Search

We consider medium access control (MAC) in multihop sensor networks, where only partial information about the shared medium is available to the transmitter. We model our setting as a queuing problem in which the service rate of a queue is a function of a partially observed Markov chain representing the available bandwidth, and in which the arrivals are controlled based on the partial observations so as to keep the system in a desirable mildly unstable regime. The optimal controller for this problem satisfies a separation property: we first compute a probability measure on the state space of the chain, namely the information state, then use this measure as the new state on which the control decisions are based. We give a formal description of the system considered and of its dynamics, we formalize and solve an optimal control problem, and we show numerical simulations to illustrate with concrete examples properties of the optimal control law. We show how the ergodic behavior of our queuing model is characterized by an invariant measure over all possible information states, and we construct that measure. Our results can be specifically applied for designing efficient and stable algorithms for medium access control in multiple-accessed systems, in particular for sensor networks.

We consider medium access control (MAC) in multihop sensor networks, where only partial information about the shared medium is available to the transmitter. We model our setting as a queuing problem in which the service rate of a queue is a function of a partially observed Markov chain representing the available bandwidth, and in which the arrivals are controlled based on the partial observations so as to keep the system in a desirable mildly unstable regime. The optimal controller for this problem satisfies a separation property: we first compute a probability measure on the state space of the chain, namely the information state, then use this measure as the new state on which the control decisions are based. We give a formal description of the system considered and of its dynamics, we formalize and solve an optimal control problem, and we show numerical simulations to illustrate with concrete examples properties of the optimal control law. We show how the ergodic behavior of our queuing model is characterized by an invariant measure over all possible information states, and we construct that measure. Our results can be specifically applied for designing efficient and stable algorithms for medium access control in multiple-accessed systems, in particular for sensor networks.

We report the film deposition of Poly(D,L-lactide-co-glycolide) (PLGA) particle systems by matrix assisted pulsed laser evaporation (MAPLE) technique. PLGA+polyvinyl alcohol (PVA), PLGA+PVA+ bovine serum albumin (BSA) and PLGA+PVA+chitosan (CH) nanoparticles were prepared by an oil-in-water emulsion-diffusion-evaporation method. The average diameter of PLGA particles was between 180-250 nm. The coatings were obtained by laser evaporation of frozen targets prepared by mixing appropriate PLGA aqueous suspensions and dimethyl sulfoxide (DMSO) in three ratios. Depending on the DMSO content, we deposited PLGA particles embedded into polymeric layer mainly obtained due to the entirely or partially dissolving of nanoparticles into the initial solution. In vitro results showed that the distribution and morphology of osteoblast-like SaOs-2 cells on some PLGA particle coatings were similar with that of the positive control. The purpose of this study was to develop layers of PLGA particles for local controlled drug delivery. [ABSTRACT FROM AUTHOR]

Using this system as active compound carrier, the anti-bacterial activity of the Fe3O4/oleic acid/cephalosporins nanoparticles (core/shell/adsorption-shell) on S. aureus and E. coli was tested. The dimensions of Fe3O4 nanoparticles were in the 5-20 nm range and they were characterized by High Resolution Transmision Electron Microscopy. The antibacterial activity was observed in both, reference Fe3O4/oleic acid shell nanoparticles and adsorption shell cephalosporins case. These nanofluids may be used in drug delivery systems. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10 -5 ) and OS (P = 7.07 × 10 -5 ) than chemotherapy (n = 102; BOR: P = 1.01 × 10 -4 ; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305 ., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, and The Authors.)

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1 , BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

Introduction: Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis., Methods: This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types., Results: Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations., Discussion and Conclusions: The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study., (© 2024 Merck Sharp & Dohme LLC. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To evaluate the prevalence and prognostic role of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in patients with non-immunotherapy-treated advanced cervical cancer., Methods: Clinical data were retrospectively collected from medical records between January 1, 2008, and December 31, 2016, at Asan Medical Center (Korea); archived tumor samples were assessed for PD-L1 expression (combined positive score [CPS] ≥1) and TMB (≥175 mutations/exome). Overall survival (OS) was defined as time from advanced diagnosis or initiation of first-line or second-line systemic therapy until death/last follow-up. The association of OS with PD-L1 expression and TMB were analyzed using the log-rank test and Cox proportional hazards model adjusted for covariates., Results: Of 267 patients, 76.0% had squamous cell carcinoma (SCC), 24.0% had adenocarcinoma (AC)/adenosquamous carcinoma (ASC), 64.4% had PD-L1 CPS ≥1, and 32.6% had TMB ≥175 mutations/exome. PD-L1 CPS ≥1 and TMB ≥175 mutations/exome were more prevalent in SCC than in AC/ASC (73.9% and 37.2% vs. 34.4% and 17.7%). There was no association between OS and PD-L1 expression (CPS ≥1 vs. <1: adjusted hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.84-1.53 from advanced diagnosis); OS trended shorter for the subgroup with TMB ≥175 versus <175 mutations/exome (adjusted HR=1.29; 95% CI=0.95-1.75)., Conclusion: Retrospective analysis of non-immunotherapy-treated patients with advanced cervical cancer demonstrated a higher prevalence of PD-L1 CPS ≥1 and TMB ≥175 mutations/exome in SCC versus AC/ASC. PD-L1 CPS ≥1 was not associated with OS; TMB ≥175 mutations/exome showed a trend toward shorter OS. Additional studies are needed to confirm these findings., Competing Interests: J-YP and M-HB have nothing to disclose. LC, CS, and PJ are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. CT and XYJ are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. RC is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, owns stock in Merck & Co., Inc., Rahway, NJ, USA, and has two pending patents (Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists; patent WO 2020/167619). SI is an employee of MSD Korea (employment [JCAP asso RDMA]), registered pharmacist (Korea), and stockholder of Merck & Co., Inc., Rahway, NJ, USA., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: Authors evaluated the performance of a commercially available next-generation sequencing assay kit; this was based on genomic content from Illumina's TruSight™ Oncology 500 research assay that identifies BRCA variants and proprietary algorithms licensed from Myriad and, with additional genomic content, measures the homologous recombination deficiency (HRD) genomic instability score (GIS) in tumor tissue (TSO 500 HRD assay)., Methods: Data from the TSO 500 HRD assay were compared with data from the Myriad MyChoice®CDx PLUS assay (Myriad assay). Prevalence rates for overall HRD status and BRCA mutations (a deleterious or suspected deleterious BRCA1 or BRCA2 mutation or both) and assay agreement rates for HRD GIS and BRCA analysis were assessed in ovarian tumor samples. Pearson correlations of the continuous HRD GIS and analytic sensitivity and specificity were evaluated., Results: The prevalence of overall HRD positivity was 51.2% (TSO 500 HRD assay) versus 49.2% (Myriad assay) and the prevalence of BRCA mutations was 27.6% (TSO 500 HRD assay) versus 25.5% (Myriad assay). After post-processing optimization, concordance of the HRD GIS was 0.980 in all samples and 0.976 in the non-BRCA mutation cohort; the area under the receiver operating characteristic curve was 0.995 and 0.992, respectively., Conclusions: Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay., Competing Interests: Declaration of competing interest A.K.W., P.Q., and M.J.M. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders of Merck & Co., Inc., Rahway, NJ, USA. J.L. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA, and reports two pending patents (ANGIOGENESIS AND mMDSC GENE EXPRESSION BASED BIOMARKER OF TUMOR RESPONSE TO PD-1 ANTAGONISTS; Patent WO/2020/167619). A.Y. is an employee and stockholder of AstraZeneca. R.C. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA, and reports two pending patents (ANGIOGENESIS AND mMDSC GENE EXPRESSION BASED BIOMARKER OF TUMOR RESPONSE TO PD-1 ANTAGONISTS; Patent WO 2020/167619). L.L., K.R., S.B., and J.R.D. are employees of and hold stock or stock options with Illumina. K.M.T. reports patents planned, issued, or pending at Myriad Genetics, Inc. (self and institution); stock or stock options in Myriad Genetics, Inc. (self) and Illumina (spouse); and employment at Myriad Genetics, Inc. (self) and Illumina (spouse). W.W. has attended and given talks at advisory boards; advised and served as speaker on national and international conferences for Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Eisai, Johnson & Johnson, Janssen, Illumina, Siemens, Agilent, ADC, GSK, and Molecular Health; and receives research funding from Roche, MSD, BMS, and AstraZeneca., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset., Methods: Deidentified data for patients who had undergone comprehensive genomic profiling using FoundationOne ® CDx were collected through December 31, 2020, from a real-world multi-tumor clinico-genomic database (CGDB) capturing data from clinics in the United States. Patients eligible for inclusion in this analysis had a confirmed diagnosis with advanced or metastatic disease between January 1, 2018, and December 31, 2019, for 1 of 15 solid tumor types. Objectives were to evaluate patient treatment patterns by BRCAm, HRRm, and HRD status and to describe the timing of when (throughout disease course) comprehensive genomic profiling was performed., Results: Among 9457 patients included in the overall population with evaluable biomarker status, 7856 (83.1%) received ≥ 1 systemic therapy. Among the 7856 patients who received systemic therapy, 2324 (30.0%) underwent testing before first-line therapy, 4114 (52.4%) were tested after receiving first-line therapy and before receiving subsequent therapy (if any), 970 (12.3%) were tested after second-line therapy and before receiving subsequent therapy (if any), and 447 (5.7%) patients underwent testing after receiving third-line therapy. A higher proportion of patients with BRCAm, HRRm, or HRD-positive status were treated with poly(ADP-ribose) polymerase (PARP) inhibitors across all lines of therapy. There was no evidence of a meaningful difference in the proportion of patients who received other treatment (including chemotherapy and immunotherapy) by BRCAm, HRRm, or HRD status., Conclusion: The majority of patients from this real-world dataset underwent FoundationOne ® CDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest., Methods: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (Tcell inf GEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES)., Results: 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between Tcell inf GEP and TMB, Tcell inf GEP and microvessel density (MVD), or MVD and TMB., Conclusions: This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted., Trial Registration Number: NCT02501096., Competing Interests: Competing interests: VM is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. Study support (all funding to institution)/unpaid consultancy/advisory board membership from AstraZeneca, Clovis, Duality, Eisai, Faeth, Genentech, GSK, Immunocore, iTEOS, Kartos, Karyopharm, Moreo, Morphosys, MSD, Novartis, Takeda, and Zymeworks. MHT received honoraria for consulting/advisory board participation from Bristol-Myers Squibb, Eisai Inc, Novartis, Merck & Co., Inc., Pfizer, Bayer, Sanofi/Genzyme, Regeneron, LOXO Oncology, Blueprint Medicines, Immune-onc, Exelixis, and Cascade Prodrug. MHT received honoraria for participation in speakers' bureaus from Bristol-Myers Squibb, Eisai Inc, Blueprint Medicines, and Merck & Co., Inc. Research funding to Dr Taylor’s institution was provided by Bristol-Myers Squibb, Eisai, Merck & Co., Inc., Pfizer, Immune-Onc, and Simcha. CA: Clinical trial funding (to institution): AbbVie, Artios Pharma, AstraZeneca, Clovis, and Genentech/Roche; Advisory board (fees): Merck; Advisory board (no fees): Blueprint Medicine; Data Monitoring Committee: AstraZeneca; Leadership role: GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology, Board of Directors (unpaid). CA is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. ALC: Honoraria: Amgen; Expert Testimony: Department of Justice. MSB: Consulting/advisory board member (honoraria paid to me): Eisai Inc, Exelixis, Loxo Oncology, Eli Lilly, and Bayer Pharmaceuticals. CDS: Nothing to disclose. ZAC, AL, RC, PJ, and RO: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders in Merck & Co., Inc., Rahway, NJ, USA. LS: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. LD, JM, and CED: Employees of Eisai Inc., Nutley, NJ, USA. YM: Employee of Eisai Co. Ltd., Tsukuba, Japan, and a stockholder in Eisai Co., Ltd. MJM: Nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Homologous recombination repair mutation (HRRm) status may guide risk-stratification and treatment decisions, including polyadenosine diphosphate-ribose polymerase inhibitor use, in advanced prostate cancer. Although HRRm prevalence has been reported in single-institution studies or clinical trials, real-world HRRm prevalence in diverse populations is unknown. We describe HRRm in the clinical setting using two real-world clinicogenomic databases: the Flatiron Health and Foundation Medicine, Inc. Clinico-Genomic Database (CGDB), a national electronic health record-derived database, and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE)., Methods: This cross-sectional analysis included 3757 individuals diagnosed with prostate cancer who had next generation sequencing (NGS) as standard of care. The CGDB included men with advanced/metastatic prostate cancer and genetic data included both germline and somatic pathogenic mutations. The GENIE analysis included men with prostate cancer whose received NGS as standard of care, but the data were filtered to include somatic mutations only. Due to key differences among databases, direct comparisons were not possible. Overall prevalence of HRRm was calculated and stratified by demographic and clinical characteristics., Results: HRRm prevalence (combined germline and somatic) in CGDB (n = 487) was 24.6% (95% CI 20.9-28.7%), with no major differences across demographic and disease characteristic subgroups. HRRm prevalence (somatic) in GENIE (n = 3270) was 11.0% (95% CI 10.0-12.1%), which varied between 9.5% and 18.4% across treatment centers., Conclusions: Approximately one-quarter of patients with advanced/metastatic prostate cancer in the CGDB had germline and/or somatic HRRm, which is consistent with clinical trials such as the PROfound study that used a similar NGS platform and algorithm to define HRRm. In the GENIE database, HRRm prevalence varied by treatment center or NGS platform. More research is needed to understand real-world HRRm prevalence variations., (© 2023. The Author(s).)

Objective: This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study., Methods: Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [Tcell inf GEP] and 10 non-Tcell inf GEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for Tcell inf GEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-Tcell inf GEP signatures; all but Tcell inf GEP and TMB were adjusted for multiplicity., Results: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and Tcell inf GEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c + and CD11c + /MHCII - /CD163 - /CD68 - in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively)., Conclusions: This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c + and CD11c + /MHCII - /CD163 - /CD68 - phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC., Clinical Trial Registration: ClinicalTrials.gov, NCT02674061., Competing Interests: Declaration of Competing Interest J.A. Ledermann reports receiving research grants from AstraZeneca and Merck/MSD; lecture fees from Clovis Oncology, AstraZeneca, Neopharm, GSK and MSD/Merck; and advisory board fees from AstraZeneca, GSK, Artios Pharma, Clovis Oncology, ImmunoGen, Mersana, Bristol Myers Squibb, Nuvation, Ellipses Pharma, VBL Therapeutics, Eisai, Regeneron, and Immagene, outside of the submitted work. R. Shapira-Frommer reports receiving support with medical writing for the submitted work from MSD; a research grant from MSD; consulting fees paid to her from MSD and Clovis Oncology; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events paid to her from MSD, Bristol Myers Squibb, Roche, AstraZeneca, Sanofi, Medison Pharma, Neopharm, and Novartis; participation on a data safety monitoring board or advisory board for MSD (received personal fee), Novartis (received personal fee), and AstraZeneca (unpaid); and a role in the ENGOT early phase study group (unpaid), outside of the submitted work. A.D. Santin reports grants or contracts paid to his institution from Genentech, Immunomedics, Gilead, Merck, Boehringer Ingelheim, and Tesaro; consulting fees paid to him from Merck, Eisai, and R-Pharm US; and participation on a data safety monitoring board or advisory board for Merck, Eisai, and R-PHARM US, outside of the submitted work. A.S. Lisyanskaya reports no disclosures. S. Pignata reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, GSK, Roche, AstraZeneca, and Clovis Oncology, outside of the submitted work. I. Vergote reports contracted research via KU Leuven to his institution from Oncoinvent AS; corporate-sponsored research to his institution from Amgen and Roche; consulting fees paid to him from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, Roche, Genmab, GSK, ImmunoGen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; and travel support to himself from Karyopharm Therapeutics, Genmab, and Novocure, outside of the submitted work. F. Raspagliesi reports receiving grants or contracts from GSK, MSD, and AstraZeneca; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from GSK, MSD, and AstraZeneca; and support for attending meetings and/or travel from GSK, outside of the submitted work. G.S. Sonke reports payments to his institution for inclusion of trial subjects and medical writing support, all from MSD, for the submitted work; institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche, and Seagen; and consulting fees paid to his institution from Biovica, Novartis, and Seagen, outside of the submitted work. M. Birrer reports no disclosures. D.M. Provencher reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca and GSK and participation on a data safety monitoring board or advisory board for GSK, outside of the submitted work. J. Sehouli reports receiving consulting fees from Roche, GSK, Tesaro, Novocure, Clovis Oncology, MSD, Merck, Pfizer, and Astra Zeneca; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, GSK, Tesaro, Novocure, Clovis, MSD, Merck, Pfizer, Astra Zeneca, and Eisai; support for attending meetings and/or travel from Roche, GSK, Tesaro, and AstraZeneca; participation on a data safety monitoring board or advisory board for Roche, GSK, Tesaro, Novocure, Clovis Oncology, MSD, Merck, Pfizer, AstraZeneca, Eisai, and PharmaMar; and roles on/as the council of ESGO), president of NOGGO, president of PARSGO, speaker of the Ovarian Cancer Commission (AGO), and delegate to GCIG, outside of the submitted work. N. Colombo reports receiving medical writing support from MSD for the submitted work; grants or contracts paid to her from MSD, Roche, and GSK; consulting fees paid to her from MSD, Roche, GSK, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to her from AstraZeneca, GSK, Novartis, Clovis Oncology, and MSD; support for attending meetings and/or travel from AstraZeneca, MSD, and GSK; participation on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, OncXerna Therapeutics, Pfizer, Pieris, and Roche; and unpaid roles for ACTO Onlus and ESMO Guidelines Committee, outside of the submitted work. A. González-Martín reports receiving grants or contracts from Roche, GSK, and CCUN; consulting fees paid to him from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Sutro Biopharma, Seagen, and Takeda; consulting fees paid to him from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Sutro Biopharma, Seagen, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to him from GSK, Clovis, AstraZeneca, MSD, Mersana, and Roche; support for attending meetings and/or travel paid to him from AstraZeneca/MSD and GSK; and unpaid roles as president of GEICO and ENGOT, outside of the submitted work. A. Oaknin reports grants or contracts paid to her institution from AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology Inc., Eisai, Roche, ImmunoGen, MSD de España S.A., Millennium Pharmaceuticals, PharmaMar SA, Regeneron Pharmaceuticals, and Tesaro; consulting fees paid to her from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, Roche, Genmab, GSK, ImmunoGen, Itheos, MSD de España, S.A., Mersana Therapeutics, Novocure, PharmaMar, prIME Oncology, Roche, Sattucklabs, Seagen, Sutro Biopharma, and Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ESMO, Edizioni Minerva Medica SpA, and Doctaforum Servicios S.L; support for attending meetings and/or travel paid to her from AstraZeneca, PharmaMar, and Roche; and payment to her for participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, Roche, Genmab, GSK, ImmunoGen, Itheos, MSD de España S.A., Mersana Therapeutics, Novocure, PharmaMar, prIME Oncology, Roche, Sattucklabs, Seagen, Sutro Biopharma, and Tesaro, outside of the submitted work. P. B. Ottevanger reports receiving support for manuscript writing and provision of study patients from MSD for the submitted work. V. Rudaitis reports no disclosures. J. Kobie is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. M. Nebozhyn is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA, and reports a pending patent (WO 2020/167619) related to the application of angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. M. Edmondson is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Y. Sun is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock in Merck & Co., Inc., Rahway, NJ, USA. R. Cristescu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock in Merck & Co., Inc., Rahway, NJ, USA; and reports a pending patent (WO 2020/167619) related to the application of Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. P. Jelinic is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. S.M. Keefe is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. U.A. Matulonis reports consulting fees paid to her from Merck, GSK, and AstraZeneca; payment made to her from Med Learning Group for her role on the committee on endometrial cancer, which involved creation of the entire lecture and slides; payment made to her for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Research to Practice; payments made to her for participation on the advisory board for Allarity, NextCure, Trillium, Agenus, ImmunoGen, Novartis, Boehringer Ingelheim, Rivkin Foundation, Ovarian Cancer Research Alliance, Clearity Foundation, MorphoSys, and CureLab; and payments for participation on a data safety monitoring board for Alkermes and Symphogen, outside of the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Mutations in BRCA1 and/or BRCA2 (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy., Methods: Deidentified data were collected through December 31, 2020, from a real-world clinicogenomic database (CGDB) with data originating from approximately 280 cancer clinics in the United States. Patients age 18 years and older with an advanced/metastatic diagnosis between 2018 and 2019 for 1 of 15 solid tumors and available data in the CGDB were included. The primary analysis evaluated the association between HRR pathway biomarkers and OS, using start of second-line therapy as the index date (to reduce immortal time bias)., Results: A total of 9,457 patients had available data for BRCA/HRR and 5,792 for HRD status; 4,890 (51.7%) were women and mean (SD) age was 65.9 (11.5) years. For the primary analysis, adjusted hazard ratios for OS were BRCAm (n = 156) versus BRCA wild-type (wt; n = 3,131; 0.83 [95% CI, 0.60 to 1.17]); for HRRm (n = 467) versus HRRwt (n = 282; 0.95 [95% CI, 0.79 to 1.14]); and for HRD-positive (n = 447) versus -negative (n = 1,687; 1.22 [95% CI, 1.02 to 1.47]). Results were similar using start of first-line and start of third-line therapy as index dates., Conclusion: This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.

Therapeutic polysaccharide-based coatings have recently emerged as versatile strategies to transform a conventional medical implant into a drug delivery system. However, the translation of these polysaccharide-based coatings into the clinic as drug delivery systems still requires a deeper understanding of their drug degradation/release profiles. This claim is supported by little or no data. In this review paper, a comprehensive description of the benefits and challenges generated by the polysaccharide-based coatings is provided. Moreover, the latest advances made towards the application of the most important representative coatings based on polysaccharide types for drug delivery are debated. Furthermore, suggestions/recommendations for future research to speed up the transition of polysaccharide-based drug delivery systems from the laboratory testing to clinical applications are given.

Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a heterogenous tumor microenvironment. KEYNOTE-495/KeyImPaCT is an ongoing biomarker-directed, adaptively randomized phase 2 study investigating first-line pembrolizumab (200 mg every 3 weeks) + lenvatinib (20 mg daily), anti-CTLA-4 quavonlimab (25 mg every 6 weeks) or anti-LAG-3 favezelimab (200 mg or 800 mg every 3 weeks) in advanced NSCLC. Patients were categorized by T-cell-inflamed gene expression profile (Tcell inf GEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. The primary outcome was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 using pre-specified efficacy thresholds for each biomarker-defined subgroup (>5% (Tcell inf GEP low TMB non-high (group I)), >20% (Tcell inf GEP low TMB high (group II) and Tcell inf GEP non-low TMB non-high (group III)) and >45% (Tcell inf GEP non-low TMB high (group IV))). Secondary outcomes were progression-free survival, overall survival and safety. At data cutoff, ORR ranges were 0-12.0% in group I, 27.3-33.3% in group II, 13.6-40.9% in group III and 50.0-60.0% in group IV. ORR with pembrolizumab + lenvatinib in group III met the pre-specified efficacy threshold. The safety profile of each treatment arm was consistent with the known safety profile of each combination. These data demonstrate the feasibility of prospective Tcell inf GEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial., Methods: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) and 10 non-Tcell inf GEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for Tcell inf GEP (prespecified α=0.05) and the 10 non-Tcell inf GEP signatures (multiplicity-adjusted; prespecified α=0.10)., Results: RNA sequencing data were available for 137 patients in each treatment group. Tcell inf GEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the Tcell inf GEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel., Conclusions: This exploratory analysis of tumor Tcell inf GEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis., Trial Registration Number: NCT02370498., Competing Interests: Competing interests: KS: reports receiving research funding paid to his institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, MSD, Amgen, Eisai, and Medi Science; consulting fees for advisory role from Eli Lilly and Company, Bristol Myers Squibb, Takeda Pharmaceuticals, Pfizer, Ono Pharmaceutical, Novartis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, MSD, Astellas, Guardant Health Japan, and Janssen; and honoraria for lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, and Janssen. MDB: reports participation on a data safety monitoring board/advisory board for MDS. MM: reports no disclosures. M-HR: reports receiving consulting fees from Ono Pharmaceutical, Bristol Myers Squibb, MSD, Eli Lilly, Taiho, Novartis, AstraZeneca, and Daiichi Sankyo. CC: reports receiving payment or honoraria from MSD and Roche, and other financial or nonfinancial interests paid to his institution for participating as a principal investigator or subinvestigator for MSD, Medivation, AstraZeneca, Roche, Astellas Pharma, Bristol Myers Squibb, GlaxoSmithKline, Athenex, Daiichi Sankyo, and Sanofi. TO: reports no disclosures. HCC: reports receiving study material and medical writing support for the present work from Merck; grants or contracts paid to his institution by Eli Lilly, GSK, MSD, Merck Serono, Bristol Myers Squibb/Ono Pharmaceutical, Taiho, Amgen, BeiGene, Incyte, and Zymeworks; consulting fees from Taiho, Celltrion Healthcare, MSD, Eli Lilly, Bristol Myers Squibb/Ono Pharmaceutical, Merck-Serono, Beigene/Amgen, and Zymeworks; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck Serono and Eli Lilly; and participation on a data safety monitoring board or advisory board for MSD. KM: reports receiving research funding paid to his institution from Solasia Pharma, Merck Serono, Daiichi Sankyo, Parexel International, Pfizer, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, and Eisai; consulting fees from AstraZeneca, Ono Pharmaceutical, and Amgen; honoraria for lectures from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, and Eli Lilly; and participation on an advisory board for Ono Pharmaceutical, Amgen, AstraZeneca, Eli Lilly, and Takeda. EG: reports no disclosures. RSM: reports no disclosures. WM: reports no disclosures. ZW: reports receiving support for the present work from Merck; grants paid to his institution from Novartis, Bristol Myers Squibb, Plexxikon, and Arcus; consulting fees from AstraZeneca, Arcus, Amgen, Bristol Myers Squibb, Novartis, Eli Lilly, Bayer, Daiichi, Merck, and Astellas; support for attending meetings and/or travel from Amgen; and participation on a data safety monitoring board or advisory board for Mirati and Pfizer. C-SS: employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, New Jersey, USA. JK: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. MN: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. RC: employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA, and has stock in Merck & Co., Rahway, New Jersey, USA; and reports a pending patent (WO 2020/167619) related to the application of Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. ZAC: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. AL: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. MÖ: reports no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The genetic consequences of the subdivision of populations are regarded as significant to long-term evolution, and research has shown that the scale and speed at which this is now occurring is critically reducing the adaptive potential of most species which inhabit human-impacted landscapes. Here, we provide a rare and, to our knowledge, the first analysis of this process while it is happening and demonstrate a method of evaluating the effect of mitigation measures such as fauna crossings. We did this by using an extensive genetic data set collected from a koala population which was intensely monitored during the construction of linear transport infrastructure which resulted in the subdivision of their population. First, we found that both allelic richness and effective population size decreased through the process of population subdivision. Second, we predicted the extent to which genetic drift could impact genetic diversity over time and showed that after only 10 generations the resulting two subdivided populations could experience between 12% and 69% loss in genetic diversity. Lastly, using forward simulations we estimated that a minimum of eight koalas would need to disperse from each side of the subdivision per generation to maintain genetic connectivity close to zero but that 16 koalas would ensure that both genetic connectivity and diversity remained unchanged. These results have important consequences for the genetic management of species in human-impacted landscapes by showing which genetic metrics are best to identify immediate loss in genetic diversity and how to evaluate the effectiveness of any mitigation measures., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Purpose: In the two-cohort phase II KEYNOTE-086 study (ClinicalTrials.gov identifier: NCT02447003), first-line and second-line or later pembrolizumab monotherapy demonstrated antitumor activity in metastatic triple-negative breast cancer (mTNBC; N = 254). This exploratory analysis evaluates the association between prespecified molecular biomarkers and clinical outcomes., Methods: Cohort A enrolled patients with disease progression after one or more systemic therapies for metastatic disease irrespective of PD-L1 status; Cohort B enrolled patients with previously untreated PD-L1-positive (combined positive score [CPS] ≥ 1) metastatic disease. The association between the following biomarkers as continuous variables and clinical outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) was evaluated: PD-L1 CPS (immunohistochemistry), cluster of differentiation 8 (CD8; immunohistochemistry), stromal tumor-infiltrating lymphocyte (sTIL; hematoxylin and eosin staining), tumor mutational burden (TMB; whole-exome sequencing [WES]), homologous recombination deficiency-loss of heterozygosity, mutational signature 3 (WES), mutational signature 2 (apolipoprotein B mRNA editing catalytic polypeptide-like; WES), T-cell-inflamed gene expression profile (Tcell inf GEP; RNA sequencing), and 10 non-Tcell inf GEP signatures (RNA sequencing); Wald test P values were calculated, and significance was prespecified at α = 0.05., Results: In the combined cohorts (A and B), PD-L1 ( P = .040), CD8 ( P < .001), sTILs ( P = .012), TMB ( P = .007), and Tcell inf GEP ( P = .011) were significantly associated with ORR; CD8 ( P < .001), TMB ( P = .034), Signature 3 ( P = .009), and Tcell inf GEP ( P = .002) with PFS; and CD8 ( P < .001), sTILs ( P = .004), TMB ( P = .025), and Tcell inf GEP ( P = .001) with OS. None of the non-Tcell inf GEP signatures were associated with outcomes of pembrolizumab after adjusting for the Tcell inf GEP., Conclusion: In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and Tcell inf GEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy.

Background: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial., Patients and Methods: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome., Results: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status., Conclusion: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: Selective root canal retreatment is when the treatment is limited to root(s) with radiographic evidence of periapical pathosis. The goals of this retrospective study were as follows: (i) evaluate the clinical and radiographic (periapical radiographs [PR] or cone-beam computerized tomographs [CBCT]) outcome of selective root canal retreatment after ≥12 months follow-up; (ii) evaluate the periapical status of the unretreated roots; and (iii) assess tooth survival., Methodology: A retrospective study (January 2018 to April 2021) was conducted to identify permanent multirooted teeth that underwent selective root canal retreatment. Clinical records, PR and CBCT were examined to ascertain variables of interest. Outcomes (per root and per tooth) were classified into 'favourable' or 'unfavourable' using well-established clinical and radiographic healing criteria. Treatment outcomes for the whole tooth and per root were compared as well as bivariate associations between the treatment outcome of the retreated roots and the treatment-related parameters (quality of root filling, sealer extrusion, iatrogenic mishaps and type of restoration) were analysed using Fisher's exact test (α = .05). Survival was recorded in months., Results: A total of 75 teeth (195 roots) in 75 subjects were available for outcome analysis. The favourable outcome per tooth was 86.7%. At follow-up, 92.6% of the retreated roots had a favourable outcome. From the unretreated roots, 3.5% showed radiographic signs of an emerging periapical lesion. No statistical difference was shown between the outcomes per root and per tooth between both groups. None of the treatment-related parameters had a direct influence on the outcome of the retreated roots. The survival rate at 12-48 months after retreatment was 91.5%., Conclusions: Selective root canal retreatment is associated with a favourable outcome in a majority of cases. Unretreated roots rarely developed radiographic signs of a new periapical lesion at follow-up. Future high-quality clinical trials with larger sample sizes and longer follow-up periods are required to confirm these findings., (© 2022 The Authors. International Endodontic Journal published by John Wiley & Sons Ltd on behalf of British Endodontic Society.)

Background: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored., Methods: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcell inf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS)., Results: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcell inf GEP. TMB, PD-L1, and Tcell inf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcell inf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcell inf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcell inf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcell inf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcell inf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method., Conclusions: TMB and the inflammatory biomarkers PD-L1 and Tcell inf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: We evaluated the performance of single-nucleotide polymorphism (SNP) genotyping arrays OncoScan (Thermo Fisher Scientific, San Diego, CA) and Infinium CytoSNP-850K (CytoSNP; Illumina, Waltham, MA) for assessing homologous recombination deficiency (HRD) genomic instability., Methods: DNA (pretreatment samples) across 20 tumor types was evaluated with OncoScan, CytoSNP, and the clinically validated HRD test. Copy number variation (CNV) and loss of heterozygosity (LOH) analyses were performed with ASCATv2.5.1. Aggregate HRD genomic metrics included LOH, telomeric-allelic imbalance number (TAI), and large-scale state transition (LST). Associations between BRCA mutation (BRCAm) status and the clinically validated HRD test metric (dichotomized at a clinical cut-off) were evaluated using area under the receiver operating characteristic (AUROC); Spearman ρ was calculated for continuous metrics. CNV segmentation and HRD genomic metrics were calculated (n = 120, n = 106, and n = 126 for OncoScan, CytoSNP and clinically validated HRD test, respectively)., Results: When assessed by SNP arrays, the genomic metric demonstrated good association with BRCAm (AUROC of HRD: OncoScan, 0.87; CytoSNP, 0.75) and the clinically validated test (cut-off, 42; AUROC of HRD: OncoScan, 0.92; CytoSNP, 0.91). The genomic metrics demonstrated good correlation with the clinically validated aggregate HRD test metric (ρ: OncoScan, 0.82; CytoSNP, 0.81) and for each component (ρ: OncoScan, 0.68 [LOH], 0.76 [TAI], and 0.78 [LST]; CytoSNP, 0.59 [LOH], 0.77 [TAI], and 0.82 [LST]). HRD assessed by SNP genotyping arrays and the clinically validated test showed good correlation., Conclusion: OncoScan and CytoSNP may potentially identify most HRD-positive tumors with appropriate clinically relevant cut-offs., (© 2022. © Merck&Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited., Objective: To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC and to determine their association with overall survival (OS)., Design, Setting, and Participants: From 100 patients, mCRPC biopsies were assayed by whole exome sequencing, targeted next-generation sequencing, RNA sequencing, tumor mutational burden, T-cell-inflamed gene expression profile (TcellinfGEP) score (Nanostring), and immunohistochemistry for programmed cell death 1 ligand 1 (PD-L1), ataxia-telangiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), SRY homology box 2 (SOX2), and the presence of neuroendocrine features., Outcome Measurements and Statistical Analysis: The phi coefficient determined correlations between biomarkers of interest. OS was assessed using Kaplan-Meier curves and adjusted hazard ratios (aHRs) from Cox regression., Results and Limitations: PD-L1 and SOX2 protein expression was detected by immunohistochemistry (combined positive score ≥1 and >5% cells, respectively) in 24 (33%) and 27 (27%) mCRPC biopsies, respectively; 23 (26%) mCRPC biopsies had high TcellinfGEP scores (>-0.318). PD-L1 protein expression and TcellinfGEP scores were positively correlated (phi 0.63 [0.45; 0.76]). PD-L1 protein expression (aHR: 1.90 [1.05; 3.45]), high TcellinfGEP score (aHR: 1.86 [1.04; 3.31]), and SOX2 expression (aHR: 2.09 [1.20; 3.64]) were associated with worse OS., Conclusions: PD-L1, TcellinfGEP score, and SOX2 are prognostic of outcome from the mCRPC setting. If validated, predictive biomarker studies incorporating survival endpoints need to take these findings into consideration., Patient Summary: This study presents an analysis of immune biomarkers in biopsies from patients with metastatic prostate cancer. We describe tumor alterations that predict prognosis that can impact future studies., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials., Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1 , and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11 , KEAP1 , and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome., Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n  = 293; KEYNOTE-407, n  = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1 , STK11, or KRAS mutation status., Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen., (© 2022 The Authors.)

As a third-generation β-lactam antibiotic, cefotaxime shows a broad-spectrum with Gram-positive and Gram-negative bacteria activity and is included in WHO's essential drug list. In order to obtain new materials with sustained release properties, the present research focuses on the study of cefotaxime absorption and desorption from different functionalized mesoporous silica supports. The MCM-41-type nanostructured mesoporous silica support was synthesized by sol-gel technique using a tetraethyl orthosilicate (TEOS) route and cetyltrimethylammonium bromide (CTAB) as a surfactant, at room temperature and normal pressure. The obtained mesoporous material (MCM-41 class) was characterized through nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), N 2 absorption-desorption (BET) and Fourier transform infrared spectroscopy (FT-IR), proving a good micro-structured homogeneity (SEM images), a high surface area (BET, 1029 m 2 /g) correlated with high silanolic activity (Q 3 /Q 4 peak ratio from 29 Si MAS-NMR), and an expected uniform hexagonal structure (2-3 nm, HRTEM). In order to non-destructively link the antibiotic compound on the solid phase, MCM-41 was further functionalized in two steps: with aminopropyl trimethoxysilane (APTMS) and glutaraldehyde (GA). Three cefotaxime-loaded materials were comparatively studied for low release capacity: the reference material with adsorbed cefotaxime on MCM-41, MCM-41/APS (aminopropyl silyl surface functionalization) adsorbed cefotaxime material, and APTMS-GA bounded MCM-41-cefotaxime material. The slow-release profiles were obtained by using an on-flow modified HPLC system. A significant improved release capacity was identified in the case of MCM-41/APS/GA-cefotaxime due to the covalent surface grafting of the biological active compound, recommending this class of materials as an effective carrier of bioactive compounds in wound dressing, anti-biofilm coatings, advanced drugs, and other related applications.

Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062., Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb., Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non-MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated., Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated., (©2022 American Association for Cancer Research.)

Background: Immunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well understood, and no validated predictive biomarkers are available. This exploratory study aimed to characterize baseline differences and molecular changes arising during treatment in acral and mucosal melanomas that exhibited primary or secondary resistance to anti-PD-1 monotherapy., Methods: This was an observational retrospective study of 124 patients who had been treated for metastatic acral or mucosal melanoma with anti-PD-1 monotherapy. Tumor samples were collected at baseline (all patients) and post-treatment (resistant tumors only) and were assayed by immunohistochemistry, whole-exome sequencing, and RNA sequencing., Results: At baseline, more non-progressor than resistant tumors exhibited expression of PD-L1, immune cell infiltration, and high tumor mutational burden (TMB); baseline PD-L1 expression was also more common in secondary-resistant than in primary-resistant tumors as well as in late versus early secondary-resistant tumors. Non-progressor tumors also had higher median baseline expression of an 18-gene T cell-inflamed gene expression profile (Tcell inf GEP). Among resistant tumors, the proportion of PD-L1-positive melanomas and the expression of the Tcell inf GEP mRNA signature increased during treatment, while the expression of mRNA signatures related to WNT and INFA1 signaling decreased. There was evidence for greater changes from baseline in secondary-resistant versus primary-resistant tumors for some markers, including expression of RAS-related and WNT-related mRNA signatures and density of CD11c + and FOXP3 + T cells. Greater changes in CD11c + cell density were observed in early compared with late secondary-resistant tumors., Conclusions: Our findings suggest that Tcell inf GEP and PD-L1 expression, TMB, immune cell infiltration, and RAS and WNT signaling warrant further investigation as potential mechanisms and/or biomarkers of anti-PD-1 therapy resistance in acral and mucosal melanomas. Confirmation of these findings in larger populations is needed., Competing Interests: Competing interests: IS, XQL, QZ, YS, JHY, TC, AW, CK, and RC are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Rahway, New Jersey, USA, and may have stock in Merck & Co., Rahway, New Jersey, USA. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)