines are full time employees of H. Lundbeck A/S. Oscar Necking was employed by H. Lundbeck A/S at the time of study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers., Patient Concerns: Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization., Diagnoses: A diagnosis of skin metastasis from prostate cancer was reported., Outcomes: The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression., Lessons: A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC)., Methods: PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models., Results: From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 - 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS., Conclusions: In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes., (© 2024. The Author(s).)

Background: Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6., Aim: This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism., Methods: Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis., Results: Erythromycin increased the area under the curve (AUC τ ) and peak concentration (C max ) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (T max ). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe., Conclusion: The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy., Trial Registration: Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018., (© 2024. The Author(s).)

Purpose: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and targetable genomic alterations. Two cohorts of patients with cyclin-dependent kinase inhibitor 2A ( CDKN2A )-mutated tumors treated with palbociclib are reported: one with head and neck cancer (HNC) with both squamous and nonsquamous cell histologies, and one with histology-pooled (HP) cancers., Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. For the HNC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included OR, safety, progression-free survival, overall survival, duration of response, and duration of SD., Results: Seventy patients with HNC (N = 28) or HP cancers (N = 42) were treated with palbociclib. For the HNC cohort, DC and OR rates were 40% (one-sided 90% CI, 27 to 100) and 4% (95% CI, <1 to 18), respectively. The null hypothesis was rejected ( P = .002). For the HP cohort, DC and OR rates were 13% (one-sided 90% CI, 6 to 100) and 5% (95% CI, <1 to 17), respectively. The null hypothesis was not rejected. Thirty-one of 70 patients experienced treatment-related grade 3 to 4 adverse events (AEs) or serious AEs, the most common including neutropenia, thrombocytopenia, and leukopenia., Conclusion: Palbociclib met prespecified criteria to declare a signal of activity in patients with HNC with CDKN2A alterations, but not in the HP cohort.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence., (© 2024 Gilead Sciences, Inc. and The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18., Patients and Methods: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR)., Results: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified., Conclusions: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs., Methods: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany., Results: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP., Conclusion: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B., (© 2024. The Author(s).)

Aim: To evaluate the impact of palbociclib treatment on health-related quality of life (HRQoL) in patients with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer (HR+/HER2- aBC) or metastatic breast cancer (mBC) in both the clinical and real-world setting. Materials & methods: A systematic literature review was conducted to identify clinical trials and real-world evidence studies up to June 2023 that reported HRQoL outcomes in patients with HR+/HER2- aBC or mBC treated with Palbociclib. Results: 15 unique studies reported across 35 records were identified. Of these, seven were randomized controlled trials (RCTs), three were single-arm clinical trials and five were real-world evidence (RWE) studies. HRQoL was generally found to be maintained in patients with HR+/HER2- aBC or mBC across RCTs, single-arm clinical trials and RWE studies. HRQoL measures across instruments, study types and line of therapy, were largely reported to be at least maintained if not improved from baseline among patients treated with palbociclib and were observed to be comparable or better in the palbociclib group versus monotherapy control arm in RCTs. Similar results were seen for treatment-related outcomes (e.g., sexual functioning, upset by hair loss, systemic therapy side effects etc.), and important individual patient outcomes, including pain, fatigue and physical functioning. Findings were also consistent across key clinical characteristics (visceral metastases, neutropenia), as well as patient populations often underrepresented in clinical trials (Asian patients, older adults). Conclusion: Overall, current evidence suggests that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy in patients with HR+/HER2- aBC or mBC across study types and populations.

Purpose: In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population., Patients and Methods: In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, and 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS., Results: Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis, there was no significant difference between treatment arms in PFS [hazard ratio 1.02, 95% confidence interval (CI), 0.71-1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo]. The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73-1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results., Conclusions: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background and Objective: Olaparib + abiraterone has a combined antitumor effect in metastatic castration-resistant prostate cancer (mCRPC), but the efficacy of this combination in patients with DNA damage repair (DDR)-deficient mCRPC progressing after abiraterone is unknown. Our aim was to compare the efficacy of olaparib + abiraterone versus olaparib monotherapy for patients with DDR-deficient mCRPC progressing after abiraterone., Methods: The study included 86 consecutive patients with DDR-deficient mCRPC progressing after abiraterone: 34 received olaparib + abiraterone, and 52 received olaparib monotherapy. DDR-deficient status was defined as the presence of a DDR gene with a pathogenic or likely pathogenic variant (DDR-PV), or with a variant of unknown significance (DDR-VUS). We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. The prostate-specific antigen (PSA) response, the treatment effect across subgroups, and adverse events (AEs) were also evaluated., Key Findings and Limitations: Median follow-up was 9 mo. In the overall cohort, median PFS and OS were significantly longer in the combination arm than in the monotherapy arm (PFS: 6.0 vs 3.0 mo; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.25-0.67; p < 0.01; OS: 25.0 vs 12.0 mo; HR 0.30, 95% CI 0.14-0.67; p < 0.01). PSA responses were significantly higher following combination therapy versus monotherapy. Combination therapy had significantly better efficacy in the DDR-PV and DDR-VUS subgroups, and was an independent predictor of better PFS and OS. AE rates were acceptable. The retrospective nature, small sample size, and short follow-up are limitations., Conclusions: Olaparib + abiraterone resulted in better PFS and OS than olaparib alone for patients with DDR-deficient mCRPC progressing after abiraterone. These results need to be confirmed by a large-scale prospective randomized controlled trial., Patient Summary: Our study shows that the drug combination of olaparib plus abiraterone improved survival over olaparib alone for patients who have mutations in genes affecting DNA repair and metastatic prostate cancer resistant to hormone therapy. The results provide evidence of a synergistic effect of the two drugs in these patients., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1 flox/flox , Trp53 flox/flox , Pten flox/flox (RTP) and Rb1 flox/flox , Trp53 flox/flox , Myc LSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy,  and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

We here present a case providing valuable insights for clinicians who deliver care to patients identifying as transgender or nonbinary. A 30-year-old trans woman presented to sexual health services requesting a routine sexual health screen and was subsequently diagnosed with HIV and syphilis. She started antiretrovirals for HIV (bictegravir/tenoforvir alafenamide/emtricitabine) 12 days later and was treated with benzathine penicillin G. The patient also had a positive tuberculosis (TB) ELIspot blood test result and further investigations proved the presence of active TB in the chest with mediastinal involvement. She commenced treatment for TB with quadruple therapy, including rifampicin. Due to the clinically significant interaction between rifampicin and bictegravir, the patient's antiretroviral treatment was switched to dolutegravir 50 mg twice daily in combination with tenofovir disoproxil fumarate and emtricitabine. As the patient had transitioned from male to female and was self-medicating with oestrogen-containing feminizing hormone therapy, her hormonal treatment was optimized and blood levels of oestradiol were closely monitored and titrated to manage the drug-drug interaction between rifampicin and oestrogen to ensure the latter would be maintained within the expected therapeutic range. Our case report demonstrates the importance of combining treatment of multiple conditions under 1 team ideally integrated with gender services to prevent multiple attendances and mismanagement of feminizing hormone therapies., (© 2024 British Pharmacological Society.)

Purpose: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm)., Methods: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile., Results: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified., Conclusions: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers., Competing Interests: Declaration of competing interest J.E.A.M. reports receiving travel compensation from AstraZeneca, Roche; and research grants from AstraZeneca. J.B. has participated as invited speaker for AstraZeneca; has institutional, personal and financial interests in AstraZeneca; has institutional and other financial interests in AstraZeneca-MSD; has been involved in educational programs for AstraZeneca-MSD, declares participation in steering committees for AstraZeneca; reports institutional and financial interests in MEDSIR; and declares being a local principal investigator at MEDSIR. J.A.G.S. declares consultative and advisory services for Seagen, AstraZeneca, Daiichi Sankyo, Novaris, Gilead, Menarini; consultancy/speaker fees from Celgene, Eli Lilly, EISAI, MSD, Exact Sciences, Tecnofarma, Nolver (Adium), Asofarma, Roche; institution and research funding from AstraZeneca; and travel support from Gilead, AstraZeneca, Daiichi Sankyo. I.P. reports receiving honoraria from MSD, Novartis, AstraZeneca, Gildead; and consultancy or advisory role for AstraZeneca. M.F.A. declares speakers' bureaus from Daiichi-AstraZeneca, Lilly, Pfizer, Novartis, Eisai; expert testimony for Lilly; and receiving travel expenses from Roche, Novartis. B.B. reports receiving fees for medical education as consulting or advisory role with MSD, Roche, Pierre Fabre, Novartis, Astra Zeneca, Seagen; and speakers' bureau with Pfizer, Roche, MSD, Palex, Eisai, Daichii, Astra Zeneca, Seagen. M.H.L.C. reports speaker honoraria from Daichii, Novartis & Pierre Fabre; and travel and training grants from Roche, Pfizer, MSD & Novartis. J.P.E. is a full-time employee at MEDSIR. L.C. is a full-time employee at MEDSIR. M.S.C. reports participating in an advisory board for Optimapharm, Ability Pharma, and MD Anderson; and is a full-time employee at MEDSIR. J.M.P.G. declares having a consulting or advisory role for Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Gilead, MSD; travel compensation from Roche; and employment at MEDSIR. J.C. reports serving as a consultant/advisor Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp&Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, Abbvie, BridgeBio; receiving honoraria from Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca, Gilead, Steamline Therapeutics; research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Iqvia, Queen Mary University of London; stock of MEDSIR, MAJ3 Capital, Leuko (relative); travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead, Merck Sharp&Dhome, Steamline Therapeutics; and patents: (1) Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent.Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. (2) Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy.Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED A.L.C. reports receiving research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; consulting or advisory role for Lilly, Roche, Pfizer, and Novartis; speakers’ bureaus from Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership of MEDSIR and Initia-Research. P.S.R., F.J.S.B., S.M., A.L.M., N.F., P.Z., T.D.R., and M.G. declare that they have not conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)