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Background: Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months., Methods: Resolvin (Rv) E1, 15-epi-lipoxin (LX) A 4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants., Results: Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA 4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin., Conclusion: Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA 4 . We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation., Competing Interests: Declaration of Competing Interest CJR has received grant funding from Medtronic and was an expert witness for Olympus and ARC Medical. All the other Authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9; P < .001) or Gleason score greater than or equal to 4+3 (OR, 8.7; 95% CI: 4.5, 17.0; P < .001). MCCL also determined visibility (OR, 1.24 per millimeter increase; 95% CI: 1.15, 1.33; P < .001), but odds were lower with each prostate volume doubling (OR, 0.7; 95% CI: 0.5, 0.9). In men who were TPM-negative, the presence of PIN increased the odds of zonal visibility (OR, 3.7; 95% CI: 1.5, 9.1; P = .004). Conclusion An incremental relationship between cancer burden and prostate MRI visibility was observed. Prostatic intraepithelial neoplasia contributed to false-positive MRI findings. ClinicalTrials.gov registration no. NCT01292291 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens., Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis., Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy., Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-494/coif). EFB reports honorarium fees from Exelixis and AstraZeneca, consulting relationship with Johnson and Johnson, and grants from Pfizer and Astellas, and owns stock in Exelixis, Becton Dickinson, Calithera Biosciences, Medtronic, Macrogenics, Arvinas, Autolus. The other authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR's precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Merchak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation., (© 2022. The Author(s).)

Offal tissues carry a lower market value compared to skeletal meats in some global markets. The inclusion of offal in any meat product in the EU and UK must be declared on the label. While many technologies have been applied to the challenge of determining adulteration with offal in meat products, no single method has been recognised and validated as a reliable test to support legislative requirements. This literature review investigated appropriate methods to determine the adulteration of meat with offal. The aim was to identify technologies suitable for future validation to underpin a high throughput, low-cost method suitable for application by enforcement laboratories. Considering all of the methods, technologies which determine elemental composition and peptide markers were particularly highlighted as demonstrating potential for future development to determine a wide range of offal tissues to support the safety and integrity of the food chain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical efficacy of this strategy has been questioned. We systematically reviewed and meta-analyzed clinical trials for an association between the use of PGx-guided antidepressant therapy and depressive symptom remission in patients with major depressive disorder (MDD). We included prospective, controlled clinical trials published in English up to July 12, 2022. Data extraction and synthesis adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Each trial was assessed for risk of bias and a random-effects model was used to estimate pooled risk ratios. Thirteen trials comprising 4,767 patients were analyzed, including 10 randomized controlled trials, and three open label trials. Across all included trials, those that received PGx-guided antidepressant therapy (n = 2,395) were 1.41 (95% confidence interval (CI) = 1.15-1.74, P = 0.001) more likely to achieve remission compared with those that received unguided antidepressant therapy (n = 2,372). Pooled risk ratios for randomized controlled trials and open label trials were 1.46 (95% CI: 1.13-1.88) and 1.26 (95% CI = 0.84-1.88), respectively. These results suggest that PGx-guided antidepressant therapy is associated with a modest but significant increase in depressive symptom remission in adults with MDD. Efforts to address the heterogeneity in PGx test composition (i.e., genes and alleles tested) and accompanying prescribing recommendations across trials will likely reduce the uncertainty about the efficacy of PGx-guided antidepressant therapy in the literature., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The synthesis of deuteriated tri-tert-butyl phosphine is reported. This synthesis is an adaptation of the known procedure for tri-tert-butyl phosphine via a Grignard intermediate., (© 2022 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

Background: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy., Methods: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1., Results: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GE high ) on the 5-gene panel was 29% (14/48), compared with low gene expression (GE low ) 3% (1/38, χ 2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GE high and GE low in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS., Conclusion: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab., Competing Interests: Competing interests: LCB declares the following relationships: Consulting with Seattle Genetics. JZ declares the following relationships: Consulting with Tempus. KD declares the following relationship: Consulting with Tyra BioSciences. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. YHL is/was an employee at OmniSeq. SP is/was an employee at OmniSeq. MKL declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. JT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. KHD declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. LJT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. FD declares that he has received research grants (to the institution) from AstraZeneca, Bristol Myers Squibb, Merck, Genentech/Roche, Taiho, Exelixis, Trishula, Leap Therapeutics, has received a speaker honorarium from Amgen, Eisai, Ipsen, Exelixis, Sirtex, Deciphera, Ipsen, Natera, and has received a consultancy honorarium from Natera, QED, Eisai, Exelixis, Genentech/Roche. RTG declares the following relationships: Bayer Pharma AG—consultant & speakers bureau, Invivo—consultant, Bard—consultant, DxTx Medical—consultant, Quibim—consultant, Bracco Diagnostics—consultant. SM declares the following relationships: AstraZeneca—consultant; Takeda Pharmaceuticals—speaker, honorarium. DJG declares the following relationships: Acerta Pharmaceuticals—research; American Association for Cancer Research—senior editor; Astellas—consultant, research, advisory board; AstraZeneca—consultant, advisory board; Axess Oncology—independent contractor; Bayer H/C Pharmaceuticals—research, consultant, speaker, honorarium, travel accommodations; SC, BMS—consultant, research, steering committee; Calithera—research; Capio Biosciences—scientific advisory board; EMD Serono—honorarium; Exelixis—research, consultant, speaker, honorarium, travel accommodations; Flatiron—consultant; Ipsen—honorarium; Janssen Pharmaceuticals—research, consultant, Independent Data Monitoring Committee; Leidos Biomedical Research—consultant; Merck Sharp & Dohme—consultant; Michael J Hennessey Associates—honorarium, consultant; Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—co-editor-in-chief; Modra Pharmaceuticals B.V.—advisory board; Myovant Sciences—consultant; Nektar Therapeutics—steering committee; Novartis—research; Physician Education Resource LLC—consultant; Pfizer—research, consultant, steering committee, honorarium; Sanofi—research, consultant, speaker, honorarium, travel accommodations; UroGPO—honorarium; UroToday—honorarium, travel accommodations; Vizuri Health Sciences, LLC—consultant; NCI—steering committee. YHL is/was an employee at OmniSeq. STG is/was an employee at OmniSeq. MKN is/was an employee at OmniSeq. SG declares the following relationships: Aveo—advisory board, personal, advisor/consultant; Bayer—advisory board, personal, advisor/consultant; BMS—advisory board, personal, advisor/consultant; Corvus—advisory board, personal, advisor/consultant; Eisai—advisory board, personal, advisor/consultant; EMD Serono—advisory board, personal, advisor/consultant; Exelixis—advisory board, personal, advisor/consultant; Merck—advisory board, personal, advisor/consultant; Pfizer—advisory board, personal, advisor/consultant; QED Therapeutics—advisory board, personal, advisor/consultant; Sanofi/Genzyme—advisory board, personal, advisor/consultant; Seattle Genetics—advisory board, personal, advisor/consultant; Agensys—local PI, institutional, no financial interest; Aravive—local PI, institutional, no financial interest; Aveo—local PI, institutional, no financial interest; Bayer—local PI, institutional, no financial interest; BMS—local PI, institutional, no financial interest; Calithera—local PI, institutional, no financial interest; Corvus—local PI, institutional, no financial interest; Eisai—local PI, institutional, no financial interest; Exelixis—local PI, institutional, no financial interest; Gilead—local PI, institutional, no financial interest; Merck—local PI, institutional, no financial interest; Novartis—local PI, institutional, no financial interest; Pfizer—local PI, institutional, no financial interest; Seattle Genetics—local PI, institutional, no financial interest; Surface Oncology—local PI, institutional, no financial interest. MZ declares the following relationships: Consulting or advisory roles for: Exelixis, Pfizer, Aveo, EMD Serono, Janssen, Blue Earth; Institutional research funding from Bristol Myers Squibb, Exelixis. CM is/was an employee at OmniSeq. MCO declares the following relationships: Consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; speakers bureaus for Bristol Myers Squibb and Exelixis; institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas; reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, and Exelixis. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting/Advisory board with AstraZeneca, Bayer, Pfizer, Janssen, Merck, Amgen, MJH Associates, BMS, Dendreon, Calithera, QED therapeutics, Aveo Therapeutics, Eli Lilly, SeaGen, Sanofi-Aventis, Pharmacyclics, Aptitude Health, PeerView, Clinical Care Options. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© 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.)

Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown., Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression., Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10 -6 ). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037)., Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes., Trial Registration: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT  2004-000193-31 , registered on October 4, 2004., (© 2022. The Author(s).)

A lower baseline neutrophil-to-eosinophil ratio (NER) has been associated with improved responses to immune checkpoint inhibitors (ICI)-treated metastatic renal cell carcinoma (mRCC). This study investigated the decrease in NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. A retrospective study of ipi/nivo-treated mRCC at two US academic cancer centers was conducted. A landmark analysis at week 6 was performed to assess the association between the change in NER and clinical responses (progression-free survival (PFS)/overall survival (OS)). Week 6 NER was modeled as a continuous variable, after log transformation (Ln NER), and a categorical variable by percent change. There were 150 mRCC patients included: 78% had clear cell histology, and 78% were IMDC intermediate/poor risk. In multivariable regression analysis, every decrease of 1 unit of Ln NER at week 6 was associated with improved PFS (adjusted hazard ratio (AHR): 0.78, p-value:0.005) and OS (AHR: 0.67, p-value: 0.002). When NER was modeled by percent change, decreased NER > 50% was associated with improved PFS (AHR: 0.55, p-value: 0.03) and OS (AHR: 0.37, p-value: 0.02). The decrease in week 6 NER was associated with improved PFS/OS in ipi/nivo-treated mRCC. Prospective studies are warranted to validate NER change as a biomarker to predict ICI responses.

Background: Sickle cell disease (SCD) leads to end-organ damage and shortened life expectancy. The second highest incidence of SCD in Indiana is in Lake County, but until 2017, there was no SCD expert within 65 miles. The Indiana Hemophilia and Thrombosis Center (IHTC) developed the Sickle Care coordination OutReach and Education (SCORE) program in 2017 to bring high-quality, guideline-based care to children with SCD., Procedure: The St. Vincent IRB deemed this retrospective analysis of SCORE clinic care from 2017 to 2020 exempt. Data on the number of transcranial Dopplers (TCD) performed, HU dosing escalation, and vaccine rates were collected along with the number of school and home visits completed., Results: Fifty-three children, adolescents, and young adults completed 288 SCORE clinic visits during the study period; over 75% completed at least three clinic visits. Mean HU dose increased significantly with SCORE clinic care. TCD screening rates increased every year starting in 2018 through 2020 when we added local care coordination. One hundred seventy-three vaccines were administered in SCORE outreach clinics. The PPSV23 vaccines had a 100% acceptance rate, and seasonal influenza had a 75.8% acceptance rate., Conclusion: Access to care coordination services and local hematology specialty care alleviates barriers to care and enables comprehensive SCD care delivery to children in need. Prior to the establishment of the SCORE clinic, 75% of children in Lake County were not receiving recommended stroke screening. The SCORE clinic model demonstrates feasibility and impact when delivering on the promise of high-quality care for children with SCD., (© 2022 Wiley Periodicals LLC.)

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p corrected  = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation., (© 2022. The Author(s).)

Objectives:   Partial response to pharmacotherapy is common in major depressive disorder (MDD) and many patients require alternative pharmacotherapy or augmentation, including adjunctive L-methylfolate. Given that L-methylfolate augmentation is rarely included in major clinical practice guidelines, we sought to systematically review evidence for L-methylfolate augmentation in adults with MDD and to examine its efficacy meta-analytically., Methods:  We systematically searched PubMed for articles up to December 31, 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Included studies were published in peer-reviewed, English-language journals and examined L-methylfolate adjunctive therapy in depressive disorders or its effect on antidepressant response. A fixed- and random-effects meta-analysis and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted., Results:   Qualitative assessment of nine articles (N=6,707 patients) suggests that adjunctive L-methylfolate improved antidepressant response. In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N= 483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p= 0.004). A meta-analysis of four studies ( N= 507) using a continuous measure of depressive symptoms showed a similar effect of adjunctive L-methylfolate (standardized mean difference=- 0.38, 95% CI=- 0.59 to-0.17, p= 0.0003)., Conclusion:   Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD., Competing Interests: LCB was an employee of Tempus Labs which provides MTHFR genetic testing. AAM, EAP, CAB, and LCB are members of the Pharmacogenomics Research Network (PGRN) and Clinical Pharmacogenetics Implementation Consortium (CPIC). AAM, LCB, and CAB are members of the International Society for Psychiatric Genetics (ISPG)., (Thieme. All rights reserved.)

A series of amphiphilic statistical copolymers involving poly(ethylene glycol) monomethacrylate (PEGMA, -OH terminated, average Mn 200 molecular weight) and various hydrophobic acrylates were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The gradient copolymers were characterized by gel-permeation chromatography (GPC), 1 H nuclear magnetic resonance (NMR), and attenuated total reflection Fourier transform infrared spectroscopy (FTIR-ATR). Solution properties of the copolymers were investigated utilizing surface tension measurement, dynamic light-scattering (DLS), as well as foam analysis using a dynamic foam analyzer (DFA). The PEG-functionalized copolymers showed a systematic trend depending on the hydrophobic moiety in properties including surface tension, critical micelle concentration (CMC), foam lifetime, and liquid drainage from the foam. Copolymers with alkyl-acrylates exhibited the best foam lifetime, demonstrating that the choice of hydrophobic moiety is crucial for foam stability. The PEG-functionalized materials described are considered promising additives for foam-stability purposes.

Background: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years., Methods: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials., Results: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised., Conclusion: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

Background: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients., Methods: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19., Results: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder., Conclusions: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

There is an emerging body of evidence regarding the use of immunotherapy in early-stage triple negative breast cancer (TNBC), with the recent publication of several phase III and randomised phase II studies examining the role of immune checkpoint inhibitors (ICI) in the neoadjuvant setting in combination with chemotherapy. Evidence to date suggests that the addition of PD-1/PD-L1 inhibitors results in slight increases in the rate of pathologic complete response (pCR) seen at the time of surgery, and improved event free survival (EFS) has now been reported. However, a number of questions remain such as the optimal chemotherapy backbone; whether traditional third generation chemotherapy regimens can safely be de-escalated in the presence of an ICI; and the most appropriate sequencing of treatment in order to best harness a durable immune response and if continuation of post operative ICI is needed if one achieves a pCR. A predictive biomarker is also yet to be established, given that PD-L1 protein expression does not seem discriminatory. Given that long-term clinical outcome improvements seen thus far in early stage trials do not seem to be mediated through small changes in pathological complete response rates, new approaches in early stage trial design are now needed., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population., Methods: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544., Findings: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I 2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death)., Interpretation: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas., Competing Interests: Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas Pharma during the conduct of the study; personal fees or travel support from Pfizer, Ipsen, Novartis/AAA, Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Beigene, Takeda, AstraZeneca, and Sanofi-Aventis; and grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics, outside the submitted work; in addition, GA's former employer, The Institute of Cancer Research, receives royalty income from abiraterone and GA receives a share of this income through the Institute's Rewards to Discoverers Scheme. NWC reports personal fees from Janssen Pharmaceuticals and Astellas Pharma, during the conduct of the study; and personal fees from Bayer outside the submitted work. WC reports personal fees from Janssen and Bayer, outside the submitted work. RJJ reports grants from Sanofi, and grants and non-financial support from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Sanofi and Novartis, and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. CCP reports personal fees from AAA and Janssen, and research funding and speaker's honoraria from Bayer, outside the submitted work. SG reports personal fees from Bayer, Janssen Cilag, Dendreon Corporation, Millennium Pharmaceuticals, Orion, Sanofi, and MaxiVax; and speaker's fees and travel support from Bayer, CureVac, Janssen Cilag, Astellas, AAA Advanced Accelerator Applications International, Bristol-Myers Squibb (BMS), Ferring, Roche, Orion, lnnocrin Pharmaceuticals, Sanofi, Novartis, Nektar Therapeutics, and ProteoMedix, outside the submitted work. SC reports grants and personal fees from Sanofi-Aventis and personal fees from Janssen Pharmaceutical, outside the submitted work. ZM reports consultancy and advisory board membership for Janssen Consultancy, advisory board membership for Sanofi and Astellas, and sponsorship to attend medical conferences from Astellas, Bayer, and Janssen. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. JB reports payments from Janssen for webinar presentations. AL reports payment or honoraria for lectures, presentation, or events from BMS, and support for attending meetings or travel from Astellas, Bayer, BMS, and Merck Sharpe and Dohme. IP reports sponsorship from Bayer for attending the European Society for Medical Oncology congress virtually in 2021. JMO reports participating on a data safety monitoring board or advisory board for AA, Astellas, Bayer, Janssen, Novartis, and Sanofi. AB reports speaker's fees and travel support from Astellas, and personal fees, speaker's fees, and travel support from Sanofi and Janssen, during the conduct of the study; speaker's fees and travel support from Bayer and AstraZeneca, outside the submitted work; and speaker fee payment from Janssen. NS reports support for attending meetings or travel from Jansen, Astellas, and Eusa Pharma UK. JT reports support for travel and speaker fees from Jansen, Roche, and Bayer, and participating on a data safety monitoring board or advisory board for AstraZeneca, Astellas, and Bayer. JWa reports a paid consultancy for BMS, Eisai, Novartis, and MSD, oustide the submitted work. OP reports participating on a data safety monitoring board and advisory board for Janssen in October, 2021. IS reports support for attending meetings or travel for the 2020 American Society of Clinical Oncology Genitourinary Cancers symposium from Bayer. AZ reports payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from Pfizer, Janssen, Astellas, and Sanofi, and received support for attending meetings or travel from Bayer and Merck Sharpe and Dohme. JSdB reports employment by the Institute of Cancer Research that has a commercial interest in abiraterone acetate and personal fees from Janssen, during the conduct of the study; and personal fees, speaker's fees, and travel support from AstraZeneca, Pfizer, GlaxoSmithKline, Taiho, Daiichi, Novartis, Genmab, Merck Serono, Merck, and Genentech/Roche, outside the submitted work. DPD reports personal fees and speaker's fees and travel support from Takeda, Amgen, Astellas, Sandoz, and Cadence Research; personal fees and non-financial support from Janssen; travel support from Clovis; and personal fees and non-financial support from International Society for the Study and Exchange of evidence from Clinical research And Medical experience, outside the submitted work; in addition, DPD has a patent (GB9305269–17-substituted steroids useful in cancer treatment) with royalties paid to Janssen Pharmaceutical. MDM reports personal fees from Sanofi, Bayer, Dendreon, BMS, and Janssen, outside the submitted work. REL reports support for the present manuscript with funding from the UK Medical Research Council, part of the UK Research and Innovation. DM reports grants or contracts from Health Education England made to their institution, University of Wolverhampton, payments from Routledge for royalties on a book, payments from Authors' licensing and collecting society for royalties on photocopies of the book and chapters, and unpaid role as chair of a patient advocacy group, Prostate Cancer Research. MRS reports grants and non-financial support from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. MKBP reports grants and non-financial support from Janssen, during the conduct of the study; and grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work. NDJ reports grants and personal fees from Sanofi and Novartis, during the conduct of the study; and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The manner of bonding between constituent atoms or molecules invariably influences the properties of materials. Perhaps no material family is more emblematic of this than porous frameworks, wherein the namesake modes of connectivity give rise to discrete subclasses with unique collections of properties. However, established framework classes often display offsetting advantages and disadvantages for a given application. Thus, there exists no universally applicable material, and the discovery of alternative modes of framework connectivity is highly desirable. Here we show that chalcogen bonding, a subclass of σ-hole bonding, is a viable mode of connectivity in low-density porous frameworks. Crystallization studies with the triptycene tris(1,2,5-selenadiazole) molecular tecton reveal how chalcogen bonding can template high-energy lattice structures and how solvent conditions can be rationalized to obtain molecularly programmed porous chalcogen-bonded organic frameworks (ChOFs). These results provide the first evidence that σ-hole bonding can be used to advance the diversity of porous framework materials.

Purpose: Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy., Methods: FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability., Results: Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups., Conclusion: Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy., Competing Interests: Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck SeronoResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Matthew SeymourResearch Funding: Amgen, AstraZeneca Richard KaplanResearch Funding: AstraZeneca Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche have filed a patent jointly with my UniversityTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Ewan BrownResearch Funding: MSD Oncology Fiona CollinsonResearch Funding: Bristol Myers Squibb Stephen FalkStock and Other Ownership Interests: GlaxoSmithKlineSpeakers' Bureau: Merck Serono, Servier, AmgenResearch Funding: Gilead SciencesTravel, Accommodations, Expenses: CelgeneOther Relationship: Servier Harpreet WasanHonoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Roche/Genentech, ERYTECH Pharma, Incyte, ZymeworksConsulting or Advisory Role: Roche Pharma AG, ERYTECH Pharma, Shire, Incyte, Sirtex Medical, Pierre Fabre, Pfizer, BayerSpeakers' Bureau: Sirtex Medical, Celgene, Merck KGaA, Servier, IncyteResearch Funding: Sirtex Medical, Merck KGaA, Pfizer, Merck Sharp & Dohme Kai-Keen ShiuHonoraria: Merck Serono, MSD Oncology, Innovent Biologics, Servier, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: MSD Oncology, Roche, Mirati TherapeuticsResearch Funding: MSD Oncology, Roche Gary MiddletonConsulting or Advisory Role: BMS, D2G, MSDSpeakers' Bureau: Roche, BMS, Servier, PierreFabre, AZTravel, Accommodations, Expenses: BMS Leslie SamuelHonoraria: ServierConsulting or Advisory Role: MerckResearch Funding: Merck, Array BioPharma, Tesaro, Servier, Hutchison MediPharma Richard H. WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Louise C. BrownResearch Funding: AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Purpose: Outcomes in RAS -mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition., Methods: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level., Results: FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53 -mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%)., Conclusion: In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53 -mutant mCRC. Further testing is required in this sizable population of unmet need., Competing Interests: Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Louise C. BrownResearch Funding: AstraZeneca Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck Serono, AstraZeneca, Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche has filed a patent jointly with my University; I may receive income but none to dateTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Michael BraunHonoraria: Servier, Amgen, Pierre FabreTravel, Accommodations, Expenses: Servier Fiona CollinsonResearch Funding: Bristol Myers Squibb Rob JonesHonoraria: Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Seattle Genetics, Sanofi, Bayer, Roche/Genentech, EUSA Pharma, Pharmacyclics, Clovis Oncology, Merck Serono, EisaiConsulting or Advisory Role: Clovis OncologyResearch Funding: Roche, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Exelixis, Clovis Oncology, BayerTravel, Accommodations, Expenses: Ipsen, Bayer, Janssen, Astellas Pharma, MSD Ewan BrownResearch Funding: MSD Oncology Timothy C. HumphreyResearch Funding: Debiopharm Group Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Richard KaplanResearch Funding: AstraZeneca Richard WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Matthew SeymourResearch Funding: Amgen, AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Background: The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC., Methods: We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients., Results: A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with mNLR group., Conclusions: A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted., (© 2021. The Author(s).)

The quorum-sensing signaling systems in Vibrio bacteria converge to control levels of the master transcription factors LuxR/HapR, a family of highly conserved proteins that regulate gene expression for bacterial behaviors. A compound library screen identified 2-thiophenesulfonamide compounds that specifically inhibit Vibrio campbellii LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure-activity relationship effects on Vibrio quorum sensing. The most potent molecule identified, PTSP (3-phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole), inhibits quorum sensing in multiple strains of V. vulnificus, V. parahaemolyticus, and V. campbellii at nanomolar concentrations. However, thiophenesulfonamide inhibition efficacy varies significantly among Vibrio species: PTSP is most inhibitory against V. vulnificus SmcR, but V. cholerae HapR is completely resistant to all thiophenesulfonamides tested. Reverse genetics experiments show that PTSP efficacy is dictated by amino acid sequence in the putative ligand-binding pocket: F75Y and C170F SmcR substitutions are each sufficient to eliminate PTSP inhibition. Further, in silico modeling distinguished the most potent thiophenesulfonamides from less-effective derivatives. Our results revealed the previously unknown differences in LuxR/HapR proteins that control quorum sensing in Vibrio species and underscore the potential for developing thiophenesulfonamides as specific quorum sensing-directed treatments for Vibrio infections., (© 2021 John Wiley & Sons Ltd.)

Vibrio campbellii BB120 (previously classified as Vibrio harveyi) is a fundamental model strain for studying quorum sensing in vibrios. A phylogenetic evaluation of sequenced Vibrio strains in Genbank revealed that BB120 is closely related to the environmental isolate V. campbellii DS40M4. We exploited DS40M4's competence for exogenous DNA uptake to rapidly generate greater than 30 isogenic strains with deletions of genes encoding BB120 quorum-sensing system homologues. Our results show that the quorum-sensing circuit of DS40M4 is distinct from BB120 in three ways: (i) DS40M4 does not produce an acyl homoserine lactone autoinducer but encodes an active orphan LuxN receptor, (ii) the quorum regulatory small RNAs (Qrrs) are not solely regulated by autoinducer signalling through the response regulator LuxO and (iii) the DS40M4 quorum-sensing regulon is much smaller than BB120 (~100 genes vs. ~400 genes, respectively). Using comparative genomics to expand our understanding of quorum-sensing circuit diversity, we observe that conservation of LuxM/LuxN proteins differs widely both between and within Vibrio species. These strains are also phenotypically distinct: DS40M4 exhibits stronger interbacterial cell killing, whereas BB120 forms more robust biofilms and is bioluminescent. These results underscore the need to examine wild isolates for a broader view of bacterial diversity in the marine ecosystem., (© 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.)

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials., Competing Interests: Competing interests: LCB declares the following relationships: consulting with Seattle Genetics. KD declares the following relationship: consulting with Tyra BioSciences. WW declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. DG declares the following relationships: Acerta Pharmaceuticals—Research, American Association for Cancer Research—Sr Editor, Astellas—Consultant, Research, Advisory Board, Astrazeneca—Consultant, Advisory Board, Axess Oncology—Independent Contractor, Bayer H/C Pharmaceuticals—Research, Consultant, Speaker, Honorarium, Travel accommodations, SC, BMS—Consultant, Research, Steering Committee, Calithera—Research, Capio Biosciences—Scientific Advisory Board, EMD Serono—Honorarium, Exelixis—Research, Consultant, Speaker, Honorarium, Travel accommodations, Flatiron—Consultant, Ipsen—Honorarium, Janssen Pharmaceuticals—Research, Consultant, Independent Data Monitoring Committee (IDMC), Leidos Biomedical Research—Consultant, Merck Sharp & Dohme—Consultant, Michael J Hennessey Associates—Honorarium, Consultant, Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—Co-Editor-in-Chief, Modra Pharmaceuticals B.V.—Advisory Board, Myovant Sciences—Consultant, Nektar Therapeutics—Steering Committee, Novartis—Research, Physician Education Resource—Consultant, Pfizer—Research, Consultant, Steering Committee, Honorarium, Sanofi—Research, Consultant, Speaker, Honorarium, Travel accommodations, UroGPO—Honorarium, UroToday—Honorarium, Travel accommodations, Vizuri Health Sciences—Consultant, NCI—Steering Committee. BR declares the following relationships: Research funding (to Vanderbilt University) from Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive and Exelixis; Consulting with Bristol Myer Squibb, Pfizer, Roche/Genentech, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai. Stock ownership in PTC Therapeutics. MCO declares the following relationships: Consulting with BMS, Merck, Pfizer, Aveo, Exelixis and Eisai. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting with AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Merck, Amgen, MJH Associates, and BMS. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance., Experimental Design: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY)., Results: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset ( n = 173; HR, 5.7; 95% CI, 2.6-12.7)., Conclusions: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions., (©2021 American Association for Cancer Research.)

The title compound, C 14 H 6 F 4 O 2 , crystallizes with half of a mol-ecule per asymmetric unit and exhibits bond lengths and angles typical of α-diketones. A network of C-H⋯F contacts and π-π stacking inter-actions is observed within the structure., (© Brown and Balaich 2021.)

Introduction: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study., Methods: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30 min  < 10% (≥1 biopsy with <10% CD30 expression), or CD30 min  ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS)., Results: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30 min  < 10% (40.9% versus 9.5%), with CD30 min  ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30 min  < 10% (16.7 versus 2.3 months), with CD30 min  ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups., Conclusion: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status., Clinical Trial Registration: Clinicaltrials.gov, NCT01578499., Competing Interests: Conflict of interest statement Y.H.K. reports advisory roles for Seagen and Takeda. H.M.P. reports advisory board for and grants or funds from Takeda. D.F. reports advisory roles for Kyowa Kirin. S.M.H. reports consulting fees from ADC Therapeutics, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, Seagen, Takeda, Verastem and Vividion Therapeutics, and research grants or funds from ADC Therapeutics, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium/Takeda, Portola Pharmaceuticals, Seagen, Trillium Therapeutics and Verastem. M.D. reports research funding from Takeda and Millennium for this study, Seagen for a physician IST, and institutional funding from Solenginex, miragene, Rhizen and Eisai. O.B. reports consulting fees from Novartis, BMS, Sanofi, Pierre, Fabre and MSD. J.A.S. reports speaker’s bureau, and consultancy/advisory roles for Takeda (Brazil). J.S. reports consulting fees from/Clinical Expert for Takeda. P.Q. reports advisory boards and speaker fee for Takeda, Kiowa, Therakos, Miragen, Helsinn-Recordati, Innate Pharma, 4SC and Actelion. P.L.Z. reports advisory roles for and honoraria from Merck, BMS, Servier, Takeda, TG Therapeutics, ADC Therapeutics, Abbvie, Incyte, Janssen, Gilead, Eusapharma, Roche, Debiopharm and Novartis. H.E. reports advisory roles for Abbvie and Genentech, honoraria from Abbvie, Genentech, Takeda and Pharmacyclics, grants or funds from Abbvie, Genentech, Pharmacyclics, Acerta, Celgene and Astrazeneca. L.C.P-B. reports advisory roles for and honoraria from Seagen. P.L.O-R. reports advisory roles for Takeda, Helsinn, 4SC, Actelion, Innate Pharma, Recordati Rare Diseases, Kyowa and miRagen, grants or funds from MEDA, and PLCG1 mutation patent. O.E.A. reports advisory roles for Trillium Therapeutics, Bioniz, Kyowa Kirin and Meivir, and research grants or funds from Actelion, Adaptive Biotechnology, Trillium Therapeutics, Pfizer and Kyowa Kirin. J.T. reports research funding from Takeda, Celgene, Roche, Beigene, Janssen and PCYC. M.W. reports honoraria from Takeda and Kyowa Kirin, and research grants or funds from Millennium. J.W. reports advisory roles for Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, BMS, Abbvie, Novartis and Gilead, honoraria from Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, Abbvie, Gilead and Novartis, grants or funds from Roche, GSK/Novartis, Takeda and Janssen-Cilag, and conference travel support from Roche. A.A.G. reports advisory roles for Seagen, Innate Pharma and StemLine Therapeutics, honoraria and grants or funds from StemLine Therapeutics, and consultancy fees from Innate Pharma and StemLine. L.B. reports employment for Zymeworks. M.C.P-W., J.L. and M.O. report employment for and ownership of stocks/shares from Seagen. V.B. reports employment for Takeda Pharmaceuticals. M.L. reports employment for and ownership of stocks/shares from Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. W.L.T. reports employment for and ownership of stocks/shares from Takeda Pharmaceuticals. R.D. reports intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron and Alligator. S.W., R.S., P.W., K.T., and M.M. have no conflicts of interest to disclose., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches., Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1., Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event., Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B ) is a putative tumor suppressor, and preliminary evidence suggests LRP1B- mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI)., Methods: We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status., Results: We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB)., Conclusions: This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted., Competing Interests: Competing interests: JZ: consulting: NGM Biopharmaceuticals, UroToday; Travel Expenses: UroToday. RTG: speakers bureau: Bayer Pharma AG; Consulting Fees: Bayer Pharma AG, Invivo Corp, Bard. TZ: research funding: AstraZeneca, Janssen, OmniSeq, PGDx, Pfizer, Merrimack, AbbVie/Stemcentrx, Novartis, Merck, Mirati and Regeneron; Advisory/consultant role: Genentech Roche, Exelixis, Bayer, AstraZeneca, Pfizer, Sanofi-Aventis, Janssen, Foundation Medicine, Amgen, Bristol-Myers Squibb, Merck, Pharmacyclics and Seattle Genetics; speakers bureau: Genentech Roche, Exelixis, Sanofi-Aventis, Genomic Health; Stocks/Employment: Capio Biosciences (spouse), Archimmune Therapeutics (spouse). MH: consultant: AstraZeneca, Bayer, Bristol-Myers Squibb, Exelixis, Genentech, Janssen, Pfizer; speakers bureau: Exelixis and Genentech; Research Funding (to institution): Acerta, Bristol-Myers Squibb, Clovis, Exelixis, Genentech, Merck, Pfizer, Seattle Genetics. DG: Acerta Pharmaceuticals—Research, American Association for Cancer Research—Sr Editor, Astellas—Consultant, Research, Advisory Board, AstraZeneca—Consultant, Advisory Board, Axess Oncology—Independent Contractor, Bayer H/C Pharmaceuticals—Research, Consultant, Speaker, Honorarium, Travel accommodations, SC, Bristol-Myers Squibb—Consultant, Research, Steering Committee, Calithera—Research, Capio Biosciences—Scientific Advisory Board, EMD Serono—Honorarium, Exelixis, Inc—Research, Consultant, Speaker, Honorarium, Travel accommodations, Flatiron—Consultant, Ipsen—Honorarium, Janssen Pharmaceuticals—Research, Consultant, Independent Data Monitoring Committee (IDMC), Leidos Biomedical Research—Consultant, Merck Sharp & Dohme—Consultant, Michael J Hennessey Associates – Honorarium, Consultant, Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—Co-Editor-in-Chief, Modra Pharmaceuticals—Advisory Board, Myovant Sciences, Inc—Consultant, Nektar Therapeutics—Steering Committee, Novartis—Research, Physician Education Resource LLC—Consultant, Pfizer—Research, Consultant, Steering Committee, Honorarium, Sanofi—Research, Consultant, Speaker, Honorarium, Travel accommodations, UroGPO—Honorarium, UroToday—Honorarium, Travel accommodations, Vizuri Health Sciences, LLC—Consultant, NCI—Steering Committee. AJA: consultant and/or advisor for AstraZeneca; Bristol-Myers Squibb; Merck & Co; Pfizer, EMD Serono. Paid DSMB member: Eisai. Grant/Research Support from AstraZeneca; Bristol-Myers Squibb and Merck & Co. Other financial or material support from Arcus Biosciences; Astellas Pharma US; Celgene Corporation; Clovis Oncology; Pfizer; Prometheus Biosciences and Seattle Genetics in the form of research support to institution. EA: grants and personal fees from Janssen, personal fees from Astellas, grants and personal fees from Sanofi, grants and personal fees from Dendreon, personal fees from Pfizer, personal fees from Invitae, grants and personal fees from AstraZeneca, grants and personal fees from Clovis, grants and personal fees from Merck, grants from Johnson & Johnson, grants from Genentech, grants from Novartis, grants from Bristol Myers-Squibb; and a patent (PCT/US2015/046806; US20170275673A1) on an AR-V7 biomarker technology that is licensed to Qiagen. AJA: consulting fees: AstraZeneca, Merck, Dendreon, Janssen, Clovis, Bayer and Medivation/Astellas; speaking fees: Bayer and Dendreon, Research funding to Duke: Janssen, Medivation/Astellas, Sanofi-Aventis, Active Biotech, Bayer, Dendreon, Merck, AstraZeneca, Genentech/Roche, Bristol-Myers Squibb, Constellation, Novartis and Pfizer., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL., Experimental Design: Preclinical studies included the delivery of cobomarsen to highly miR-155-expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment., Results: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient., Conclusions: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression., (©2020 American Association for Cancer Research.)

Background: False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer., Objective: To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM)., Design, Setting, and Participants: PROMIS participants (n=235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3+4 of any length and/or maximum cancer core length ≥4mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4+3 of any length and/or maximum cancer core length ≥6mm of any grade)., Outcome Measurements and Statistical Analysis: Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics., Results and Limitations: Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p< 0.001). In the former group, index lesions were larger (mean volume 0.68 vs 0.50 ml; p< 0.001, Wilcoxon test), more conspicuous (Likert 4-5: 79% vs 22%; p< 0.001), and diffusion restricted (mean apparent diffusion coefficient [ADC]: 0.73 vs 0.86; p< 0.001, Wilcoxon test). In men with Likert 3 index lesions, log 2 PSA density and index lesion ADC were significant predictors of definition 1/2 disease in a logistic regression model (mean cross-validated area under the receiver-operator characteristic curve: 0.77 [95% confidence interval: 0.67-0.87])., Conclusions: Significant cancer-associated MRI lesions in biopsy-naïve men have clinical-radiological differences, with lesions seen in prostates without significant disease. MRI-calculated PSA density and ADC could predict significant cancer in those with indeterminate MRI phenotypes., Patient Summary: Magnetic resonance imaging (MRI) lesions that mimic prostate cancer but are, in fact, benign prompt unnecessary biopsies in thousands of men with raised prostate-specific antigen. In this study we found that, on closer look, such false positive lesions have different features from cancerous ones. This means that doctors could potentially develop better tools to identify cancer on MRI and spare some patients from unnecessary biopsies., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Abstract: Triple-negative breast cancer (TNBC) continues to represent an unmet need because of its significantly poorer outcomes, including higher relapse rates following early-stage disease and dismal survival times in the advanced setting, when compared with other breast cancer subtypes (Cancer 2012;118:5463-5472). Furthermore, there remains a lack of established systemic treatment options beyond conventional cytotoxic chemotherapy, with the exception of PARP inhibitors in the small subset of patients who harbor a BRCA mutation (N Engl J Med 2018;379:753; Lancet Oncol 2020;21:1269-1282; Ann Oncol 2019;30:558-566) and recently the use of immunotherapy in the first-line metastatic setting in those who are programmed death ligand 1-positive (Lancet Oncol 2020;21(1):44-59; N Engl J Med 2018;379(22):2108-2121). Suitable biomarkers for improving prognostication and directing therapy in both the early and advanced TNBC settings are required in order for improvements in survival outcomes to be continued to be attained. Tumor-infiltrating lymphocytes are gaining increasing relevance as an immunological biomarker in this arena., Competing Interests: Conflicts of Interest and Sources of Funding: R.S. reports nonfinancial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology, and Roche; and personal fees from Roche for an advisory board related to a trial-research project. P.S.S. declares being an uncompensated consultant to Roche-Genentech. S.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, Eli Lilly, Nektar Therapeutics, Astra Zeneca, and Seattle Genetics; she has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech and as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Puma Biotechnology, Astra Zeneca, Silverback Therapeutics, and G1 Therapeutics. R.S. is supported by a grant from the Breast Cancer Research Foundation (BCRF, grant 17-194). S.L. is supported by Breast Cancer Research Foundation (BCRF) NY and the National Breast Cancer Foundation (NBCF) of Australia. For the remaining authors none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer., Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial ( n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial ( n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer., Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer., Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status., (©2020 American Association for Cancer Research.)

The aggressive peripheral T-cell lymphomas (PTCLs) are a heterogenous group of uncommon lymphomas of mature T lymphocytes dominated by 3 subtypes: systemic anaplastic large-cell lymphoma, both anaplastic lymphoma kinase positive and negative; nodal PTCL with T-follicular helper phenotype; and PTCL, not otherwise specified. Although the accurate diagnosis of T-cell lymphoma and the subtyping of these lymphomas may be challenging, there is growing evidence that knowledge of the subtype of disease can aid in prognostication and in the selection of optimal treatments, in both the front-line and the relapsed or refractory setting. This report focuses on the 3 most common subtypes of aggressive PTCL, to learn how current knowledge may dictate choices of therapy and consultative referrals and inform rational targets and correlative studies in the development of future clinical trials. Finally, I note that clinical-pathologic correlation, especially in cases of T-cell lymphomas that may present with an extranodal component, is essential in the accurate diagnosis and subsequent treatment of our patients., Competing Interests: Conflict-of-interest disclosure: Consultant to Kyowa Kirin, Acro Biotech, and Seattle Genetics., (© 2020 by The American Society of Hematology.)

The past 30 years have borne witness to a gradual evolution in the treatment landscape of advanced renal cell carcinoma (aRCC). Early immunotherapy approaches such as interferon-α and high-dose interleukin-2 (IL-2) therapy in this immunogenic tumor provided durable responses in only a minority of patients and came with toxic side effects. A growing understanding of the tumor biology elucidated pathways of tumorigenesis, which in turn revealed novel targets amenable to targeted therapies. Inhibition of angiogenesis and cell signaling emerged as cornerstones of treatment with the approval of bevacizumab and several pan-kinase and tyrosine kinase inhibitors. Though effective, their use has been limited by low rates of durable response, resistance, and side effects. The immunotherapy revolution of the past decade has led to immunotherapy-based combination regimens such as ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib, displacing single agent anti-angiogenic therapy in the first-line setting by demonstrating durable responses and improved survival over sunitinib. These immunotherapy-based combinations define first-line standard of care for aRCC today. The pipeline of second-line agents for consideration in patients who have disease progression despite immunotherapy regimens is robust but still in early stages of development.

Introduction: We examined patient characteristics, treatments, and outcomes of patients with transformed mycosis fungoides (tMF) from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the United States., Methods: Patients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified patients with tMF with completed baseline, treatment, and follow-up records. Median survival was assessed using Kaplan-Meier methodology., Results: Of the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase, and 9 had lymph node involvement. Approximately one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate, and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and 2-year survival rates were 56% and 44%, respectively., Conclusions: tMF often expresses CD30 and presents with lymph node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Multiparametric magnetic resonance imaging (MP-MRI) is established in the diagnosis of prostate cancer, but the need for enhanced sequences has recently been questioned., Objective: To assess whether dynamic contrast-enhanced imaging (DCE) improves accuracy over T2 and diffusion sequences., Design, Setting, and Participants: PROMIS was a multicentre, multireader trial, with, in this part, 497 biopsy-naïve men undergoing standardised 1.5T MP-MRI using T2, diffusion, and DCE, followed by a detailed transperineal prostate mapping (TPM) biopsy at 5 mm intervals. Likert scores of 1-5 for the presence of a significant tumour were assigned in strict sequence, for (1) T2 + diffusion and then (2) T2 + diffusion + dynamic contrast-enhanced images., Outcome Measurements and Statistical Analysis: For the primary analysis, the primary PROMIS outcome measure (Gleason score ≥4 + 3 or ≥6 mm maximum cancer length) on TPM was used, and an MRI score of ≥3 was considered positive., Results and Limitations: Sensitivity without and with DCE was 94% and 95%, specificity 37% and 38%, positive predictive value 51% and 51%, and negative predictive value 90% and 91%, respectively (p >  0.05 in each case). The number of patients avoiding biopsy (scoring 1-2) was similar (123/497 vs 121/497, p =  0.8). The number of equivocal scores (3/5) was slightly higher without DCE (32% vs 28% p =  0.031). The proportion of MRI equivocal (3/5) and positive (4-5) cases showing significant tumours were similar (23% and 71% vs 20% and 69%). No cases of dominant Gleason 4 or higher were missed with DCE, compared with a single case with T2 + diffusion-weighted imaging. No attempt was made to correlate lesion location on MRI and histology, which may be considered a limitation. Radiologists were aware of the patient's prostate-specific antigen., Conclusions: Contrast adds little when MP-MRI is used to exclude significant prostate cancer., Patient Summary: An intravenous injection of contrast may not be necessary when magnetic resonance imaging is used as a test to rule out significant tumours in the prostate., (Copyright © 2020. Published by Elsevier B.V.)

An investigation into the crystalline to amorphous phase transitions of prepared 1,3,6-substituted pentafulvenes showed the expected reversible heated melt and cooling recrystallization in only a few examples. Systematic incorporation of bulky substituents at the 6-position of the fulvene ring led to the nonreversible thermal behavior, rendering phases that were locked into glassy, vitrified states. These molecular glasses produced physically translucent and amorphous features with glass transition temperatures in the range of 61-77 °C, comparable with high-strength plastics such as polyethylene terephthalate. Additionally, the melting point transitions and the resulting heat of fusion values were found to be directly influenced by the nature of the 6-position substituent. Single crystal X-ray crystallography showed that in some cases, fulvenes possessing fused aromatics exhibited a high degree of intermolecular π-π stacking. These results point to a class of molecular glass formers as host materials possessing tunable bulk properties for potentially new optical applications.