CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Impact of sarcopenia and myosteatosis on survival outcomes for patients with head and neck cancer undergoing curative-intent treatment.

Malnutrition and sarcopenia are prevalent in patients with head and neck squamous cell carcinoma (HNSCC). Pre-treatment sarcopenia and adverse oncological outcomes in this population are well described. The impact of myosteatosis and post-treatment sarcopenia is less well known. Patients with HNSCC (n = 125) undergoing chemoradiotherapy, radiotherapy alone and/or surgery were assessed for sarcopenia and myosteatosis, using cross-sectional computed tomography (CT) imaging at the third lumbar (L3) vertebra, at baseline and 3 months post-treatment. Outcomes were overall survival (OS) at 12 months and 5 years post-treatment. One hundred and one participants had a CT scan evaluable at one or two time points, of which sixty-seven (66 %) participants were sarcopenic on at least one time point. Reduced muscle attenuation affected 93 % (n = 92) pre-treatment compared with 97 % (n = 90) post-treatment. Five-year OS favoured those without post-treatment sarcopenia (hazard ratio, HR 0·37, 95 % CI 0·16, 0·88, P = 0·06) and those without both post-treatment myosteatosis and sarcopenia (HR 0·33, 95 % CI 0·13, 0·83, P = 0·06). Overall, rates of myosteatosis were high at both pre- and post-treatment time points. Post-treatment sarcopenia was associated with worse 5-year OS, as was post-treatment sarcopenia in those who had myosteatosis. Post-treatment sarcopenia should be evaluated as an independent risk factor for decreased long-term survival post-treatment containing radiotherapy (RT) for HNSCC.

Beyond standard data collection - the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry).

BACKGROUND: Real-world data (RWD) is increasingly being embraced as an invaluable source of information to address clinical and policy-relevant questions that are unlikely to ever be answered by clinical trials. However, the largely unrealised potential of RWD is the value to be gained by supporting prospective studies and translational research. Here we describe the design and implementation of an Australian brain cancer registry, BRAIN, which is pursuing these opportunities. METHODS: BRAIN was designed by a panel of clinicians in conjunction with BIOGRID to capture comprehensive clinical data on patients diagnosed with brain tumours from diagnosis through treatment to recurrence or death. Extensive internal and external testing was undertaken, followed by implementation at multiple sites across Victoria and Tasmania. RESULTS: Between February 2021 and December 2021, a total of 350 new patients from 10 sites, including one private and two regional, were entered into BRAIN. Additionally, BRAIN supports the world's first registry trial in neuro-oncology, EX-TEM, addressing the optimal duration of post-radiation temozolomide; and BioBRAIN, a dedicated brain tumour translational program providing a pipeline for biospecimen collection matched with linked clinical data. CONCLUSIONS: Here we report on the first data collection effort in brain tumours for Australia, which we believe to be unique worldwide given the number of sites and patients involved and the extent to which the registry resource is being leveraged to support clinical and translational research. Further directions such as passive data flow and data linkages, use of artificial intelligence and inclusion of patient-entered data are being explored.

Protocol for SARS-CoV-2 post-vaccine surveillance study in Australian adults and children with cancer: an observational study of safety and serological and immunological response to SARS-CoV-2 vaccination (SerOzNET).

BACKGROUND: Cancer is associated with excess morbidity and mortality from coronavirus disease 2019 (COVID-19) following infection by the novel pandemic coronavirus SARS-CoV-2. Vaccinations against SARS-CoV-2 have been rapidly developed and proved highly effective in reducing the incidence of severe COVID-19 in clinical trials of healthy populations. However, patients with cancer were excluded from pivotal clinical trials. Early data suggest that vaccine response is less robust in patients with immunosuppressive conditions or treatments, while toxicity and acceptability of COVID-19 vaccines in the cancer population is unknown. Unanswered questions remain about the impact of various cancer characteristics (such as treatment modality and degree of immunosuppression) on serological response to and safety of COVID-19 vaccinations. Furthermore, as the virus and disease manifestations evolve, ongoing data is required to address the impact of new variants. METHODS: SerOzNET is a prospective observational study of adults and children with cancer undergoing routine SARS-CoV-2 vaccination in Australia. Peripheral blood will be collected and processed at five timepoints (one pre-vaccination and four post-vaccination) for analysis of serologic responses to vaccine and exploration of T-cell immune correlates. Cohorts include: solid organ cancer (SOC) or haematological malignancy (HM) patients currently receiving (1) chemotherapy, (2) immune checkpoint inhibitors (3) hormonal or targeted therapy; (4) patients who completed chemotherapy within 6-12 months of vaccination; (5) HM patients with conditions associated with hypogammaglobulinaemia or immunocompromise; (6) SOC or HM patients with allergy to PEG or polysorbate 80. Data from healthy controls already enrolled on several parallel studies with comparable time points will be used for comparison. For children, patients with current or prior cancer who have not received recent systemic therapy will act as controls. Standardised scales for quality-of-life assessment, patient-reported toxicity and vaccine hesitancy will be obtained. DISCUSSION: The SerOzNET study was commenced in June 2021 to prospectively study immune correlates of vaccination in specific cancer cohorts. The high proportion of the Australian population naïve to COVID-19 infection and vaccination at study commencement has allowed a unique window of opportunity to study vaccine-related immunity. Quality of life and patient-reported adverse events have not yet been reported in detail post-vaccination for cancer patients. Trial registration This trial is registered on the Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001004853. Submitted for registration 25 June 2021. Registered 30 July 2021 (Retrospectively registered). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382281&isReview=true.

Is interviewer support associated with the reduced reluctance and enhanced informativeness of alleged child abuse victims?

Child maltreatment victims are often reluctant to report abuse when formally interviewed. Evidence-based guidelines like the National Institute of Child Health and Human Development Standard Investigative Interview Protocol do not adequately address such reluctance because they are focused on cognitive rather than socioemotional strategies. The present study was designed to determine whether the Revised National Institute of Child Health and Human Development Protocol, which emphasizes supportive interviewing more than the standard protocol does, might predict increases in the overall informativeness and reductions in the reluctance of alleged victims. A total of 254 interviews, 166 using the revised protocol and 88 using the standard protocol, were conducted with 4.06- to 13.98-year-old children (M = 9.20, SD = 2.49) who disclosed multiple incidents of physical abuse by their parents and were thus expected to be more reluctant than victims of extrafamilial abuse. We coded indices of interviewer support and question types, children's reluctance, and informativeness in each utterance during the substantive phases of the interviews. The Revised Protocol was associated with better interviewer support and questioning as well as reduced reluctance and increased informativeness on the part of the children. These findings document the value of training interviewers to attend to the socioemotional needs of suspected abuse victims during investigative interviews. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A Case Study Perspective: The Experiences of Young Persons Testifying to Child Sexual Exploitation in British Criminal Court.

Three young persons who gave evidence about child sexual exploitation in criminal court using various testimonial supports were interviewed about their testimony experiences. The witnesses reported that they felt extreme pressure to remember events accurately and cared greatly about being believed. None reported their own coping strategies to alleviate stress and took comfort breaks only after they cried on the stand. Defense attorney questions were reportedly repetitive, rapid, confusing, and focused on secondary content rather than the central criminal acts. The witnesses mentioned dissatisfaction in having supportive social workers whom they trusted leave the case and be replaced.

Children's Uncertain Responses when Testifying about Alleged Sexual Abuse in Scottish Courts.

This study examined the uncertain responses of 56 alleged sexual abuse victims, aged 5-17 years, testifying in Scottish criminal court trials. Don't know/remember ground rules were explained to 38% of the children and each child reported uncertainty in response to 15% of the questions on average. Uncertain responding was associated with expressions of resistance and confusion, questioning context (proportionally more regarding substantive than non-substantive issues), question content (least to disclosure-focused questions), utterance type (more to directives, particularly those posed by defense lawyers; more to recall-based than recognition prompts), and age (children in mid-adolescence were less likely to respond uncertainly than those who were either older or younger). There were no associations between expressions of uncertainty and ground rule administration, or with whether or not the question focused on central rather than peripheral details about the alleged crimes. Findings highlight concerns surrounding preparatory procedures to help witnesses, especially adolescents, indicate uncertainty when testifying. Copyright © 2017 John Wiley & Sons, Ltd.

Practitioner Perspectives on Child Sexual Exploitation: Rapport Building With Young People.

Young people suspected of being sexually exploited are unlikely to have made prior disclosures before being approached by authorities, and this can make them especially uncomfortable when involved in investigations. Semistructured interviews were conducted with frontline social workers and law enforcement practitioners about their experiences interacting with youth during child sexual exploitation investigations. The findings provided some tentative insights into the processes by which practitioners sought to establish rapport with young people who have been exploited and establish themselves as trustworthy abuse disclosure recipients. Practitioners reported that rapport building in child sexual exploitation cases not only occurred over lengthy periods of time (e.g., months or years) but also required repeated contacts between the practitioners and young people, during which practitioners minimized their roles as authorities and maximized their authenticity as caring people. Practitioners mentioned the importance of dependability, lightheartedness, and having a casual demeanor. Findings have implications for managing reluctance and understanding rapport building when working with possible victims.

The Effects of Secret Instructions and Yes/no Questions on Maltreated and Non-maltreated Children's Reports of a Minor Transgression.

This study examined the effects of secret instructions (distinguishing between good/bad secrets and encouraging disclosure of bad secrets) and yes/no questions (DID: "Did the toy break?" versus DYR: "Do you remember if the toy broke?") on 262 maltreated and non-maltreated children's (age range 4-9 years) reports of a minor transgression. Over two-thirds of children failed to disclose the transgression in response to free recall (invitations and cued invitations). The secret instruction increased disclosures early in free recall, but was not superior to no instruction when combined with cued invitations. Yes/no questions specifically asking about the transgression elicited disclosures from almost half of the children who had not previously disclosed, and false alarms were rare. DYR questions led to ambiguous responding among a substantial percentage of children, particularly younger children. The findings highlight the difficulties of eliciting transgression disclosures without direct questions. Copyright © 2017 John Wiley & Sons, Ltd.

Do Prosecutors Use Interview Instructions or Build Rapport with Child Witnesses?

This study examined the quality of interview instructions and rapport-building provided by prosecutors to 168 children aged 5-12 years testifying in child sexual abuse cases, preceding explicit questions about abuse allegations. Prosecutors failed to effectively administer key interview instructions, build rapport, or rely on open-ended narrative producing prompts during this early stage of questioning. Moreover, prosecutors often directed children's attention to the defendant early in the testimony. The productivity of different types of wh- questions varied, with what/how questions focusing on actions being particularly productive. The lack of instructions, poor quality rapport-building, and closed-ended questioning suggest that children may not be adequately prepared during trial to provide lengthy and reliable reports to their full ability.

Eliciting maltreated and nonmaltreated children's transgression disclosures: narrative practice rapport building and a putative confession.

This study tested the effects of narrative practice rapport building (asking open-ended questions about a neutral event) and a putative confession (telling the child an adult "told me everything that happened and he wants you to tell the truth") on 4- to 9-year-old maltreated and nonmaltreated children's reports of an interaction with a stranger who asked them to keep toy breakage a secret (n = 264). Only one third of children who received no interview manipulations disclosed breakage; in response to a putative confession, one half disclosed. Narrative practice rapport building did not affect the likelihood of disclosure. Maltreated children and nonmaltreated children responded similarly to the manipulations. Neither narrative practice rapport building nor a putative confession increased false reports.

Disclosing adult wrongdoing: maltreated and non-maltreated children's expectations and preferences.

Little is known about the process by which children disclose adult wrongdoing, a topic of considerable debate and controversy. In the current study, we investigated children's evaluations of disclosing adult wrongdoing by focusing on children's preferences for particular disclosure recipients and perceptions of the consequences of disclosure in hypothetical vignettes. We tested whether children thought that disclosure recipients would believe a story child as a truth teller and what actions the recipients would take against the "instigator" who committed the transgression. Maltreated and non-maltreated 4- to 9-year-olds (N=235) responded to questions about vignettes that described a parent's or stranger's transgression. Older children preferred caregiver recipients over police officer recipients when disclosing a parent's transgression but not a stranger's transgression. Maltreated children's preference for caregiver recipients over police officer recipients developed more gradually than that of non-maltreated children. Older children expected disclosure recipients to be more skeptical of the story child's account, and older children and maltreated children expected disclosure recipients to intervene formally less often when a parent, rather than a stranger, was the instigator. Results contribute to understanding vulnerable children's development and highlight the developmental, experiential, and socio-contextual factors underlying children's disclosure patterns.

Support and reluctance in the pre-substantive phase of alleged child abuse victim investigative interviews: revised versus standard NICHD protocols.

Children's unwillingness to report abuse places them at risk for re-victimization, and interviewers who do not respond sensitively to that unwillingness may increase the likelihood that victims will not disclose abuse. Interviewer support and children's reluctance were examined on a turn-by-turn basis using sequential analyses in 199 forensic interviews of 3- to 13-year-olds who alleged maltreatment. Half of the children were interviewed using the Revised Protocol that emphasized rapport-building (RP), the others using the Standard National Institute of Child Health and Human Development Protocol (SP). When using the RP, interviewers provided proportionally more support than when using the SP, but even when using the RP they did not specifically provide support when children expressed reluctance. The RP promoted immediate cooperation when reluctant utterances were met with support, however, suggesting that supportive statements were valuable. The findings enhance our understanding of children's willingness to participate in investigative interviews and the means through which interviewers can foster the comfort and well-being of young witnesses.

Evolving Practice and Outcomes in Grade 2 Glioma: Real-World Data from a Multi-Institutional Registry.

Background: Grade-2 gliomas (G2-glioma) are uncommon. In 2016, RTOG9802 established the addition of chemotherapy after radiation (CRT) as a new standard of care for patients with high-risk G2-glioma, defined as subtotal resection or age ≥40 yrs. Here, we report current practices using real-world data. Methods: Patients diagnosed with G2-glioma from 1 January 2016 to 31 December 2022 were identified in BRAIN, a prospective clinical registry collecting data on patients with brain tumours. High- and low-risk were defined as per RTOG9802. Two time periods, January 2016-December 2019 (TP1) and January 2020-December 2022 (TP2), were defined. Survival was estimated using the Kaplan-Meier method. Results: 224 patients were identified. Overall, 38 (17%) were low-risk, with 35 (91%) observed without further treatment. A total of 186 (83%) were high-risk, with 96 (52%) observed, 63 (34%) receiving CRT, and 19 (10%) receiving radiation. Over time, CRT use increased (TP1 vs. TP2: 22% vs. 36%, p = 0.004), and the rate of biopsy (TP1 vs. TP2: 35% vs. 20%, p = 0.02) and radiotherapy alone (TP1 vs. TP2: 14% vs. 4%, p = 0.01) decreased. Median progression-free survival (PFS) was significantly longer in high-risk patients who received CRT (NR) over observation (39 months) (HR 0.49, p = 0.007). In high-risk patients who were observed, 59 (61%) were progression-free at 12 months and 10 (10%) at 5 years. OS data remains immature. Conclusions: Congruent with RTOG9802, real-world BRAIN data shows CRT is associated with improved PFS compared to observation in high-risk G2-glioma. Whilst CRT use has increased over time, observation after surgery remains the most common strategy, with some high-risk patients achieving clinically meaningful PFS. Validated biomarkers are urgently required to better inform patient management.

Improving Clinical Registry Data Quality via Linkage With Survival Data From State-Based Population Registries.

PURPOSE: Real-world data (RWD) collected on patients treated as part of routine clinical care form the basis of cancer clinical registries. Capturing accurate death data can be challenging, with inaccurate survival data potentially compromising the integrity of registry-based research. Here, we explore the utility of data linkage (DL) to state-based registries to enhance the capture of survival outcomes. METHODS: We identified consecutive adult patients with brain tumors treated in the state of Victoria from the Brain Tumour Registry Australia: Innovation and Translation (BRAIN) database, who had no recorded date of death and no follow-up within the last 6 months. Full name and date of birth were used to match patients in the BRAIN registry with those in the Victorian Births, Deaths and Marriages (BDM) registry. Overall survival (OS) outcomes were compared pre- and post-DL. RESULTS: Of the 7,346 clinical registry patients, 5,462 (74%) had no date of death and no follow-up recorded within the last 6 months. Of the 5,462 patients, 1,588 (29%) were matched with a date of death in BDM. Factors associated with an increased number of matches were poor prognosis tumors, older age, and social disadvantage. OS was significantly overestimated pre-DL compared with post-DL for the entire cohort (pre- v post-DL: hazard ratio, 1.43; P < .001; median, 29.9 months v 16.7 months) and for most individual tumor types. This finding was present independent of the tumor prognosis. CONCLUSION: As revealed by linkage with BDM, a high proportion of patients in a brain cancer clinical registry had missing death data, contributed to by informative censoring, inflating OS calculations. DL to pertinent registries on an ongoing basis should be considered to ensure accurate reporting of survival data and interpretation of RWD outcomes.

Corrigendum: Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.

[This corrects the article DOI: 10.3389/fimmu.2024.1345473.].

Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.

Interviewing children versus tossing coins: accurately assessing the diagnosticity of children's disclosures of abuse.

We describe a Bayesian approach to evaluating children's abuse disclosures and review research demonstrating that children's disclosure of genital touch can be highly probative of sexual abuse, with the probative value depending on disclosure spontaneity and children's age. We discuss how some commentators understate the probative value of children's disclosures by: confusing the probability of abuse given disclosure with the probability of disclosure given abuse, assuming that children formally questioned about sexual abuse have a low prior probability of sexual abuse, misstating the probative value of abuse disclosure, and confusing the distinction between disclosure and nondisclosure with the distinction between true and false disclosures. We review interviewing methods that increase the probative value of disclosures, including interview instructions, narrative practice, noncontingent reinforcement, and questions about perpetrator/caregiver statements and children's reactions to the alleged abuse.

Factors that influence clinical trial participation by patients with cancer in Australia: a scoping review protocol.

INTRODUCTION: Clinical trials are the backbone of research. It is well recognised that patient participation in clinical trials can be influenced by a myriad of factors such as access to a clinical trial, restrictive trial eligibility criteria and perceptions held by patients or physicians about clinical trials. Australia is a key stakeholder in the global clinical trials sphere. This scoping review protocol aims to identify and map the current literature describing factors that influence clinical trial participation of patients with cancer, in Australia. METHODS AND ANALYSES: The Joanna Briggs Institute (JBI) methodology for scoping reviews will be used to conduct this review. Four electronic databases will be systematically searched for relevant published literature on this topic, as a collaborative process involving the lead investigator and a health science librarian. We will hand search of citations and reference lists of the included papers, and a grey literature search through Google scholar, Grey Literature Report, Web of Science Conference Proceedings. All published papers pertaining to patients diagnosed with solid organ or haematological malignancies will be included. Studies which did not involve patients from Australia will also be excluded. A customised data extraction tool will be pilot tested and refined, and subsequently two independent reviewers will perform data screening and extraction. Results will be collated and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews: PRISMA-Scoping Reviews. Quantitative data will be presented using descriptive statistics. Qualitative data will be synthesised using thematic analyses. This scoping review does not require ethical approval as the methodology focuses on analysing information from available published data. ETHICS AND DISSEMINATION: Results will be disseminated to relevant stakeholders including consumers, clinicians, professional organisations and policy-makers through peer-reviewed publications and national and international conferences.