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AIMS: To compare belief in own effort to stay healthy, health behaviour and body mass index (BMI) among non-Western immigrants with Danish citizenship and citizens with Danish background. METHODS: Based on the National Health Interview Survey 2005, logistic regression analyses were used to examine differences in belief in own effort to stay healthy, in health behaviour and in BMI between 136 non-Western immigrants with Danish citizenship and 9,901 citizens with Danish background in the age group 25-64 years. RESULTS: Non-Western immigrants had lower odds for reporting that own effort is very important to maintain good health (odds ratio (OR) 0.45; 95% confidence interval (CI) 0.32-0.62) and for reporting consuming more alcohol on a weekly basis than recommended by the Danish National Board of Health (OR 0.21, 95% CI 0.09-0.51). The odds were higher for non-Western immigrants for than citizens with Danish background for reporting sedentary spare-time activities (OR 2.96, 95% CI 1.96-4.17), daily consumption of boiled vegetables (OR 2.50, 95% CI 1.77-3.53), and daily consumption of salad/raw vegetables (OR 2.84, 95% CI 2.02-3.99). We found no differences in daily smoking, daily fruit consumption, BMI> or =25 or BMI> or =30. CONCLUSIONS: The non-Western immigrants are healthier in terms of alcohol and vegetable consumption and unhealthier with regard to leisure-time physical activity. The non-Western immigrants are less likely to report that their own effort is important in maintaining good health. [ABSTRACT FROM AUTHOR]

Purpose: This phase 1b trial evaluated FAP-IL2v, a novel immune-cytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Patients received FAP-IL2v either on a continuous weekly (QW) schedule, or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses., Results: A total of 58 patients were enrolled, 19 patients into the dose-escalation, and 39 patients into the expansion part. The MTD of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v-related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode-of-action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, the objective response rate was 7% (95% CI: 3.2, 14.7)., Conclusions: The safety profile of FAP-IL2v in combination with cetuximab was acceptable and pharmacodynamic markers support the proposed mode-of-action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].

Early phase clinical trials provide an initial evaluation of therapies' risks and benefits to patients, including safety and tolerability, which typically relies on reporting outcomes by investigator and laboratory assessments. Use of patient-reported outcomes (PROs) to inform risks (tolerability) and benefits (improvement in disease symptoms) is more common in later than early phase trials. We convened a two-day expert roundtable covering: (1) the necessity and feasibility of a universal PRO core conceptual model for early phase trials; (2) the practical integration of PROs in early phase trials to inform tolerability assessment, guide dose decisions, or as real-time safety alerts to enhance investigator-reported adverse events. Participants (n = 22) included: patient advocates, regulators, clinicians, statisticians, pharmaceutical representatives, and PRO methodologists working across diverse clinical areas. In this manuscript, we report major recommendations resulting from the roundtable discussions corresponding to each theme. Additionally, we highlight priority areas necessitating further investigation., Competing Interests: C.Y. has received consulting fees from Faron Pharmaceuticals and an honoraria from Bayer. O.L.A. reported receiving grants from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research center, NIHR Applied Research Collaboration West Midlands, NIHR Blood Transplant Research Unit (BRTU), UK Research and Innovation (UKRI), Health Foundation, Gilead, Anthony Nolan, GlaxoSmithKline, Merck, and Sarcoma UK. OLA declares personal fees from Gilead Sciences Ltd, Merck, and GlaxoSmithKline, Innovate UK outside the submitted work. E.B. has received payments as a scientific advisor for Navigating Cancer, AstraZeneca, Resilience, N-Power Medicine, and Verily. J.B. is an employee of AstraZeneca, with ownership interest in AstraZeneca and is engaged by Evinova, a separate healthtech business within the AstraZeneca group. A.H. has Research funding (paid to institution): Advancell, BMS, MSD, Macrogenics, Tyra Biosciences, Janssen, Seagen, Aveo, Roche/Genetech; Consulting (paid personally): MSD, Pfizer, Eisai, Astellas, Bayer. P.K. has shares in Merck Healthcare KgaA and is a Full-time employee of Merck Healthcare KgA. B.K.K. has grants paid direct to organisation from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Jazz Pharma, Genentech, Eli Lilly, Janssen, Takeda, Dachii Sankyo, Blueprint, Medicines, Janssen, Amgen, Seagen, Manta Cares and personal consultancy fees from Eli Lilly, BMS, AbbVie, Shionogi. H.M.K. has received grants unrelated to the work from the American Heart Association to Jansson; Agency for Healthcare Research and Quality to Kenvue; National Institutes of Health to Novartis; Centers for Medicare & Medicaid Services to Pfizer and Centers for Disease Control and Prevention. These grants and contracts are unrelated to the work above and are through Yale University or Yale New Haven Hospital. Received consulting fees from Massachusetts Medical Society (to Co-Editor, Journal Watch Cardiology); UpToDate (as Section Editor) and Ensight (unpaid advisor). Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events would have received occasional travel expenses and/or honoraria to speak at various educational/academic venues. Received travel expenses and/or honoraria to speak at various educational/academic venues. Stocks in Element Science and Identifeye. A.M. has served on advisory boards for Janssen Pharmaceuticals, GSK, Merck Pharmaceuticals, Takeda Pharmaceuticals, MSD Pharmaceuticals, Faron Pharmaceuticals, Pfizer Pharmaceuticals, AZ, Genmab Pharmaceuticals and Immutep Pharmaceuticals. Has received honoraria from Chugai Pharmaceuticals, Faron Pharmaceuticals, Merck Pharmaceuticals, GSK, Seagen, Takeda Pharmaceuticals and Janssen Pharmaceuticals. Has travel support from Amgen Pharmaceuticals and Janssen Pharmaceuticals. Has received research funding from Astex Pharmaceutical, Merck Pharmaceuticals and MSD. J.P. is a Patient representative on CCTG. S.R. Research grants with Medical Research Council, NIH/NEI, NIHR outside permitted work. A.R. reported receiving grants from National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC) paid to University of Birmingham and has funding outside the submitted work from NIHR, Birmingham City Council, ACCELERATE, Office of Health Disparity and Inequality. Support for attending meetings from Outsourcing in Clinical Trials UK/Ireland as invited speaker. Honoraria from Wellcome Sanger Institute Representative Research Strategy Advisory Group and ACCELERATE (Innovations for Children and Adolescents with Cancer) International Patient-Reported Outcomes Working Group—Core Group Member and Work-package Lead (unpaid). S.R. is employed by Veloxis Pharmaceuticals, Inc. Stock in the following companies: Bristol Myers-Squibb, Gilead Sciences, IGM Biosciences, Merck & Co, Pfizer. L.I.W. has received consulting fees from Celgene/Bristol Myers Squibb; Connect Multiple Myeloma registry, member Scientific Steering Committee. L.K.S. reports funding to institution from AZ, Bayer, Roche, GSK, Treadwell, REPARE, Novartis, Janssen, MERCK. Shares: AZ. H.A.W. is employed by Pfizer AG, Switzerland and owns non-voting shares of Roche Ltd. M.J.C. is the Director of Birmingham Health Partners Centre for Regulatory Science and Innovation and Centre for Patient Reported Outcomes Research and a National Institute for Health and Care Research (NIHR) senior investigator; has received funding from Anthony Nolan, European Regional Development Fund-Demand Hub and Health Data Research UK, Gilead, GSK, Janssen, Macmillan Cancer Support, Merck, NIHR, NIHR ARC WM, NIHR Birmingham BRC, NIHR BTRU Precision and Cellular Therapeutics, UCB Pharma, UKRI, and UK SPINE; and has received consultancy fees from Aparito, Astellas, Boehringer Ingelheim, CIS Oncology, Daiichi Sankyo, Gilead, Glaukos, GSK, Halfloop, Merck, Patient-Centered Outcomes Research Institute, Pfizer, Takeda, and Vertex Pharmaceuticals Incorporated, outside of the submitted work. The views and opinions expressed in this publication are those of the individual co-authors and may not be understood or quoted as being made on behalf of or reflecting the position of any organisation, committee, working party or group with which the co-authors are affiliated., (© 2024 The Author(s).)

Background: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib)., Methods: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing., Results: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes., Conclusions: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We aimed to develop an automated, low-volume method for thrombocyte counting in capillary blood using the Sysmex predilution (PD) mode., Methods: Microsamples were prepared by resuspension of 50 μL blood in 300 μL DCL CellPack. Thrombocyte counting was done in the impedance (PLT-I) and fluorescence (PLT-F) channels. The imprecision and bias was evaluated in >394 microsamples from adult blood. Preanalytical factors (skin-piercing, storage, and transportation in our pneumatic tube system) was assessed, and studies on pediatric microsamples were made for comparison. The improvement in analytical quality and turnaround time was examined., Results: For PLT-F, the imprecision was 1.1%-3.7%, and the bias was 10.1% (95% CI: 8.8-11.3). After skin-piercing, the bias was 8.1% (95% CI: 5.6-10.6) and the imprecision 1.9% (95% CI: 1.3-2.5). Thrombocyte counts kept stable after 4 h at room temperature (94.8% [95% CI: 93.2-96.4]) and after pneumatic tube transportation [6.7% (95% CI: 4.8-8.6)]. The bias of the PD mode for pediatric microsamples was 13.0% (95% CI: -8.4-34.4) in the PLT-F channel. The automated method had a considerably lower imprecision than the existing manual thrombocyte counting method and reduced turnaround times., Conclusion: The automated microsample method offers a low-volume alternative for measurement of thrombocytes. The method appears useful also in pediatric samples., (© 2024 The Author(s). International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A., (© 2024. The Author(s).)

Purpose: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups. VIGex-Hot has been associated with better IO treatment outcomes. Here, we investigated the performance of VIGex and other IO biomarkers in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial (ClinicalTrials.gov identifier: NCT02644369)., Materials and Methods: Patients with advanced solid tumors were treated with pembrolizumab 200 mg IV once every 3 weeks. Tumor RNA-seq data from baseline tumor samples were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera assay. VIGex-Hot was compared with VIGex I-Cold + Cold and four groups were defined on the basis of the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA)., Results: Seventy-six patients were enrolled, including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma, and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher overall survival (OS) and progression-free survival (PFS) when included in a multivariable model adjusted for tumor type, tumor mutation burden, and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS., Conclusion: Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.

Background: Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741)., Methods: In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity., Results: A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts., Conclusions: Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Neonatal hypothermia is a major cause of preventable morbidity and mortality, especially among the world's poorest newborns. A heat-producing wrap is necessary when kangaroo mother care (KMC) is insufficient or unavailable, yet there is little published research on such wraps. The Dream Warmer is a wrap designed to complement KMC and has been extensively studied in formal research settings but not in real-world conditions. Objectives: We used implementation science methodology to understand the safety, effectiveness, and functionality of the Dream Warmer (hereafter, "Warmer"); its effect on clinical workflows; its interaction with other aspects of care such as KMC; and the Warmer's reception by healthcare providers (HCPs) and parents. Methods: We conducted a prospective, interventional, one-arm, open-label, mixed-methods study in 6 district hospitals and 84 associated health centers in rural Rwanda. Our intervention was the provision of the Warmer and an educational curriculum on thermoregulation. We compared pre and post intervention data using medical records, audits, and surveys. Findings: The Warmer raised no safety concerns. It was used correctly in the vast majority of cases. The mean admission temperature rose from slightly hypothermic (36.41 °C) pre, to euthermic (36.53 °C) post intervention ( p = 0.002). Patients achieved a temperature ≥36.5 °C in 86% of uses. In 1% of audits, patients were hyperthermic (37.6-37.9 °C). Both HCPs and parents reported a generally positive experience with the Warmer. HCPs were challenged to prepare it in advance of need. Conclusions: The Warmer functions similarly well in research and real-world conditions. Ongoing education directed toward both HCPs and parents is critical to ensuring the provision of a continuous heat chain. Engaging families in thermoregulation could ease the burden of overtaxed HCPs and improve the skill set of parents. Hypothermia is a preventable condition that must be addressed to optimize neonatal survival and outcome., Competing Interests: Anne Hansen is the founder of Global Newborn Solutions, a nonprofit organization that manufactures and distributes the Dream Warmer. This is an unpaid position. The rest of the authors have no declarations., (Copyright: © 2024 The Author(s).)

Background: Mental health impacts a person's quality of life and ability to engage in healthy behaviors. Rural communities in the United States have limited access to mental and behavioral health treatment., Aim: To conduct a systematic review to identify existing rural community-based mental health interventions and identify commonalities and differences by extracting study attributes and intervention components., Methods: March 2022 CINAHL, EMBASE, PsycInfo, Scopus, and Academic Search Complete were searched for studies that met the inclusion criteria of rural, community-based mental health interventions in the United States., Results: Ten publications satisfied the criteria for this review. The most common intervention components identified were peer interaction, developed coping skills, and activity-based interventions., Conclusion: While this review excluded a meta-analysis, it did illuminate the components of existing community-based mental health interventions and highlighted gaps in the current research. Our findings suggest that future community-based mental health interventions would benefit from the inclusion of peer interaction, coping skills development, activity-based, cultural & historical context, service referral, and spirituality.

Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab., Significance: Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects., Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control., Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022., Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0., Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings., Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%)., Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Background: Existing data on the impact of Hispanic ethnicity on outcomes for patients with renal cell carcinoma (RCC) is mixed. The authors investigated outcomes of Hispanic and non-Hispanic White (NHW) patients with advanced RCC receiving systemic therapy at large academic cancer centers using the International Metastatic Renal Cell Carcinoma Database (IMDC)., Methods: Eligible patients included non-Black Hispanic and NHW patients with locally advanced or metastatic RCC initiating systemic therapy. Overall survival (OS) and time to first-line treatment failure (TTF) were calculated using the Kaplan-Meier method. The effect of ethnicity on OS and TTF were estimated by Cox regression hazard ratios (HRs)., Results: A total of 1563 patients (181 Hispanic and 1382 NHW) (mostly males [73.8%] with clear cell RCC [81.5%] treated with tyrosine kinase inhibitor [TKI] monotherapy [69.9%]) were included. IMDC risk groups were similar between groups. Hispanic patients were younger at initial diagnosis (median 57 vs. 59 years, p = .015) and less likely to have greater than one metastatic site (60.8% vs. 76.8%, p < .001) or bone metastases (23.8% vs. 33.4%, p = .009). Median OS and TTF was 38.0 months (95% confidence interval [CI], 28.1-59.2) versus 35.7 months (95% CI, 31.9-39.2) and 7.8 months (95% CI, 6.2-9.0) versus 7.5 months (95% CI, 6.9-8.1), respectively, in Hispanic versus NHW patients. In multivariable Cox regression analysis, no statistically significant differences were observed in OS (adjusted hazard ratio [HR], 1.07; 95% CI, 0.86-1.31, p = .56) or TTF (adjusted HR, 1.06; 95% CI, 0.89-1.26, p = .50)., Conclusions: The authors did not observe statistically significant differences in OS or TTF between Hispanic and NHW patients with advanced RCC. Receiving treatment at tertiary cancer centers may mitigate observed disparities in cancer outcomes., (© 2024 American Cancer Society.)

Background: Gut microbiome modulation to boost antitumor immune responses is under investigation., Methods: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis., Results: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics., Conclusions: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates and Maxime Chénard-Poirier, Aaron R. Hansen, Martin E. Gutierrez, Drew Rasco, Yan Xing, Manish R. Sharma.)

Metastatic castrate resistant prostate cancer (mCRPC) continues to have poor survival rates due to limited treatment options. Bi-specific T cell engagers (BiTEs) are a promising class of novel immunotherapies with demonstrated success in haematological malignancies and melanoma. BiTEs developed for tumour associated antigens in prostate cancer have entered clinical testing. These trials have been hampered by high rates of treatment related adverse events, minimal or transient anti-tumour efficacy and generation of high titres of anti-drug antibodies. This paper aims to analyse the challenges faced by the different BiTE therapy constructs and the mCRPC tumour microenvironment that result in therapeutic resistance and identify possible strategies to overcome these issues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lampe, Tam and Hansen.)

Aims: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT)., Patients and Methods: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method., Results: Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001)., Conclusion: Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silke Gillessen: Personal honoraria: advisory boards from Amgen, MSD; invited speaker ESMO, Swiss group for Clinical Cancer Research (SAKK), German-speaking European School of Oncology (DESO), Swiss Academy of Multidisciplinary oncology (SAMO); travel grant from AstraZeneca, Bayer. Institutional honoraria: advisory boards or in Independent Data Monitoring-/Steering Committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, DAIICHI Sankyo, Innomedica, Ipsen, Meister-ConCept, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma; invited speaker SAKK, ASCO GU, ESMO, PeerVoice, Silvio Grasso Consulting, WebMD-Medscape. Patent for a research method for biomarker WO2009138392. Karim Fizazi: Participation to advisory boards and talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi. Honoraria go to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for Arvinas, CureVac, Macrogenics and Orion. Darren Feldman: Consulting: BioNTech, Telix, Renibus, Xencor. Research Funding: Telix, Exelixis, BMS, Decibel. Royalties: UpToDate. All other authors did not declare any conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Plasmablastic Lymphoma (PBL) is a rare aggressive B-cell lymphoma that primarily affects immunocompromised individuals, including those living with HIV. Historically, survival estimates are dismal and range from 8 to 15 months. We aimed to evaluate epidemiologic characteristics, treatment patterns and survival trends on a national scale., Patients and Methods: Patients diagnosed with PBL from 2010 to 2020 were identified in the National Cancer Database (NCDB) and in the Surveillance, Epidemiology, and End Results (SEER) program. Incidence rates were calculated using SEER. Demographic features, treatment characteristics, and overall survival (OS) were identified using the NCDB., Results: We identified 1153 patients in the SEER database and 1822 patients in the NCDB. The incidence of PBL is 0.07 cases per 100,000 US population per year. PBL is more common in males (77%), and white patients (77%), with 50% of cases in patients with HIV. Patients who were treated with multiagent chemotherapy had a median OS of 58.6 months. On multivariate Cox regression, we found that HIV status did not have a significant impact on OS. Factors associated with worse OS included advancing age and stage., Conclusion: We present the largest study to date on PBL. Among treated patients, we described a median OS of 58.6 months, greatly improved from previously reported estimates. We found that HIV status did not have a significant impact on OS. While OS remains poor, therapeutic advances over the last decade are promising and highlight the need for continued clinical advances aimed at improving therapeutic options for this rare lymphoma., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The operational building data presented in this paper has been collected from six office rooms located in an office building (research and educational purposes) located on the main campus of Aalborg University in Denmark. The dataset consists of measurements of occupancy, indoor environmental quality, room-level and system-level heating, ventilation and lighting operation at a 5 min resolution. The indoor environmental quality and building system data were collected from the building management system. The occupancy level in each monitored room is established from the computer vision-based analysis of wall-mounted camera footage of each office. The number of people present in the room is estimated using the YOLOv5s image recognition algorithm. The present dataset can be used for occupancy analysis, indoor environmental quality investigations, machine learning, and model predictive control., (© 2024 The Author(s).)

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3-27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7-5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2-9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7-6.8) and 2.8 months (95% CI: 1.8-3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization., Competing Interests: Authors had no conflict of interest to declare., (Copyright: Esmail Al-Ezzi et al.)

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2., (© 2024. The Author(s).)

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Whole genome sequencing (WGS) is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases and for identification of actionable cancer drivers. Compared to other molecular genetic methods, WGS captures most genomic variation and eliminates the need for sequential genetic testing. Whereas, the laboratory requirements are similar to conventional molecular genetics, the amount of data is large and WGS requires a comprehensive computational and storage infrastructure in order to facilitate data processing within a clinically relevant timeframe. The output of a single WGS analyses is roughly 5 MIO variants and data interpretation involves specialized staff collaborating with the clinical specialists in order to provide standard of care reports. Although the field is continuously refining the standards for variant classification, there are still unresolved issues associated with the clinical application. The review provides an overview of WGS in clinical practice - describing the technology and current applications as well as challenges connected with data processing, interpretation and clinical reporting., (© 2024. The Author(s).)

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Purpose: International guidelines advocate for active surveillance as the preferred treatment strategy for patients with stage 1 testicular cancer after orchidectomy although a personalized discussion is required., Materials and Methods: We conducted an analysis of individuals registered in iTestis, Australia's testicular cancer registry, to describe the patterns of relapse and outcomes of patients treated in Australia where the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Surveillance Recommendations are widely adopted., Results: A total of 650 individuals diagnosed between 2000 and 2020 were included, 63% (411 of 650) seminoma and 37% (239 of 650) nonseminoma. The median age was 34 years (range 14-74). 26% (106 of 411) with seminoma and 15% (36 of 239) nonseminoma received adjuvant chemotherapy. After a median follow-up of 43 months (range 0-267) postorchidectomy, relapse occurred in 10% (43 of 411) of seminoma and 18% (43 of 239) of nonseminoma. The two-year relapse-free survival was 92% (95% CI, 89 to 95) and 82% (95% CI, 78 to 87) in seminoma and nonseminoma, respectively. All relapses (86 of 86) were detected at a routine surveillance visit; 98% (85 of 86) were asymptomatic and detected solely through imaging (62 of 86, 72%), tumor markers (6 of 86, 7%), or a combination (17 of 86, 20%). The most common relapse site was isolated retroperitoneal lymphadenopathy (53 of 86, 62%). No nonpulmonary visceral metastases occurred. At relapse, 98% (84 of 86) had International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis; 2 of 86 intermediate prognosis (both nonseminoma). No deaths occurred., Conclusion: In our cohort of stage 1 testicular cancer, where national surveillance recommendations have been widely adopted, recurrences were detected at routine surveillance visits and, almost exclusively, asymptomatic with IGCCCG good-prognosis disease. This provides reassurance that active surveillance is safe.

Background: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb)., Methods: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal-Wallis test. MFI 500 was used as threshold to define autoAb reactivity., Results: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009)., Conclusions: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311)., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

Purpose: Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma., Patients and Methods: Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters., Results: Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival., Conclusions: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated., (©2023 American Association for Cancer Research.)

Purpose: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer., Patients and Methods: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile., Results: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078)., Conclusions: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer., (©2023 American Association for Cancer Research.)

Objectives: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT)., Methods: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT., Results: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed., Conclusions: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)