Miriam Hospital

Weight stigma and weight discrimination refer to the negative attitudes and behaviours towards people with higher weight, because of their body size. Experiences of weight stigma in healthcare settings and within weight management interventions contribute to poor psychological and physical health and healthcare avoidance. This study aimed to develop a checklist for healthcare professionals and providers of weight management interventions to minimize weight stigmatisation, to the extent possible, in these interventions and settings. Based on existing literature on the contributors to weight stigma in healthcare, members of the Eating Disorders In Weight-Related Therapy (EDIT) Collaboration Weight Stigma Working Group drafted and refined the checklist items using an iterative process. The items were then pilot-tested by two reviewers. A 21-item checklist, organized into four domains: (1) planning and personnel; (2) intervention design and content; (3) outcomes and monitoring; and (4) additional components, was validated via an online survey. Healthcare professionals, researchers, and individuals with lived experience of higher weight evaluated the clarity, relevance, and importance of each item. The Content Validity Index (CVI), Content Validity Ratio (CVR), and participant feedback were used to refine the final version of the checklist. Respondents (n = 28, 79% women, Mage = 44, SD = 10.6) completed the survey. Most items were rated as clear, and 20 out of 21 items were deemed relevant to the checklist's aim (CVI range 0.61-1.0). Four items were rated as essential, with many remaining items rated as 'important but not essential'. The final checklist consists of nine items across three sections: (A) essential elements of planning/design, (B) additional considerations, and (C) feedback on the service. The EDIT Weight Stigma Reduction Checklist has value in assisting providers to design, deliver, and implement weight management interventions to take a priori action to minimise weight stigma in practice.

551 Background: In addition to the association of SDHB genomic alterations (GA) with paraganglioma and pheochromocytoma, SDHB GA are also linked to a rare form of RCC with inactivation or homozygous deletion (complete loss) of the SDHB gene (SDHBdef-RCC) which carries a high risk for metastasis and adverse prognosis. We studied the GA landscape of SDHBdef-RCC and compared it to RCC lacking SDHB GA (SDHBwt-RCC) . Methods: 9,462 cases of clinically advanced RCC underwent hybrid capture based comprehensive genomic profiling (CGP) using the FoundationOneCDx assay to identify all classes GA. Microsatellite instability status (MSI) and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by IHC using the Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). All cases had relapsed either loco-regionally or with metastatic disease at the time sequencing. Results: 17 (0.6%) of the sequenced advanced RCC were SDHBdef-RCC) and included 7 (41.2%) with germline short variant (SV) SDHB mutations, 6 (35.5%) with somatic SV SDHB mutations and 4 (23.5%) with homozygous SDHB deletions (complete loss of 8 of 8 exons). Their histologic RCC subtypes included 5 sarcomatoid, 5 high grade NOS, 4 oncocytic, 2 clear cell and 1 collecting duct RCC morphology; 10 RCC were sequenced using the primary kidney tumor and 7 from a metastatic site biopsy for CGP. Patients with SDHBdef-RCC were younger (mean age 45.9 yrs vs 62.5 yrs; p<.0001) and had a similar gender distribution (29.4% - 30.9% female). Biomarkers of checkpoint inhibitor efficacy including MSI-high status (0% - 0.6%), TMB level (mean 3.6 to 3.9 mutations/Mb) and any level of PD-L1 expression (40.0% vs 35.7%) were similar in both groups. Noteworthy GA summaries are shown in attached Table. Conclusions: SDHBdef-RCC is a rare form of clinically advanced RCC with predominantly oncocytic and sarcomatoid non-clear cell histology featuring either inactivating short variant SDHB germline or somatic mutations or homozygous deletion of SDHB gene. When compared with SDHDwt-RCC, SDHBdef-RCC occurs in younger patients, features non-clear cell histology, less frequent GA in tumor suppressor genes ( VHL , PBRM1 , SETD2 , BAP1 ), less frequent GA in cell cycle regulatory genes ( CDKN2A / B , T P53 ) and significant increased GA in NF2 . Further investigation of GA in this rare RCC type for clinical trial design and germline screening strategies is warranted. Limitations of this study include its retrospective nature, potential selection bias, and lack of clinically relevant data. Genomic alteration summaries of sequenced advanced RCC. SDHBmut RCC (N=17) SDHBwt RCC (N=9445) P value VHL 23.5% 43.7% NS PBRM1 0.0% 24.9% .011 SETD2 0.0% 17.0% NS BAP1 0.0% 11.3% NS CDKN2A 11.8% 25.6% NS CDKN2B 11.8% 20.1% NS MTAP 7.7% 15.0% NS TP53 5.9% 21.1% NS NF2 23.5% 6.7% .024

219 Background: The HRDsig biomarker has emerged as a putative predictor of PARP inhibitor (PARPi) efficacy in multiple tumor types including CAPC. Previous studies of HRDsig+ CAPC focused on BRCA1/2 genomic alterations (GA); while non-BRCA ( BRCA1/2 wt) GA have not been widely considered as drivers of HRDsig+ CAPC PARPi response. Methods: Using the FoundationOne CDx assay, 23,336 BRCA1/2 wt CAPC cases underwent hybrid capture based CGP to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI), tumor mutation burden (TMB), HRD signature (professional services assay), genomic ancestry and genomic signature were determined from the sequencing data. PD-L1 expression was determined by IHC using Dako TPS score (≥1%: positive). Comparisons were evaluated by χ2 2-tailed using the Yates correction. Results: In this analysis of BRCA1/2 wt CAPC only, 1,107 (4.7%) were HRDsig+. Men with BRCA1/2 wt HRDsig+ CAPC were slightly older (median age 71 vs 69; p<.0001) and featured a slightly higher median number of GA per tumor (4 vs 3; p<.0001). Genomic ancestry distribution revealed just slightly higher African ancestry in the BRCA1/2 wt HRDsig- CAPC (15.2% vs 12.5%; p<.0001) and just slightly higher European ancestry in the BRCA1/2 wtHRDsig+ cases (77.9% vs 74.7%; p=.020). Putative biomarkers of anti-PD1/L1 response including TMB ≥ 10 mut/Mb (range 3.0% to 2.2%; NS) and PD-L1 expression ≥1% (range 10.8% to 11.2%; NS) were similar, although the highly infrequent MSI-high status was more frequent in the BRCA1/2 wt HRDsig- CAPC group (2.2% vs 0.6%; p<.0001). Individual GA more frequent in the BRCA1/2 wt HRDsig+ CAPC involved AR (23.4% vs 10.1%; p<.0001), ATM (8.3% vs 5.7%; p=.0004), FANCA (1.7% vs 0.9%; p=.01), MYC (17.1% vs 8.8%; p<.0001), PTEN (36.1% vs 32.5%; p=.013), RAD21 (12.6% vs 6.1%; p<.0001), RB1 (8.7% vs 4.6%; p<.0001) and TP53 (48.8% vs 38.5%; p<.0001). GA more frequent in the BRCA1/2 wt HRDsig- CAPC included CDK12 (5.3% vs 2.2%; p<.0001), SPOP (11.6% vs 7.2%; p<.0001) and TMPRSS2 (32.4% vs 29.9%; NS). Although relatively uncommon, chromosome 9p loss including CDKN2A / B and MTAP were more frequent in the BRCA1/2 wt HRDsig+ CAPC (MTAP 3.1% vs 1.6%; p=.003). Conclusions: The genomic landscape of BRCA1/2 wt CAPC with HRDsig+ status seems relatively distinct from HRDsig- BRCA1/2 wt cases, involving HRD pathway-associated and other genes that may impact prognosis and help guide clinical trial designs. Limitations include retrospective nature and lack of clinical outcomes data annotation. CAPC HRDsig- (22,229 cases) CAPC HRDsig+ (1,107 cases) P Value AR 10.1% 23.4% <.0001 ATM 5.7% 8.3% 0.0004 CDK12 5.3% 2.2% <.0001 FANCA 0.9% 1.7% 0.01 RAD21 6.1% 12.6% <.0001 RB1 4.6% 8.7% <.0001 SPOP 11.6% 7.2% <.0001 TMPRSS2 32.4% 29.9% NS

11 Background: Clinically advanced penSCC is a highly aggressive malignancy with poor prognosis, and thus further exploration of genomic profiling is essential in development of targeted therapies. Recent evidence has emerged that novel anti-cancer treatments focused on synthetic lethality mechanisms may have efficacy in patients with clinically advanced malignancies. Methods: Using the FoundationOne CDx assay, 459 clinically advanced penRCC underwent hybrid capture based comprehensive genomic profiling (CGP) to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI) and tumor mutation burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by immunohistochemistry (IHC) using the Dako TPS score (0% = negative; 1-49% = low positive and &gt; 50% = high positive). Results: 30 (6.5%) of clinically advanced penSCC featured whole or partial loss (homozygous deletion) of MTAP gene. Of the 30 penSCC with MTAP loss ( MTAP loss+) there were 21 (70.0%) cases with 8/8 MTAP exons lost, 1 (3.3%) with 5/8 MTAP exons lost, 5 (16.7%) with 4/8 MTAP exons lost, 2 (6.6%) with 3/8 MTAP exons lost and 1 (3.3%) with 2/8 MTAP exons lost. The penSCC with MTAP loss+ group was of similar age (median age 64.5 vs 66 years; p &lt; .0001) vs MTAP wild type ( MTAP loss-) group. Genomic ancestry distributions were similar in both groups with European ancestry more frequent in the MTAP loss- group and African ancestry was more frequent in the MTAP loss+ group. APOBEC signature was more frequent in the MTAP loss+ group. A positive HRD signature was uncommon in both groups. The frequency of HPV detection was slightly higher in the MTAPloss- group (26.7% vs 33.3%; NS). Putative biomarkers of immunotherapy response including MSI High status and TMB &gt; 10mutations were uncommon in both groups. At least 1% PD-L1 expression was also similarly high in both groups (85.7% vs 76.7%; NS). CDKN2A (100% vs 39.2%; p &lt; .0001) and CDKN2B (90.0% vs 2.8%; p &lt; .0001) were co-deleted with MTAP in the MTAP loss+ group (Table). Conclusions: MTAP loss was identified in 6.5% of clinically advanced penSCC cases and was frequently associated with complete loss of all 8 exons (70%) of the MTAP gene. While biomarkers linked to immunotherapy response (MSI, TMB, PD-L1) and HPV positivity were comparable between groups, the genomic landscape of MTAP-loss+ penSCC showed notable distinctions from MTAP-loss– cases. Study limitations include its retrospective design, limited clinical annotation, and potential selection or confounding biases. Multi-tumor trials of PRMT5 and MAT2A inhibitors might consider allowing inclusion of patients with MTAP loss and PenSCC. PenSCC MTAP loss+ (N=30) MTAP loss- (N=429) P value CDKN2A 100.0% 39.2% &lt;.0001 CDKN2B 90.0% 2.8% &lt;.0001 EGFR 6.7% 12.1% NS FGFR1 6.7% 1.6% NS FGFR2 6.7% 0.7% NS NFE2L2 20.0% 5.8% 0.085 NOTCH1 26.7% 16.1% NS PIK3CA 33.3% 23.3% NS TP53 <jats:td c

87 Background: Treatment-emergent neuroendocrine prostate cancer (tNEPC) arises as a phenotype of metastatic castration-resistant prostate cancer (mCRPC) under therapeutic pressure. Despite its poor prognosis, no consensus diagnostic criteria exist for tNEPC. Its clinical and molecular features remain unclear due to the rarity of disease. This study assessed clinical characteristics, biomarkers and outcomes of tNEPC as compared to adenocarcinoma (ACPC) in the mCRPC setting. Methods: This was a retrospective study of adult patients with tNEPC and a matched ACPC cohort (up to 1:2 ratio based on the biopsy date) diagnosed with mCRPC from 01/01/2013 to 12 months before data collection (04/15/2024-11/30/2024) at two US academic institutions. Biopsies obtained after mCRPC diagnosis (index biopsy) were reviewed by two central pathologists to confirm histological diagnosis, using pre-specified standardized definition and pathology criteria. Patients’ characteristics, immunohistochemistry (IHC) markers, treatments and outcomes were compared between tNEPC and ACPC. Results: This study included 79 patients (28 site-defined tNEPC and 51 matched ACPC). The majority were &gt;65 years (mean age: 73 vs 72 years) and white (84% vs 83%), with comparable baseline clinical characteristics between groups. Median follow-up was 13.3 months (tNEPC 6.3; ACPC 15.6). The central pathologists confirmed site diagnoses in 76 patients (κ agreement= 0.91), leaving 71 matched patients (25 tNEPC [24 small cell carcinoma]; 46 ACPC) in the final analysis. All biopsies were metastatic and most came from the liver (tNEPC 44.0% vs ACPC 35.2%). For IHC markers, tNEPC patients had higher positivity of synaptophysin (92% vs 35%) and chromogranin (79% vs 33%), while NKX3.1 positivity was higher in ACPC (24% vs 97%). The most common first lines of therapy (1L) after index were platinum-based chemotherapy (50%) for tNEPC, and androgen receptor pathway inhibitors (53%) for ACPC, but 20% of tNEPC and 22% of ACPC had no record of mCRPC-specific treatments constituting a 1L. While PSA response (≥50% decline) in the post-index period was similar between tNEPC and ACPC (41% vs 42%), tNEPC patients had significantly worse overall survival (OS) after index than ACPC (median OS: 6.3 vs 14.7 months; HR=1.99, 95% CI 1.14–3.42). In tNEPC patients, NKX3.1 positivity appeared associated with better OS (HR=0.29; 95% CI: 0.1-0.9). Conclusions: tNEPC shows distinct histological and IHC profiles, treatment patterns, and worse OS compared with ACPC. These findings highlight important unmet medical need in tNEPC. While the high concordance between central review and site pathologists’ review could be due to expertise in genitourinary/prostate pathology at the academic institutions, our results suggest standardized histopathologic criteria for tNEPC, along with IHC markers, help improve disease classification and diagnostic accuracy in clinical practice.

BackgroundThe U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a Phase 3, multicenter, 2‐year, randomized controlled trial assessing the effects of two multidomain lifestyle interventions on cognition in older adults at risk for cognitive decline due to well‐established factors such as sedentary behavior, suboptimal diet, and suboptimal cardiometabolic health. A key aim was to test the generalizability of the FINGER findings in a diverse, representative U.S. cohort. Interventions were modeled on FINGER, adapted to U.S. culture, and delivered in collaboration with community partners.MethodParticipants aged 60‐79 years meeting pre‐specified risk criteria for cognitive decline were randomized (1:1) at five sites to one of two intervention arms. Both arms targeted physical activity, nutrition, cognitive/social challenge and cardiometabolic risk management, but differed in intensity and accountability. The Structured arm (STR) included frequent peer team meetings, regular exercise, the MIND diet, BrainHQ cognitive training, social/cognitive challenge, and monthly blood pressure monitoring. The Self‐Guided arm (SG) included fewer peer team meetings and general health education with support to encourage health behaviors. The primary outcome, assessed at baseline and every six months, was change in global cognition, measured using a composite score based on tests of executive function, episodic memory, and processing speed. Secondary outcomes included domain‐specific cognitive scores, Clinical Dementia Rating‐Sum of Boxes, functional ability, frailty, and intervention response by subgroups (e.g., APOE4 carriers).ResultA total of 2,111 participants (mean age 68±5 years, 69% female, 31% from minoritized ethnoracial groups) were randomized. Retention exceeded 94%, and intervention adherence remained high throughout the 2‐year intervention period. Topline findings on intervention effects for primary and secondary outcomes will be presented. Additionally, two participants will share testimonials about their trial experiences.ConclusionU.S. POINTER, the largest lifestyle intervention trial globally, successfully met ambitious recruitment goals and engaged a diverse, at‐risk cohort while maintaining high retention and participation rates. The topline results will provide pivotal evidence on the effectiveness of multidomain interventions to improve cognition or slow decline in older U.S. adults, with high potential to inform public health initiatives aimed at reducing Alzheimer's disease and related dementia risk.

Most US drug use events that lead to a fatal overdose are unwitnessed. Given the scale of the overdose crisis, interventions to help detect and respond to overdoses in community settings are urgently needed. Overdose detection technologies (ODT), including reverse-motion restroom sensors, are a promising set of interventions that are underutilized. This study explored the perspectives of frontline harm reduction workers, clinicians, housing shelter staff, and their clients on restroom sensors. Staff and program client focus groups conducted between December 2022 and January 2024 discussed prior experiences of responding to overdoses and existing organizational overdose policies and procedures. A verbal and visual description of restroom sensors was given and supplemented with brief captioned educational videos to assess the feasibility and acceptability of restroom sensor implementation. We conducted N = 8 discussions (n = 40 participants total). Staff described the anxiety and cognitive burden of monitoring client restrooms and the trauma of witnessing and responding to overdoses. Sites varied in their safety procedures, ranging from manual door knocks every 5 minutes to every 24 hours. Participants embraced the prospect of restroom sensor implementation in community drop-in centers, housing programs, and public restrooms (eg, food service). Perceived benefits of restroom sensors, in addition to saving lives, included the low-threshold and automated nature of the technologies and potential reductions in stress, anxiety, and trauma. However, participants shared concerns surrounding data confidentiality, potential legal repercussions of being found onsite after overdosing (eg, loss of housing, job, children, freedom), stigmatizing attitudes among first responders, reactions to ODTs among clients who mistrust technologies, corporations, and the government, staff fatigue, and technology maintenance. Our findings demonstrated high acceptability of ODTs among staff and patients but revealed several programmatic and policy considerations that could support future implementation efforts.

Objective Screening for obesity and eating disorders (EDs) offers a pathway to treatment. The current study surveyed U.S. college healthcare providers regarding screening for obesity and EDs. Participants Providers (n = 1,159) from a nationally-representative sample of 384 college health centers. Methods Providers completed surveys regarding obesity and ED screening practices and beliefs. Provider-level and organizational-level factors were examined as predictors of screening frequency. Results Providers reported screening larger percentages of female students for obesity (70%) than EDs (30%) and were more likely to report a center-wide policy to screen for obesity (59.1%) than EDs (33.9%). Providers reporting a routine screening policy predicted screening frequency in both obesity and EDs. Most providers believed screening for obesity (75.6%) and EDs (82.5%) was a good idea. Conclusion Obesity is screened for more often than EDs in college health centers. Understanding screening barriers will be beneficial in connecting students with obesity and/or EDs to care.

Weight loss maintenance (WLM) is one of the most difficult challenges in obesity treatment. Continuous care, which involves frequent behavioral weight management sessions delivered by professional staff, shows promise; however, this care is costly and unsustainable. Thus, new, efficacious treatment models are needed for WLM. To examine the efficacy of an entirely patient-delivered treatment for WLM compared with professionally delivered standard-of-care treatment (SOC). This randomized clinical trial used a 2-phase WLM design. During phase 1, participants received an online weight loss program. Those who achieved 5% or greater weight loss in phase 1 were eligible for phase 2, the actual 18-month WLM trial. Participants in the maintenance trial were randomized to either an entirely patient-delivered lifestyle intervention for WLM or SOC delivered by professional staff. Participants aged 18 to 75 years with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 to 50 were recruited from a single academic research center. Data were collected from February 2018 to March 2023, and data were analyzed from September 2024 to February 2025. Patient-to-patient treatment involved no professional staff; instead, mentors (successful weight losers) delivered intervention sessions and peers (fellow participants) provided ongoing, remotely delivered evidence-based social support. SOC was current best practice for WLM-group lifestyle intervention led by professionals. Both WLM interventions were 18 months in duration. Primary outcome was weight change during the 18-month trial. Secondary outcomes included blood pressure, heart rate, physical activity, and sedentary behavior. Among the 287 randomized participants (240 [83.6%] female; mean [SD] age, 53.6 [0.9] years), 268 (93.4%) completed the trial. There was a statistically significant difference in weight change by arm; patient-to-patient treatment yielded significantly less weight regain than SOC (month 6: -1.44 kg [95% CI, -2.35 to 0.54] vs -0.16 [95% CI, -1.13 to 0.82]; month 12: 0.04 kg [95% CI, -0.86 to 0.95] vs 0.77 [95% CI, -0.21 to 1.47]; month 18: 0.77 kg [95% CI, -0.14 to 1.68] vs 2.37 [95% CI, 1.40 to 3.34]; P = .002). Parallel findings were observed for diastolic blood pressure, heart rate, physical activity, and sedentary behavior. In this trial, patient-delivered lifestyle intervention (mentor interventionists plus peer support) yielded significantly better WLM and cardiovascular risk outcomes compared with SOC delivered by professionals. Future research may examine the effectiveness of this novel treatment approach in community and clinical settings. ClinicalTrials.gov Identifier: NCT03396653.