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Importance Accurate representation of racial and ethnic population subgroups in clinical trials is fundamental to ensure universal effectiveness of new therapies as well as to decrease disparities in oncology care. Objective To determine whether Hispanic people are underrepresented in Phase I and II clinical trials for liver cancer in the United States. Participants A database search was performed in clinicaltrials.gov for interventional liver cancer studies based only in the US with reported results from September 1, 2002, to February 1, 2023. A total of 37 trials with 963 total patients met inclusion criteria and were included for further analysis. Proportion of total patients by race/ethnicity was calculated for non‐Hispanic white, non‐Hispanic black, Asian, Hispanic, and American Indian/Alaska Native subpopulations. The age‐adjusted incidence rates of liver and intrahepatic bile duct were acquired from the National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Results Liver cancer incidence rates (per 100,000 people) were highest in Indians/Alaska Native people (18.8 cases) followed by Hispanic people (15.1 cases), then Asian people (12.5 cases), then non‐Hispanic black people (11 cases), and non‐Hispanic white people (7.5 cases). From a total of 91 phase I or II clinical trials for liver cancer in the US, 41% reported race/ethnicity enrollment data; among these, 62.8% of patients were non‐Hispanic White, 15.9% were non‐Hispanic black, 8.8% were Hispanic, 12.7% Asian, and 0.5% American Indian/Alaska Native. Conclusions and Relevance Less than half of phase I or II clinical trials for liver cancer in the US in the last 20 years reported race/ethnicity data to clinicaltrials.gov. Compared to the relative incidence rate of liver cancer, non‐Hispanic black people and Hispanic people are underrepresented in these clinical trials. Less than half of phase I or II clinical trials for liver cancer in the US in the last 20 years reported race/ethnicity data to clinicaltrials.gov. Compared to the relative incidence rate of liver cancer, non‐Hispanic black people and Hispanic people are underrepresented in these clinical trials.

Background/Objectives This study aims to characterize PI3K and TP53 pathway alterations in Hispanic/Latino patients with early‐onset colorectal cancer (CRC), focusing on potential differences compared to non‐Hispanic White patients. Understanding these differences may shed light on the molecular basis of CRC health disparities. Methods Using cBioPortal, we conducted a bioinformatics analysis to evaluate CRC mutations within the PI3K and TP53 pathways. CRC patients were stratified by age and ethnicity: (1) early‐onset (< 50 years) versus late‐onset (≥ 50 years) and (2) early‐onset in Hispanic/Latino patients compared to early‐onset in non‐Hispanic White patients. Mutation frequencies were assessed using descriptive statistics, with chi‐squared tests comparing proportions between early‐onset Hispanic/Latino and non‐Hispanic White groups. Kaplan–Meier survival curves were generated to assess overall survival for early‐onset Hispanic/Latino patients, stratified by the presence or absence of PI3K and TP53 pathway alterations. Results Significant differences were noted when comparing early‐onset CRC in Hispanic/Latino patients to early‐onset CRC in non‐Hispanic White patients. PI3K (47.1% vs. 35.2%, p = 9.39e‐3) and TP53 (89.1% vs. 81.7%, p = 0.04) pathway alterations were more prevalent in early‐onset CRC among Hispanic/Latino patients, with AKT1 (5.1% vs. 1.8%, p = 0.03), INPP4B (4.3% vs. 1.4%, p = 0.04), and TSC1 (7.2% vs. 3.1% p = 0.03) gene alterations also significantly higher in this group. Significant differences were observed in TP53 mutations between colon adenocarcinomas (90% vs. 79.1%, p = 0.03), with higher prevalence in Hispanic/Latino patients when stratified by tumor site. No significant differences were observed between early‐onset and late‐onset CRC patients within the Hispanic/Latino cohort. Conclusions These findings highlight the distinct role of PI3K and TP53 pathway disruptions in early‐onset CRC among Hispanic/Latino patients, suggesting that pathway‐specific mechanisms may drive cancer health disparities. Insights from this study could inform the potential development of precision medicine approaches and targeted therapies aimed at addressing these disparities. This study identifies distinct PI3K and TP53 pathway disruptions in early‐onset colorectal cancer among Hispanic/Latino patients, with findings suggesting a higher prevalence of PI3K alterations and potential differences in outcomes associated with TP53 disruptions compared to non‐Hispanic Whites. While these results provide valuable insights into potential molecular drivers of disparities, further research is needed to fully understand their clinical implications. These findings may suggest new directions for precision medicine approaches aimed at addressing cancer health disparities and improving equity in colorectal cancer care.

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC. This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy. This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC. NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.ConclusionIn patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained.Trial registration numberNCT04166383.

Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression — with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.Cancer stem cells (CSCs) are implicated in cancer development, progression and resistance to treatment; therefore, the signalling pathways that mediate the CSC phenotype are attractive therapeutic targets. In this Review, the authors provide an update on the progress in targeting the Notch, WNT, Hedgehog and Hippo signalling pathways. Additionally, they discuss the interactions of CSCs with the immune system, the roles of CSC-related signalling pathways in immune cells and novel approaches to CSC-directed immunotherapy.

Hispanic individuals comprise the second-largest subpopulation after non-Hispanic White (NHW) individuals in the United States (US). We compared the relative contribution of Hispanic individuals to the ten most common causes of cancer-related deaths and studied enrollment of Hispanic patients in multinational phase III advanced liver cancer trials with the aim to investigate whether racial subpopulations are adequately represented in liver cancer trials. Relative cancer incidence rates in Hispanic individuals, NHW individuals, non-Hispanic black (NHB) individuals, and Asian individuals were obtained from both the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results Program and the Center for Disease Control and Prevention (CDC), United States Cancer Statistics (USCS) database. Searching PubMed, Embase, and Web of Science, we identified phase III clinical trials studying advanced liver cancer in the last ten years and collected enrollment for each race and ethnicity. Incidence rates of liver cancer and enrollment rates in phase III trials were compared by race and ethnicity. The cancer type with the relatively highest contribution of Hispanic individuals was liver cancer. From 2015 to 2019, 15.1% of liver cancer cases occurred in Hispanic individuals compared to 12.5% in Asian individuals, 11% in NHB individuals, and 7.5% in NHW individuals. In the last ten years, Hispanic individuals made up 1.6% of patients and NHB individuals 1.3% of patients included in phase III multinational liver cancer trials, compared to 31% NHW individuals and 47% Asian individuals. Hispanic individuals are disproportionately underrepresented in multinational phase III clinical trials for liver cancer despite having the highest relative incidence rates among the four major racial or ethnic groups in the US.

Background Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti‐PD1/PD‐L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti‐PD‐L1) and tremelimumab (anti‐CTLA‐4), with and without an interventional radiology (IR) procedure in advanced BTC. Methods Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6‐month progression‐free survival (PFS). Results Twenty‐three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3–3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9–4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5–6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9–40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1–2. Conclusion Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC. The purpose of this study was to explore the efficacy and safety of two ICIs, durvalumab and tremelimumab, with and without an interventional radiology (IR) procedure in patients with advanced BTC. Durva/Treme + IR showed no difference in efficacy compared with Durva/Treme alone, but the safety profile of both cohorts was manageable. Larger studies are needed to fully characterize efficacy of Durva/Treme with or without IR in advanced BTCs.

Cooperation and bullying have a subtle yet important interaction that influences the social dynamics in elementary school classrooms. We investigate this interplay in a large sample of 1112 students across 47 public primary classrooms in Chile. Using a video game interface to create a dyadic, non-anonymous social dilemma, we map the cooperative social network within each classroom. In addition, we collect peer nomination data and use the Illinois Bullying Scale to categorize students as bullies, victims, or bully victims. Our results indicate that low levels of received cooperation significantly increase the likelihood of students being identified with the dual role of both bully and victim, known as the bully-victim profile. This negative relationship remains robust even after controlling for demographic and classroom context variables using multilevel regression models and is consistent when employing causal inference techniques such as statistical matching. We propose that the relationship between received cooperation and the bully-victim profile stems from the capacity of received cooperation to capture key factors influencing social relationships among students, such as popularity, prosociality, GPA, and aggressiveness. Our study contributes to the understanding of human interaction in educational settings and it offers a new framework for targeted interventions in primary education, providing insights for future educational policies and practices.

Patients with advanced hepatocellular carcinoma have a dismal prognosis; only a subset of patients with advanced HCC will benefit from treatment with immunotherapy. We searched for clinical characteristics predicting exceptional long-term survival in HCC patients treated with immune checkpoint inhibitors. We compared clinical characteristics of 59 patients with advanced hepatocellular carcinoma treated with immunotherapy with and without locoregional therapy between 2013-2019. We compared patients who lived less than 12 months with patients who lived more than 3 years. Traits of short-term (31 patients) and long-term (5 patients) survivors were compared. Patients who died between 12 months and 3 years of starting treatment on protocol were not included in the analysis. Two out of five patients (40%) in the long-term survival group had a partial response (PR) or a complete response (CR) per the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while, of the 31 patients in the short-term survival group, only 2 (6.5%) had a CR or PR. Two of the 5 patients with a long-term survival had immune-related adverse events grade 3 or 4 (IrAEs-3/4). None of the patients in the short-term survival group had IrAEs-3/4. The patients, who presented with IrAEs-3/4, which included colitis and adrenal insufficiency, continued to have a response off treatment. The median overall survival (OS) was 11.8 months (95% CI: 7.8-15.4 months), with a 12-month OS of 46.6% (95% CI: 33.4-58.8%) and a 3-year OS of 12.5% (95% CI: 5.0-23.7%). We found a possible association between immune-related adverse events grade 3 and 4 and long-term survival in patients with advanced HCC. The cases in our analysis represent extraordinary defiance of the usual predicted dismal course of advanced HCC.