Disrupting prostate cancer research: Challenge accepted; report from the 2023 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2023 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, themed "Disrupting Prostate Cancer Research: Challenge Accepted," was convened at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA, from June 22 to 25, 2023. METHODS: The 2023 marked the 10th Annual CHPCA Meeting, a discussion-oriented scientific think-tank conference convened annually by the Prostate Cancer Foundation, which centers on innovative and emerging research topics deemed pivotal for advancing critical unmet needs in prostate cancer research and clinical care. The 2023 CHPCA Meeting was attended by 81 academic investigators and included 40 talks across 8 sessions. RESULTS: The central topic areas covered at the meeting included: targeting transcription factor neo-enhancesomes in cancer, AR as a pro-differentiation and oncogenic transcription factor, why few are cured with androgen deprivation therapy and how to change dogma to cure metastatic prostate cancer without castration, reducing prostate cancer morbidity and mortality with genetics, opportunities for radiation to enhance therapeutic benefit in oligometastatic prostate cancer, novel immunotherapeutic approaches, and the new era of artificial intelligence-driven precision medicine. DISCUSSION: This article provides an overview of the scientific presentations delivered at the 2023 CHPCA Meeting, such that this knowledge can help in facilitating the advancement of prostate cancer research worldwide.

Perspectives on the role of industry in informatics research and authorship.

OBJECTIVES: Advances in informatics research come from academic, nonprofit, and for-profit industry organizations, and from academic-industry partnerships. While scientific studies of commercial products may offer critical lessons for the field, manuscripts authored by industry scientists are sometimes categorically rejected. We review historical context, community perceptions, and guidelines on informatics authorship. PROCESS: We convened an expert panel at the American Medical Informatics Association 2022 Annual Symposium to explore the role of industry in informatics research and authorship with community input. The panel summarized session themes and prepared recommendations. CONCLUSIONS: Authorship for informatics research, regardless of affiliation, should be determined by International Committee of Medical Journal Editors uniform requirements for authorship. All authors meeting criteria should be included, and categorical rejection based on author affiliation is unethical. Informatics research should be evaluated based on its scientific rigor; all sources of bias and conflicts of interest should be addressed through disclosure and, when possible, methodological mitigation.

Developing a novel screening tool to address pediatric COVID-19 vaccine hesitancy at point of care.

Many children are still not vaccinated against COVID-19, often attributed to rising pediatric vaccine hesitancy. To address this complex public health issue, interventions that uncover parental thinking at point of care are needed to help facilitate discussions in the exam room. The cognitive science framework of Rule Developing Experimentation helps distinguish how people think about day-to-day topics by presenting respondents with a systematic combination of messages that determines the ideas primarily driving their decisions. We hypothesized that Rule Developing Experimentation can empirically assess and identify parental mind-sets in deciding to vaccinate their children to prevent COVID-19. Artificial intelligence was also incorporated to more efficiently help formulate messages. Through an iterative process, surveying a total of 600 participants, three mind-sets emerged regarding the types of messages which parents believe would convince them to vaccinate their children to prevent COVID-19. These three mind-sets are summarized by the following phrases - "Covid is Serious," "Science Says Vaccine Works," and "Vaccine Returns Kids to Normalcy". Using these mind-sets, a simple six-question instrument (i.e., Personal Viewpoint Identifier) was then created to quickly discern at point of care a parent's mind-set surrounding pediatric COVID-19 vaccination. By quickly identifying a parent's mindset at point of care, providers can then utilize the results of the assessment to deliver individualized messaging to parents about the benefits of COVID-19 vaccination. A future study is planned to evaluate the impact of incorporating the Personal Viewpoint Identifier into routine pediatric care settings on COVID-19 vaccination rates.

Squaring the Circle. Brain death and organ transplantation.

PURPOSE OF REVIEW: The adoption of brain death played a crucial role in the development of organ transplantation, but the concept has become increasingly controversial. This essay will explore the current state of the controversy and its implications for the field. RECENT DEVELOPMENTS: The brain death debate, long limited to the bioethics community, has in recent years burst into the public consciousness following several high-profile cases. This has culminated in the reevaluation of the Uniform Determination of Death Act (UDDA), which is in the process of being updated. Any change to the UDDA has the potential to significantly impact the availability of organs. SUMMARY: The current update to the UDDA introduces an element of uncertainty, one the brain death debate had not previously had.

The 29th Annual Prostate Cancer Foundation Scientific Retreat Report.

BACKGROUND: The 29th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held from October 27 to 29, 2022, at the Omni La Costa Resort in Carlsbad, CA. This was the first-ever hybrid PCF Retreat. METHODS: The Annual PCF Scientific Retreat is a prominent international scientific gathering centered on groundbreaking, unpublished, and influential studies in basic, translational, and clinical prostate cancer research. It also covers research from related fields with a strong potential for influencing prostate cancer research and patient care. RESULTS: Key areas of research that were focused on at the 2022 PCF Retreat included: (i) the contributions of molecular and genomic factors to prostate cancer disparities; (ii) novel clinical trial updates; (iii) lessons from primary prostate cancer; (iv) lessons from single-cell studies; (v) genetic, epigenetic, epitranscriptomic and posttranslational mechanisms and clinical heterogeneity in prostate cancer; (vi) biology of neuroendocrine and lineage-plastic prostate cancer; (vii) next generation prostate cancer theranostics and combination therapies; (viii) the biology and therapeutic potential of targeting phosphoinositide 3-kinases pathways; (ix) combining immunomodulatory treatments for prostate cancer; (x) novel gamma delta (γδ) T-cell therapy platforms for oncology; and (xi) lessons from other cancers. CONCLUSIONS: This article provides a summary of the presentations from the 2022 PCF Scientific Retreat. By disseminating this knowledge, we hope to enhance our understanding of the present research landscape and guide future strides in both prostate cancer research and patient care.

Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Real-World Utilization of Radiation Therapy in Multiple Myeloma: An Analysis of the Connect MM Registry.

PURPOSE: Radiation therapy (RT) is an important treatment modality for patients with multiple myeloma (MM). Although patients are living longer with MM, they are more likely to have comorbidities related to treatment, such as bone pain; however, RT can provide symptom relief. To date, the characterization of patients who have received RT in the real-world setting has been limited. METHODS AND MATERIALS: The Connect® MM Registry is a large, US multicenter, prospective observational cohort study of adult patients with newly diagnosed MM from mostly community sites. RT utilization and outcomes were analyzed quarterly throughout treatment. Factors associated with RT use were identified via multivariable analysis. RESULTS: A total of 3011 patients were enrolled in the Connect MM Registry with 903 patients (30%) having received RT at any time. There was a significant difference (P < .05) in overall RT use among patients with an Eastern Cooperative Oncology Group performance status of 0 to 1 versus ≥2, International Staging System disease stage I/II versus III, a history of plasmacytoma or a novel agent in their first regimen, and any number of bone lesions or severe osteoporosis/fracture. RT use was associated with having bone lesions or severe osteoporosis (vs not having bone lesions). Additionally, RT use was associated with ethnicity (Hispanic vs not) and Connect MM Registry cohort (cohort 1 [enrolled 2009-2011] vs 2 [enrolled 2012-2016]). In the 6 months before death, increased RT use was associated with increasing number of treatment lines (P < .0001) and high- versus standard-risk disease (per International Myeloma Working Group criteria; P = .0028). CONCLUSIONS: Real-world results from the Connect MM Registry show RT is frequently used and is associated with clinical factors, including performance status and disease stage. Earlier in MM diagnosis, RT may be used as an adjunct to palliate symptoms or delay systemic therapy. Toward the end of life, RT is more frequently used for palliation when treatment options are often limited.

What makes a winner? Symbiont and host dynamics determine Caribbean octocoral resilience to bleaching.

Unlike reef-building, scleractinian corals, Caribbean soft corals (octocorals) have not suffered marked declines in abundance associated with anthropogenic ocean warming. Both octocorals and reef-building scleractinians depend on a nutritional symbiosis with single-celled algae living within their tissues. In both groups, increased ocean temperatures can induce symbiont loss (bleaching) and coral death. Multiple heat waves from 2014 to 2016 resulted in widespread damage to reef ecosystems and provided an opportunity to examine the bleaching response of three Caribbean octocoral species. Symbiont densities declined during the heat waves but recovered quickly, and colony mortality was low. The dominant symbiont genotypes within a host generally did not change, and all colonies hosted symbiont species in the genus Breviolum. Their association with thermally tolerant symbionts likely contributes to the octocoral holobiont's resistance to mortality and the resilience of their symbiont populations. The resistance and resilience of Caribbean octocorals offer clues for the future of coral reefs.

Three-dimensional species distribution modelling reveals the realized spatial niche for coral recruitment on contemporary Caribbean reefs.

The three-dimensional structure of habitats is a critical component of species' niches driving coexistence in species-rich ecosystems. However, its influence on structuring and partitioning recruitment niches has not been widely addressed. We developed a new method to combine species distribution modelling and structure from motion, and characterized three-dimensional recruitment niches of two ecosystem engineers on Caribbean coral reefs, scleractinian corals and gorgonians. Fine-scale roughness was the most important predictor of suitable habitat for both taxa, and their niches largely overlapped, primarily due to scleractinians' broader niche breadth. Crevices and holes at mm scales on calcareous rock with low coral cover were more suitable for octocorals than for scleractinian recruits, suggesting that the decline in scleractinian corals is facilitating the recruitment of octocorals on contemporary Caribbean reefs. However, the relative abundances of the taxa were independent of the amount of suitable habitat on the reef, emphasizing that niche processes alone do not predict recruitment rates.

The Value of Pharmaceutical Industry-Sponsored Patient Registries in Oncology Clinical Research.

In May 2019, the US Food and Drug Administration (FDA) released the Framework for FDA's Real-World Evidence (RWE) Program, a draft guidance to evaluate the potential use of real-world data in facilitating regulatory decisions. As a result, pharmaceutical companies and medical communities see patient registries, which are large, prospective, noninterventional cohort studies, as becoming increasingly important in providing evidence of treatment effectiveness and safety in clinical practice. Patient registries are designed to collect longitudinal clinical data on a broad population to address critical medical questions over time. With their large sample sizes and broad inclusion criteria, patient registries are often used to generate RWE in the general and underrepresented patient populations that are less likely to be studied in controlled clinical trials. Here, we describe the value of industry-sponsored patient registries in oncology/hematology settings to healthcare stakeholders, in drug development, and in fostering scientific collaboration.

Computer Vision Identifies Recurrent and Nonrecurrent Ductal Carcinoma in Situ Lesions with Special Emphasis on African-American Women.

Although nonrecurrent and recurrent forms of ductal carcinoma in situ (DCIS) of the breast are observed, no evidence-based test can make this distinction. The current retrospective case-control study used archival DCIS samples stained with anti-phospho-Ser226-glucose transporter type 1 and anti-phosphofructokinase type L antibodies. Immunofluorescence micrographs were used to create machine learning models of recurrent and nonrecurrent biomarker patterns, which were evaluated in cross-validation studies. Clinical performance was assessed by holdout studies using patients whose data were not used in training. Micrographs were stratified according to the recurrence probability of each image. Recurrent patients were defined by at least one image with a probability of recurrence ≥98%, whereas nonrecurrent patients had none. These studies found no false-negatives, identified true-positives, and uniquely identified true-negatives. Roughly 20% of the microscope fields of recurrent lesions were computationally recurrent. Strong prognostic results were obtained for both white and African-American women. This machine tool provides the first means to accurately predict recurrent and nonrecurrent patient outcomes. Data indicate that at least some false-positive findings were true-positive findings that benefited from surgical intervention. The intracellular locations of phospho-Ser226-glucose transporter type 1 and phosphofructokinase type L likely participate in cancer recurrences by accelerating glucose flux, a key feature of the Warburg effect.

Cancer Decedents' Hospital End-of-Life Care Documentation: A Retrospective Review of Patient Records.

Objective: International standards of end-of-life care (EOLC) intend to guide the delivery of safe and high-quality EOLC. Adequately documented care is conducive to higher quality of care, but the extent to which EOLC standards are documented in hospital medical records is unknown. Assessing which EOLC standards are documented in patients' medical records can help identify areas that are performed well and areas where improvements are needed. This study assessed cancer decedents' EOLC documentation in hospital settings. Methods: Medical records of 240 cancer decedents were retrospectively evaluated. Data were collected across six Australian hospitals between 1/01/2019 and 31/12/2019. EOLC documentation related to Advance Care Planning (ACP), resuscitation planning, care of the dying person, and grief and bereavement care was reviewed. Chi-square tests assessed associations between EOLC documentation and patient characteristics, and hospital settings (specialist palliative care unit, sub-acute/rehabilitation care settings, acute care wards, and intensive care units). Results: Decedents' mean age was 75.3 years (SD 11.8), 52.0% (n = 125) were female, and 73.7% lived with other adults or carers. All patients (n = 240; 100%) had documentation for resuscitation planning, 97.6% (n = 235) for Care for the Dying Person, 40.0% for grief and bereavement care (n = 96), and 30.4% (n = 73) for ACP. Patients living with other adults or carers were less likely to have a documented ACP than those living alone or with dependents (OR 0.48; 95% CI 0.26-0.89). EOLC documentation was significantly greater in specialist palliative care settings than that in other hospital settings (P < .001). Conclusion: The process of dying is well documented among inpatients diagnosed with cancer. ACP and grief and bereavement support are not documented enough. Organizational endorsement of a clear practice framework and increased training could improve documentation of these aspects of EOLC.

Medication Decision Making in Low-Income Families of Black Children With ADHD: A Mixed Methods Study.

OBJECTIVES: The purpose of this study was to explore how and why some low-income Black caregivers seek medication treatment for their children with ADHD. METHODS: Using a sequential exploratory mixed method design, Phase 1 comprised an indepth case study design of seven low-income Black caregivers of children receiving medication for ADHD. Based on findings from Phase 1, the second phase involved a secondary analysis of data on Black uninsured or publicly insured children age 6 to 17 with ADHD (n = 450). RESULTS: Factors influencing medication decision-making included child safety and volatility, caregiver mental health, caregiver aggravation, family centered care (FCC), shared decision making (SDM), sole caregiver status, and school involvement. After adjusting for ADHD severity, previous receipt of special education services and experiences of FCC and SDM were independently associated with receipt of a medication for ADHD. CONCLUSIONS: Clinicians and school personnel can intervene to decrease disparities in the treatment of ADHD.

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer.

PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). EXPERIMENTAL DESIGN: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. RESULTS: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. CONCLUSIONS: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis.

BACKGROUND: Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). METHODS: In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. RESULTS: Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. CONCLUSIONS: These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

Association between risk of dementia and very late-onset schizophrenia-like psychosis: a Swedish population-based cohort study.

BACKGROUND: Although the incidence of psychotic disorders among older people is substantial, little is known about the association with subsequent dementia. We aimed to examine the rate of dementia diagnosis in individuals with very late-onset schizophrenia-like psychosis (VLOSLP) compared to those without VLOSLP. METHODS: Using Swedish population register data, we established a cohort of 15 409 participants with VLOSLP matched by age and calendar period to 154 090 individuals without VLOSLP. Participants were born between 1920 and 1949 and followed from their date of first International Classification of Diseases [ICD], Revisions 8-10 (ICD-8/9/10) non-affective psychotic disorder diagnosis after age 60 years old (or the same date for matched participants) until the end of follow-up (30th December 2011), emigration, death, or first recorded ICD-8/9/10 dementia diagnosis. RESULTS: We found a substantially higher rate of dementia in individuals with VLOSLP [hazard ratio (HR): 4.22, 95% confidence interval (95% CI) 4.05-4.41]. Median time-to-dementia-diagnosis was 75% shorter in those with VLOSLP (time ratio: 0.25, 95% CI 0.24-0.26). This association was strongest in the first year following VLOSLP diagnosis, and attenuated over time, although dementia rates remained higher in participants with VLOSLP for up to 20 years of follow-up. This association remained after accounting for potential misdiagnosis (2-year washout HR: 2.22, 95% CI 2.10-2.36), ascertainment bias (HR: 2.89, 95% CI 2.75-3.04), and differing mortality patterns between groups (subdistribution HR: 2.89, 95% CI 2.77-3.03). CONCLUSIONS: Our findings demonstrate that individuals with VLOSLP represent a high-risk group for subsequent dementia. This may be due to early prodromal changes for some individuals, highlighting the importance of ongoing symptom monitoring in people with VLOSLP.

Exploring new frontiers in prostate cancer research: Report from the 2022 Coffey-Holden prostate cancer academy meeting.

INTRODUCTION: The 2022 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Exploring New Frontiers in Prostate Cancer Research," was held from June 23 to 26, 2022, at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA. METHODS: The CHPCA Meeting is an annual discussion-oriented scientific conference organized by the Prostate Cancer Foundation, that focuses on emerging and next-step topics deemed critical for making the next major advances in prostate cancer research and clinical care. The 2022 CHPCA Meeting included 35 talks over 10 sessions and was attended by 73 academic investigators. RESULTS: Major topic areas discussed at the meeting included: prostate cancer diversity and disparities, the impact of social determinants on research and patient outcomes, leveraging real-world and retrospective data, development of artificial intelligence biomarkers, androgen receptor (AR) signaling biology and new strategies for targeting AR, features of homologous recombination deficient prostate cancer, and future directions in immunotherapy and nuclear theranostics. DISCUSSION: This article summarizes the scientific presentations from the 2022 CHPCA Meeting, with the goal that dissemination of this knowledge will contribute to furthering global prostate cancer research efforts.

Treatment Patterns, Survival, Quality of Life, and Healthcare Resource Use Among Patients With Triple-Class Refractory Multiple Myeloma in US Clinical Practice: Findings From the Connect MM Disease Registry.

BACKGROUND: Adults with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognosis, but the burden of TCR MM has not been well characterized. This study evaluated treatment patterns, overall survival (OS), health-related quality of life (HRQoL), and healthcare resource use (HCRU) among patients with TCR MM in US clinical practice. PATIENTS AND METHODS: Patients with TCR MM in the Connect MM Registry (NCT01081028; a large, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM) were included. Patient characteristics, treatment patterns, HRQoL, and HCRU were analyzed using descriptive statistics. OS was calculated using Kaplan-Meier methodology for the overall cohort and for patients with/without ≥1 post-TCR line of therapy (LOT). RESULTS: A total of 232 patients with TCR MM were included; 155 (67%) had ≥1 post-TCR LOT (post-TCR-Treated subgroup; median 9.9 months of follow-up). Most common post-TCR treatments were carfilzomib (47%), pomalidomide (40%), and daratumumab (26%); median treatment duration was 3.3 months. Median OS was 9.9 months in the overall population, 10.8 months in post-TCR-Treated patients, and 2.6 months for those with no new post-TCR LOT. HRQoL deteriorated and pain increased over 1 year of follow-up, with clinically meaningfully changes in EQ-5D (mean, -0.06 points) and FACT-G (mean, -9.9 points). 124 (53%) patients had ≥1 all-cause hospitalization and 58 (25%) had ≥1 MM-related hospitalization; median annualized length of stay was 35.3 and 42.9 days, respectively. CONCLUSION: The burden of TCR MM is substantial, emphasizing the need for more effective treatment options in the TCR setting.

Growing up is hard to do: a demographic model of survival and growth of Caribbean octocoral recruits.

Background: Among species with size structured demography, population structure is determined by size specific survival and growth rates. This interplay is particularly important among recently settled colonial invertebrates for which survival is low and growth is the only way of escaping the high mortality that small colonies are subject to. Gorgonian corals settling on reefs can grow into colonies of millions of polyps and can be meters tall. However, all colonies start their benthic lives as single polyps, which are subject to high mortality rates. Annual survival among these species increases with size, reflecting the ability of colonies to increasingly survive partial mortality as they grow larger. Methods: Data on survival and growth of gorgonian recruits in the genera Eunicea and Pseudoplexaura at two sites on the southern coast of St John, US Virgin Islands were used to generate a stage structured model that characterizes growth of recruits from 0.3 cm until they reach 5 cm height. The model used the frequency distributions of colony growth rates to incorporate variability into the model. Results: High probabilities of zero and negative growth increase the time necessary to reach 5 cm and extends the demographic bottleneck caused by high mortality to multiple years. Only 5% of the recruits in the model survived and reached 5 cm height and, on average, recruits required 3 y to reach 5 cm height. Field measurements of recruitment rates often use colony height to differentiate recruits from older colonies, but height cannot unambiguously identify recruits due to the highly variable nature of colony growth. Our model shows how recruitment rates based on height average recruitment and survival across more than a single year, but size-based definitions of recruitment if consistently used can characterize the role of supply and early survival in the population dynamics of species.