Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study.

BACKGROUND: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING: F Hoffmann-La Roche.

Ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients with advanced solid tumours.

BACKGROUND: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. STUDY DESIGN: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). RESULTS: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. CONCLUSIONS: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.

Evaluating a shared care pathway intervention for people receiving chemotherapy to reduce post-treatment unplanned hospital presentations: a randomised controlled trial.

PURPOSE: The aim of this randomised controlled trial (RCT) was to explore whether a community nursing intervention for outpatients receiving systemic therapy reduced unplanned hospital presentations and improved physical and psychosocial health outcomes over the first three cycles of treatment compared to a control group receiving standard care. METHODS: The number of and reasons for unplanned presentations were obtained for 170 intervention and 176 control group adult patients with solid tumours starting outpatient chemotherapy. Poisson regression was used to compare the number of presentations between the intervention and control groups. Patients self-completed the Hospital Anxiety and Depression Scale, the Cancer Behavior Inventory and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) at the start of the first four cycles. Linear regression techniques were used to compare quality of life outcomes. RESULTS: The reduction in unplanned presentations in the intervention group relative to the control group was 12% (95% CI, - 25%, 37%; P = 0.48). At the start of cycle 4, there was no difference in anxiety (difference = 0.47 (95% CI, - 0.28, 1.22; P = 0.22)), depression (difference = 0.57 (95% CI, - 0.18, 1.31; P = 0.13)) or EORTC QLQ-C30 summary score (difference = 0.16 (95% CI, - 2.67, 3.00; P = 0.91)). Scores for self-efficacy as measured by the Cancer Behavior Inventory were higher in the intervention group (difference = 4.3 (95% CI, 0.7, 7.9; P = 0.02)). CONCLUSION: This RCT did not demonstrate a benefit in reducing unplanned presentations to hospital. The trial identified improved cancer-based self-efficacy in patients receiving the intervention. TRIAL REGISTRATION: Registered at Australian and New Zealand Clinical Trials Registry: ACTRN12614001113640, registered 21/10/2014.

Social Norms and Concussion Disclosure Behavior: Clarification of Terms and Measurement Recommendations.

Nondisclosed sport-related concussion symptoms pose a significant risk to athletes' health and well-being. Many researchers have focused on understanding the factors affecting athletes' concussion disclosure behaviors. One of the most robust predictors of the likelihood that an athlete will disclose concussion symptoms to their coaches, athletic trainers, parents, or peers is what researchers term social norms. The extant literature regarding social norms influencing concussion disclosure behaviors is inconsistent on how the construct should be defined, conceptualized, or measured, often failing to distinguish between descriptive and injunctive social norms and their sources (direct and indirect). In this technical note, we provide an overview of these critical distinctions, their importance in assessments, and examples from the literature in which scholars have correctly operationalized these constructs in athletic populations. We conclude with a brief set of suggestions for researchers seeking to measure social norms in future research.

Social vulnerability and traumatic brain injury hospitalizations from sports and recreation among pediatric patients in the United States.

PURPOSE: This study examined the associations between individual as well as neighborhood social vulnerability and sports and recreation-related traumatic brain injury (SR-TBI) hospitalizations among pediatric patients in the U.S. METHODS: We obtained 2009, 2010 and 2011 hospitalization data in the U.S. from the National Inpatient Sample (NIS) database, linked it to 2010 neighborhood social vulnerability index (SVI) data from the Centers for Disease Prevention and Control (CDC), and assigned U.S. hospitals to one of four SVI quartiles. SR-TBI outcomes studied include: odds of hospitalization, length of stay (LOS), and discharge to post-acute care (DTPAC). RESULTS: We found associations between race/ethnicity and all SR-TBI outcomes; however, sex, primary payer, and neighborhood overall SVI were only associated with LOS. Compared to White children, Native American children had almost three times higher odds of hospitalization for SR-TBI (OR: 2.82, 95% CI: 1.30, 6.14), 27% longer LOS (ß: 27.06, 95% CI: 16.56, 38.51), but 99.9% lower odds of DTPAC (OR: 0.001, 95% CI: 0.00, 0.01). Compared to children with private insurance, children with public insurance had 11% longer LOS (ß: 10.83, 95% CI: 8.65, 13.05). Hospitalization in neighborhood with higher overall SVI was associated with longer LOS (p < 0.0001). CONCLUSIONS: These findings suggest that individual and neighborhood social vulnerability can have a significant impact on the health outcomes of children, especially in the context of SR-TBI.

Amplifying the Patient's Voice in Oncology Early-Phase Clinical Trials: Solutions to Burdens and Barriers.

Dose-finding oncology trials (DFOTs) provide early access to novel compounds of potential therapeutic benefit in addition to providing critical safety and dosing information. While access to trials for which a patient is eligible remains the largest barrier to enrollment on clinical trials, additional direct and indirect barriers unique to enrollment on DFOTs are often overlooked but worthy of consideration. Direct barriers including financial costs of care, travel and time investments, and logical challenges including correlative study designs are important to bear in mind when developing strategies to facilitate the patient experience on DFOTs. Indirect barriers such as strict eligibility criteria, washout periods, and concomitant medication restrictions should be accounted for during DFOT design to maintain the fidelity of the trial without being overly exclusionary. Involving patients and advocates and incorporating patient-reported outcomes (PROs) throughout the process, from initial DFOT design, through patient recruitment and participation, is critical to informing strategies to minimize identified barriers to offer the benefit of DFOTs to all patients.

COVID-19 related messaging, beliefs, information sources, and mitigation behaviors in Virginia: a cross-sectional survey in the summer of 2020.

Background: Conflicting messages and misleading information related to the coronavirus (COVID-19) pandemic (SARS-CoV-2) have hindered mitigation efforts. It is important that trust in evidence-based public health information be maintained to effectively continue pandemic mitigation strategies. Officials, researchers, and the public can benefit from exploring how people receive information they believe and trust, and how their beliefs influence their behaviors. Methods: To gain insight and inform effective evidence-based public health messaging, we distributed an anonymous online cross-sectional survey from May to July, 2020 to Virginia residents, 18 years of age or older. Participants were surveyed about their perceptions of COVID-19, risk mitigation behaviors, messages and events they felt influenced their beliefs and behaviors, and where they obtained information that they trust. The survey also collected socio-demographic information, including gender, age, race, ethnicity, level of education, income, employment status, occupation, changes in employment due to the pandemic, political affiliation, sexual orientation, and zip code. Analyses included specific focus on the most effective behavioral measures: wearing a face mask and distancing in public. Results: Among 3,488 respondents, systematic differences were observed in information sources that people trust, events that impacted beliefs and behaviors, and how behaviors changed by socio-demographics, political identity, and geography within Virginia. Characteristics significantly associated (p < 0.025) with not wearing a mask in public included identifying as non-Hispanic white, male, Republican political identity, younger age, lower income, not trusting national science and health organizations, believing one or more non-evidence-based messages, and residing in Southwest Virginia in logistic regression. Similar, lesser in magnitude correlations, were observed for distancing in public. Conclusions: This study describes how information sources considered trustworthy vary across different populations and identities, and how these differentially correspond to beliefs and behaviors. This study can assist decision makers and the public to improve and effectively target public health messaging related to the ongoing COVID-19 pandemic and future public health challenges in Virginia and similar jurisdictions.

"I'm Doing the Best that I Can": Mothers Lived Experience with Food Insecurity, Coping Strategies, and Mental Health Implications.

Background: Food insecurity can have lasting physical and mental health consequences. The experience of food insecurity within a household may disproportionately impact mothers because they tend to manage the household food environment. Objective: This study sought to understand the stresses faced by United States mothers experiencing food insecurity, related coping mechanisms, and the impacts of these stressors on their mental health. Methods: Semistructured interviews were conducted in May and June 2022 with a purposive sample of Virginia mothers who reported experiences of food insecurity. Participants were recruited from a related survey and university and community LISTSERVs. Interviews were transcribed and analyzed by trained coders. A thematic analysis was conducted to describe themes that emerged from the data. Virtual interviews were 20-60 min in duration. Mothers with children living in their household, having experienced food insecurity, and living in Virginia were eligible. Results: The following 3 themes emerged from the interviews with the mothers (n = 15): 1) food insecurity added stress to mothers' lives in multiple ways (e.g. worry about obtaining the "right" foods and internalized or experienced stigma), 2) mothers used positive and negative coping strategies to address the impacts of these stressors (e.g. use of community resources and reduced personal food intake), and 3) the stressors and coping strategies had varying impacts on mothers' mental health (e.g. added to existing mental health challenges or reduced their mental capacity to make changes). Conclusions: Study findings suggest that a multilevel and tailored approach to address diverse stressors is warranted. Future research should explore emotional coping strategies that comprehensively empower mothers to manage stressors, leverage resources, and reduce social stigma associated with food insecurity and accessing nutrition and mental health assistance. This may improve their household food security and mitigate the burden of stressors on their mental health because system-level solutions to food insecurity are pursued.

Biomarkers of systemic inflammation provide additional prognostic stratification in cancers of unknown primary.

BACKGROUND: Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. PATIENTS AND METHODS: CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. RESULTS: Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable-risk cCUP. On multivariate analysis c-reactive protein (CRP) (p < 0.001) and the Scottish Inflammatory Prognostic Score (SIPS: combining albumin and neutrophil count) (p < 0.001) were independently predictive of survival. CRP and SIPS effectively stratified survival in patients with both favourable-risk and poor-risk cCUP based on clinicopathological features. CONCLUSIONS: Biomarkers of systemic inflammation are reliable prognostic factors in patients with cCUP, regardless of clinicopathological subgroup. We recommend that CRP or SIPS are incorporated into routine clinical assessments of patients with cCUP as a tool to aid investigation and/or treatment decision-making across all groups. Established clinicopathological factors can then be used to inform management pathways and specific systemic anticancer therapy selection.

A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary.

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)