Citations

Background Studies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown. Objective The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity. Methods We assessed whether plasma p-tau 181 and Aβ 42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD. Results Plasma Aβ 42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ 42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ 42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity. Conclusion Plasma Aβ 42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.

Abstract Introduction: Most people who die from prostate cancer are older than 75 years. However, prostate cancer diagnosed at younger ages is often more aggressive. While epidemiologic studies have examined the association between age and survival in patients with prostate cancer overall, the clinical drivers of this relationship in patients with advanced disease remain unclear. We leveraged the International Registry of Men with Advanced Prostate Cancer (IRONMAN, NCT03151629) to (1) quantify the association between age and overall survival and (2) explore whether this association is explained by treatments. Methods: We included 3, 734 patients enrolled from 15 countries with new diagnoses of metastatic hormone sensitive (mHSPC, N=2, 642) or castration resistant prostate cancer (CRPC, N=1, 092). Age at enrollment was categorized as <55, 55-59, 60-64 (reference), 65-69, 70-74, 75-79, 80-84, 85+ years. We computed age-specific death rates (95% confidence intervals [CIs]) by disease state (mHSPC, CRPC) at enrollment. To explore whether this relationship was explained by treatment, we fitted disease state-stratified Cox models and sequentially adjusted for (1) de novo metastatic status and country, and (2) baseline treatment (androgen deprivation therapy [ADT] alone, ADT + androgen receptor pathway inhibitors [ARPI], ADT + chemotherapy, ADT + ARPI + chemotherapy, other). Results: Over 5.5 years of follow-up (median: 3.2 years, IQR: 1.7, 4.8), 995 patients died from any cause. Younger patients were more likely to have de novo metastatic disease. Among those with mHSPC at enrollment, the age-specific death rates per 1, 000 person-years followed a J-shaped pattern: 80 (95% CI: 54, 117) in patients under 55 years, 58 (46, 74) in patients aged 60-64, 102 (78, 133) in patients aged 80-84, and 172 (125, 236) in patients aged 85 and older. The death rates among those with CRPC followed a similar pattern, albeit rates were higher in magnitude: 212 (95% CI: 140, 323) in patients under 55 years, 153 (115, 202) in patients aged 60-64, 200 (155, 258) in patients aged 80-84, and 204 (142, 291) in patients aged 85 and older. After adjusting for disease state, country, and the timing of diagnosis of metastases, death rates were substantially higher for ages 75-79 (HR 1.4; 95% CI 1.1, 1.7), 80-84 years (HR 1.6; 95% CI 1.2, 2.1), and 85 years and older (HR 2.0; 95% CI: 1.5, 2.7) compared to ages 60-64 years. Patients aged under 55 years had 1.4-fold higher death rates (95% CI: 1.0, 1.9) compared to those 60-64 years. After additionally adjusting for baseline treatment, overall survival remained worse for the older patients and the youngest age group with hazard ratios remaining meaningfully unchanged. Conclusion: Age at enrollment is associated with overall survival in people with advanced prostate cancer enrolled in IRONMAN in a J-shaped pattern. This relationship is not explained by differences in baseline treatment. Citation Format: Hannah E. Guard, Michelle O. Sodipo, Colleen B. McGrath, Anna Siefkas, Lauren E. Howard, Konrad H. Stopsack, Christopher M. Sauer, Robert Dreicer, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim N. Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, Michael Kolinsky, Vincent Khoo, Joaquin Mateo, Chidiebere N. Ogo, Rana R. McKay, Stefanie Fischer, Heather H. Cheng, Russell Szmulewitz, Young E. Whang, Anand Sharma, Frédéric Pouliot, Simon Crabb, Monica S. Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi T. Odedina, Simon Anderson, Simone Badal, Natalie Greaves, Karen A. Autio, Laurel Cannon, Alyssa Chan-Cuzydlo, Marie Grant, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel J. George, Lorelei A. Mucci, IRONMAN investigator team. Disentangling the association between age and overall survival in an international cohort of patients with advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4935.

Abstract Introduction: With over 80, 000 new cases of non-Hodgkin's lymphoma (NHL) diagnosed annually, modifiable risk factors remain unclear. Circadian disruption, linked to cancers like breast and prostate, affects immune cells (e.g., natural killer cells and T-helper cells) by altering their trafficking and proliferation. Some studies (PMID: 30566672, 27611440) suggest long sleep may increase overall NHL risk, including a Mendelian randomization (MR) study (PMID: 32895918). However, no research has examined the causal relationship between sleep traits, including long sleep, and NHL risk, by subtypes. We hypothesize that sleep traits are causally associated with NHL subtypes in European populations, testing this using MR with data from the International Lymphoma Epidemiology Consortium (InterLymph). Methods: We conducted two-sample MR using genome-wide association studies (GWAS) summary data for sleep traits and NHL subtypes. Only independent, genome-wide significant (p < 5×10-8) Single Nucleotide Polymorphisms (SNPs) were selected as valid instruments, sourced from the UK Biobank. Sleep traits included chronotype (153 SNPs), insomnia (48 SNPs), sleep duration (78 SNPs), excessive daytime sleepiness (37 SNPs), short sleep (27 SNPs), and long sleep (8 SNPs). NHL subtype data were from InterLymph: follicular lymphoma (6, 508 cases / 64, 183 controls), mantle cell lymphoma (1, 169 cases / 61, 603 controls), Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: 1, 697 cases / 59, 333 controls), and chronic lymphocytic leukemia (8, 522 cases / 67, 653 controls). The primary analysis used inverse-variance weighted (IVW) random-effects, with MR-Egger for pleiotropy adjustment. Results: Using the IVW method, we did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes, but did yield several intriguing trends. Long sleep (sleep duration >= 9 h per night) showed a marginally increased NHL risk [Odds ratio (OR) range: 1.51 - 247.9] across each subtype. Short sleep (sleep duration < 7 h per night) showed a similar trend [OR range: 1.25 - 1.81], except for WM/LPL, where we noticed a negative trend. The confidence limit for long sleep was imprecise due to the small number of variants. We did not notice any significant directional horizontal pleiotropy or weak instrument bias. Conclusions: We found no conclusive evidence of a relationship between sleep traits and four NHL subtypes. However, we see suggestive trends of long and short sleep associated with higher risk of some NHL subtypes. These findings align with the previous studies, which showed long sleep was associated with higher risk of NHL overall. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses. Citation Format: Pankhil Shah, Brittany Crawford, Anwar Merchant, Brenda Birmann, Angelica Macauda, Michelle A. Hildebrandt, Aaron Norman, Neil E. Caporaso, Meredith Yeager, Michael Dean, Immaculata De Vivo, Lynn Goldin, Nicola J. Camp, Rosalie Griffin, Delphine Casabonne, Federico Canzian, Pelin Unal, Elad Ziv, Catherine R. Marinac, Alexandra Nieters, Stephen J. Chanock, Mitchell J. Machiela, Michael Conry, Charlie Zhong, Hanla A. Park, Simon Cheah, Jonathan N. Hofmann, Elizabeth E. Brown, Celine Vachon, Susan Slager, Sonja Berndt, Sophia S. Wang, Vijai Joseph, James McKay, Henrik Hjalgrim, Lara Sucheston-Campbell, Karl Smith-Byrne, Alyssa Clay-Gilmour. Association between sleep traits and risk of non-Hodgkin's lymphoma subtypes: a mendelian randomization study in the International Lymphoma Epidemiology (InterLymph) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7415.

Abstract Introduction: The standard of care for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the expanded approval of androgen receptor pathway inhibitors (ARPIs) alongside androgen deprivation therapy (ADT). ADT alone has been shown to affect cognitive function. However, the cognitive impact of distinct treatment combinations remains unclear. We investigated the association between first-line systemic treatments and the trajectory of subjective cognitive function among mHSPC survivors in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). Methods: This analysis included 2435 newly diagnosed mHSPC patients enrolled across 15 countries between July 2017 and August 2024. Treatments were reported by site personnel and physicians. For this analysis, we focused on first-line systemic treatment and classified treatment groups at enrollment as ADT monotherapy (referent), ADT + ARPIs, or ADT + chemotherapy. Subjective cognitive function was assessed via the EORTC QLQ-C30 Cognitive Function subscale, with patient-reported scores (range 0-100) collected at enrollment and every 3 months for up to 5 years; higher scores reflect better cognitive function. Associations were estimated using linear mixed effects models with clustering by study site and country to examine differences at enrollment and across trajectories of subjective cognitive function by first-line treatment, adjusting for demographic and clinical factors. Results: Median age at enrollment was 70 years, with a median follow-up of 1.7 years. 724 (30%) participants were treated with ADT monotherapy, 1317 (54%) with ADT + ARPIs, and 394 (16%) with ADT + chemotherapy. Mean cognitive function scores at enrollment were 85.4 (Standard Deviation [SD] 19.5) for participants treated with ADT monotherapy, 86.7 (SD 17.3) for ADT + ARPIs, and 86.7 (SD 18.0) for ADT + chemotherapy. Cognitive function scores decreased by -0.60 points (95% Confidence Interval [CI] -0.72, -0.48) per year among those treated with ADT monotherapy, with similar rates observed for those treated with ADT + chemotherapy. Participants treated with ADT + ARPIs had a slower decline in cognitive function, with scores decreasing by -0.36 points (95% CI -0.60, -0.08) per year. Conclusion: In this international cohort of mHSPC survivors, subjective cognitive function scores were generally high at enrollment but declined over time. There was no evidence of worse cognitive function in those treated with ADT + ARPIs nor ADT + chemotherapy over time compared to ADT monotherapy. Cognitive functioning is a key component of survivorship, and defining cognitive trajectories associated with first-line treatment can inform supportive interventions, patient treatment decision-making, and clinical guidelines. Citation Format: Michelle O. Sodipo, Alicia K. Morgans, Erica T. Warner, Emily M. Rencsok, Lauren E. Howard, Colleen B. McGrath, Anna Siefkas, Konrad H. Stopsack, Christopher Sauer, Robert Drecier, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, David Lorente, Elisabeth Heath, Rana McKay, Stefanie Fischer, Heather H. Cheng, Young E. Whang, Frederic Pouliot, Simon Crabb, Monica Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi Odedina, Natalie Greaves, Simone Badal, Simon Anderson, Sharon Harrison, Karen Autio, Laurel Cannon, Marie Grant, Alyssa Chan-Cuzydlo, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel George, Sebastien Haneuse, Lorelei A. Mucci, on behalf of the IRONMAN Registry. First-line therapies and subjective cognitive function trajectories among international metastatic hormone-sensitive prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3630.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.