Browse Articles

Simple Executive Function as an endophenotype of autism-ADHD, and differing associations between simple versus complex Executive Functions and autism/ADHD traits

Abstract Autism and ADHD are associated with difficulties with Executive Functions (EFs), but the prevalence and nature of these difficulties in early development is not well understood. In this longitudinal study, 107 children with a family history of autism and/or ADHD (FH-autism/ADHD), and 24 children with No-FH-autism/ADHD completed multiple EF tasks (5 at age 2 years, 7 at age 3 years). Parents reported on their child’s autism- (Q-CHAT at age 2, SRS-2 at age 3), and ADHD-related traits (CBCL DSM-ADHD scale, both ages). Compared to the No-FH-autism/ADHD group, the FH-autism/ADHD group showed lower scores on simple EFs (involving response inhibition, and holding in mind) at ages 2 and 3. Exploratory analysis linked FH-autism specifically with lower Executive Attention (top-down attentional control) at age 2, and the combination of FH-autism and FH-ADHD with lower Complex EF (involving selectively deploying responses, or updating information) at age 3. Three-year-olds’ Simple EF scores were negatively associated with ADHD-related traits. Complex EF scores were negatively associated with autism traits (before correcting for multiple comparisons). Toddlers with a family history of autism and/or ADHD may benefit from interventions to support simple EF development, whilst those already showing autistic traits may benefit from support with more-complex EF skills.

Primary tumor response to enfortumab vedotin with/without pembrolizumab in patients with upper tract urothelial cancer.

684 Background: Cisplatin-based chemotherapy remains the standard for invasive urothelial cancer (UC) in the perioperative setting. Patients with upper tract UC (UTUC) are often ineligible for cisplatin due to disease- and surgery-related renal dysfunction. Modern perioperative trials focus on bladder UC, and cap or preclude enrollment for UTUC. Given the unprecedented activity of enfortumab vedotin and pembrolizumab (EV/P) in advanced UC and safety in impaired renal function, the assessment of this combination in earlier disease settings for patients with UTUC is an urgent need. This retrospective series evaluated the primary tumor response to EV and EV/P in aUTUC, a disease which is challenging to stage radiographically. Methods: This retrospective study included patients with intact primary UTUC tumors treated with EV and EV/P at Johns Hopkins. Baseline characteristics were collected through chart review. Primary tumor and overall response were assessed by 2 radiologists using RECIST1.1 criteria. Overall and primary tumor Response Rate (RR) [Complete Response (CR) + Partial Response (PR)] and Disease Control Rate (DCR) [CR + PR + Stable Disease (SD)] were calculated. Primary tumor was defined as any lesion in the ureter and/or renal pelvis. Non-measurable and sub-centimeter lesions (long axis <10mm) were deemed non-target per RECIST 1.1. Results: From December 2017 until June 2024, 50 patients with UTUC treated with EV or EV/P were identified. 22/50 patients had intact primary tumors and were included in this study. Median age was 72 years, 13 (59.1%) patients were male and 17 (77.3%) were white. Nineteen (86.4%) patients had pure urothelial histology and 18 (81.8%) had visceral metastases at baseline. Thirteen (59.1%) received EV and 9 (40.9%) EV/P. Three (13.6%) patients started EV at a reduced dose. Median number of EV cycles was 4 (range 0.5-14) and median duration of treatment was 3.3 months (range: 0.5-10). ORR was 36.4% and DCR was 72.3% in the entire cohort. Two (9%) patients had only non-target lesions at baseline and 6 (27.3%) had only non-target primary tumor lesions (Table). Conclusions: In this small study, EV and EV/P demonstrated promising radiographic response in primary UTUC lesions. Larger prospective studies are needed to assess the efficacy of this promising regimen in the perioperative setting for patients with this rare and aggressive disease. Radiologist-assessed RECIST response among patients with and without target lesions at baseline. Overall Response, N (%) Primary Lesion Response, N (%) Target lesions at baseline 20/22 16/22 Response Rate 8/20 (40.0) 4/16 (25.0) CR 0 (0) 0 (0) PR 8 (40.0) 4 (25.0) Disease Control Rate 17/20 (85.0) 14/16 (87.5) SD 9 (45.0) 10 (45.5) PD 3 (15.0) 2 (12.5) Only non-target lesions at baseline 2/22 6/22 Non-CR/Non-PD 2 (100) 6 (100) a a Non-target primary lesions decreased in size in 4/6 patients and remained stable in 2/6.

Examining community social vulnerability domains and influence on treatment selection for men with prostate cancer.

363 Background: For men with clinically localized PCa, treatment selection guided by patient age, comorbidities, and tumor characteristics can offer improved outcomes. While informative, these observations remain difficult to translate into local, state, and federal policy change to eliminate health disparities for communities at greater risk. We sought to examine how community SVI influences primary treatment, a key determinant of cancer outcomes, for men with clinically localized PCa treated primarily in a community setting. Methods: Men diagnosed and managed in CaPSURE practices after 1998 with clinically localized disease (no cM+ or cT4) and who underwent primary management within six months of diagnosis were identified. Community social vulnerability, as defined by census tract-level rankings from 0 to 1 with >90 th percentile deemed high, was appended to participants’ geocoded baseline addresses. SVI encompasses four domains (socioeconomic status, household characteristics, racial and ethnic minority status, and housing type and transportation). Prostate cancer treatment included prostatectomy, radiation, active surveillance/watchful waiting (AS/WW), primary androgen deprivation therapy (pADT). Multivariate multinomial logistic regression analyses examined associations between SVI and treatment selection, adjusted for patient, clinical, and tumor characteristics with sensitivity analyses using each SVI domain. Odds ratios and confidence intervals were reported with a two-sided p-value < 0.05 considered significant. Analysis was performed with SAS 9.4 for Windows. Results: 9,023 men diagnosed with low (43%) or intermediate (42%) risk disease and treated at community urology practices (90%) were included. Half (52%) underwent prostatectomy, 26% radiation, 13% ADT, and 9% AS/WW. Median SVI was 0.37 (IQR 0.17-0.59) and varied by theme: socioeconomic status (median 0.35, IQR 0.18-0.57), household characteristics (median 0.41, IQR 0.22-0.64), racial and ethnic minority status (median 0.37, IQR 0.17-0.63), and housing type and transportation (median 0.44, IQR 0.21-0.70). Correlations between SVI themes varied broadly (r = 0.21-0.63, p < 0.001). Having high SVI was associated with increased odds of non-invasive treatment compared to RP: RT (OR 1.56, 95% CI 1.39-1.77), AS/WW (OR 1.21, 95% CI 1.0-1.45), or pADT (OR 1.51, 95% CI 1.27-1.79). Individuals with high SVI by household characteristics had significantly greater likelihood of pADT (OR 1.61, 95% 1.34-1.94) compared to RP. Conclusions: Community social vulnerability independently increases the likelihood of non-surgical and potentially non-curative management of prostate cancer. SVI domains can provide specificity into which community characteristics may drive vulnerability and aid in identifying communities for targeted, policy-focused interventions.

Clinical features and prognostic value of CDK12 mutation in prostate cancer patients.

103 Background: Studies have reported that biallelic loss of CDK12 in prostate cancer patients leads to genomic instability and an increase in tandem duplications. However, the prognostic relevance of CDK12 mutations has not been fully validated. Therefore, we assessed the clinical characteristics and outcomes of prostate cancer patients with CDK12 mutations, comparing this genomic subtype with prostate cancer lacking any genetic alterations. Methods: A total of 141 prostate cancer patients diagnosed between November 2010 and March 2024 were included. Genomic characteristics of biopsy tissues or plasma ctDNA were analyzed using next-generation sequencing to identify patients with CDK12 mutations and those without any genetic mutations. Due to the low incidence of biallelic CDK12 loss in this patient cohort, we integrated data from metastatic tumor biopsies and liquid biopsies. Notably, cfDNA and prostate cancer tumor biopsies from the same individuals have shown strong concordance in identifying somatic alterations. Results: We evaluated the clinical characteristics of the two groups of prostate cancer patients, and patients with CDK12 mutations were more aggressive and had a higher proportion of initial metastasis [77.05% (47/61) vs. 56.67% (51/80), P=0.013]. The median PSA at diagnosis was higher (60.63ng/ml vs. 38.02ng/ml), and the proportion of pathological Gleason score ≥8 was higher (85.25% (52/61) vs. 60.00% (48/80), P < 0.01). Patients with localized CDK12 mutations had shorter time to metastasis (median 34.10 months vs. 56.22 months, p < 0.001) and shorter survival than those without deleterious genetic alterations. Patients with CDK12 mutations had shorter median progression-free survival with conventional androgen-deprivation therapy, abiraterone, and docetaxel than those without deleterious mutations. However, the use of novel anti-male therapy, PARPi, immunotherapy or focal ablation can still prolong the survival of patients. Conclusions: CDK12 mutations are associated with metastasis and higher pathological malignancy, and they also serve as a predictive factor for poor clinical outcomes in patients receiving standard androgen deprivation therapy, abiraterone, or docetaxel treatment. Therefore, prostate cancer patients with CDK12 mutations may need to consider novel anti-androgen therapies, or combined interventions such as PARP inhibitors, immunotherapy, or focal treatments. This study underscores the importance of molecular diagnostics and the necessity of employing appropriate therapeutic strategies for CDK12-mutated prostate cancer. Overall, given the significant heterogeneity in clinical behavior, our research highlights the importance of this molecular subtype in prostate cancer and serves as a foundation for future prospective studies to further characterize the CDK12 subtype in prostate cancer.

Sea level trends along the South African coast from 1993 to 2022 using XTRACK altimetry, tide gauges, and GNSS measurements

Real world outcomes of ¹⁷⁷ Lu-PSMA-617 PSMA in a racially diverse cohort of patients with metastatic castration resistant prostate cancer (mCRPC).

97 Background: 177 Lu-PSMA-617 is approved for treatment of mCRPC based on the VISION trial cohort with limited racial diversity. We analyzed real-world outcomes of 177 Lu-PSMA-617 in a diverse cohort. We aim to determine patient characteristics predictive of a clinical response to 177 Lu-PSMA-617. Methods: A retrospective analysis was conducted on patients with mCRPC treated with 177 Lu-PSMA-617 at Emory Winship Cancer Institute between 2022-2024. Primary endpoints were PFS, OS, and PSA reduction ≥ 50% (PSA50). Univariate association by survival analysis and logistic regression was carried out. Results: We analyzed 84 patients with PSMA PET+ mCRPC treated with 177 Lu-PSMA-617; 47.6% identified as Caucasian and 42.9% identified as Black. The median cohort age was 71.5 (IQR: 64-77.5). 35.6% had grade group 5 disease. Median number of prior lines of therapy was 5 (range: 4-7). 98.8% of patients had prior treatment with novel hormonal agents; 84.5% received prior taxane treatment. 84.5% were characterized as high-volume diseases using the CHAARTED trial criterion. Median baseline PSA was 105.5 (IQR: 20.4-454.8), and ALP was 103.5 (IQR: 72-177.5). The cohort completed a median number of 4 cycles of 177 Lu-PSMA-617; 35.7% completed six cycles. The overall cohort had a 12-month survival of 84.4%. 12-month survival rate was 88.3% in the white cohort compared to 81.4% in the non-white cohort. mPFS for the overall cohort was 6 months with a 12-month PFS rate of 41.9%. 12-month mPFS for the non-white cohort was 42.7% compared to 41.5% in the white cohort. 50.0% of the overall cohort had a PSA50 response. 56.1% of the non-white cohort had a PSA50 compared to 43.9% of the white cohort (p=0.377). Net BMI decline during treatment was associated with a 56% increased risk of mortality (OS HR 1.56, CI 1.18-2.06, p<0.002). Conclusions: With similar PFS, OS, and PSA50 in this racially diverse cohort of patients with mCRPC, our results demonstrate 177 Lu-PSMA-617 effectiveness in a real-world patient population. Prospective studies are needed for further validation.

Hospitalizations in veterans treated with monotherapy vs combination therapy for metastatic hormone sensitive prostate cancer.

72 Background: Current treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) monotherapy or combination therapy (ADT + docetaxel or an androgen receptor pathway inhibitor). However, no comparative studies have been conducted to assess the hospitalization rates and causes of admission between the two treatment groups. We assessed the hospitalization rates of the different therapies to determine adverse events and improve treatment selection in mHSPC. Methods: A nationwide retrospective study of 6,651 US Veterans with de novo mHSPC in the Veterans Health Administration between 2013-2021. Baseline characteristics for each treatment group were obtained including age, prostate serum antigen (PSA), total number of cardiac drugs, and total number of Anatomic Therapeutic Chemical (ATC) drugs. The five most frequent ICD codes associated with hospitalizations were obtained for each group, excluding the ICD codes for prostate cancer and bone metastases. Quasi-Poisson regression was used to determine differences in hospitalization rates between the two groups. Results: Evaluation of the median baseline characteristics between the two groups showed increased age and decreased PSA (Table). There was no difference between the number of cardiac drugs and total number of ATC drugs between the groups. The 5 most frequent ICD codes for monotherapy were AKI (17%), UTI (11%), essential hypertension (7%), sepsis (5%), and acute post-hemorrhagic anemia (4%). The 5 most frequent ICD codes for combination therapy were AKI (17%), UTI (13%), acute hypoxic respiratory failure (8%), sepsis (7%), and malnutrition (6%). The monotherapy group had a greater increase in hospitalization rates after therapy initiation when compared to combination therapy ( see table ). Quasi-Poisson regression for the hospitalization rates between the two groups had a p-value of 0.018. Conclusions: The rate of hospitalizations increased in the monotherapy treatment group compared to combination therapy. This is likely due to the monotherapy treatment group having a more advanced age and more severe comorbidities. Future directions could include comparing hospitalization rates of combination therapy with ARPI vs docetaxel. This analysis will guide physicians in selecting the more appropriate therapy according to a patient’s individual risk profile and co-morbidities. Age (p < 0.001) PSA(p = 0.008) Pre-treatment hospitalization rate Post-treatment hospitalization rate ADT monotherapy(n = 5146) 75.0 76.2 120 per 1000 person-years 340 per 1000 person-years ADT combination therapy (n = 1505) 72.0 86.3 100 per 1000 person-years 260 per 1000 person-years

Overall survival between veterans with metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone with kidney disease.

76 Background: Enzalutamide and abiraterone are androgen receptor pathway inhibitors (ARPIs) used in metastatic castration-resistant prostate cancer (mCRPC). However, little research has compared their efficacy in this population with co-morbid chronic kidney disease (CKD). Since these medications alter androgen signaling differently and abiraterone is co-administered with prednisone, median overall survival (OS) may differ in patients with decreased renal function. Methods: Veterans within the Veterans Health Administration initially treated with abiraterone or enzalutamide for mCRPC between September 8, 2014, and October 9, 2023 were included. Age at treatment initiation, PSA at diagnosis, race, Charlson comorbidity index, and baseline serum creatinine values were acquired for each patient. Patients with an estimated glomerular filtration rate (eGFR) less than 60 mL/min were included in the CKD group. Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards modeling was used to adjust for differences in baseline characteristics between study groups. Results: We analyzed 10,356 veterans with mCRPC. 1944 (18.8%) had an eGFR less than 60 mL/min and 8412 (81.2%) had an eGFR greater than or equal to 60 mL/min. Of the CKD group, 1093 (56.2%) were treated first with abiraterone and 851 (43.8%) with enzalutamide. The enzalutamide group contained a larger percentage of patients with both cardiovascular disease and diabetes mellitus (47.7% vs. 40.4%, p = 0.06). The abiraterone group had a higher median PSA at diagnosis (7.2 vs 3.9 ng/mL, p < 0.001) and lower median eGFR at treatment initiation (48.82 vs. 49.32 mL/min, p = 0.03). There was no significant difference in median OS between patients treated with abiraterone (n = 4752) or enzalutamide (n = 3660) in the group of patients without CKD (42.9 vs. 44.0 months, p = 0.29). However, in the group of patients with CKD, enzalutamide revealed a longer median OS (35.2 vs 30.5 months, p < 0.001) and decreased mortality when adjusting for differences in baseline characteristics (Adjusted HR 0.80, 95% CI 0.77-0.94). Additionally, patients with CKD were able to take enzalutamide for a longer duration than abiraterone (11 vs. 7 months, p < 0.001). Conclusions: In Veterans with CKD, enzalutamide exhibited longer median OS and decreased risk of death relative to abiraterone. Further research into treatment selection based on comorbid disease could generate revised clinical guidelines that optimize survival in patients with mCRPC. Survival Time Hazard Ratio with 95% CI Adjusted Hazard Ratio with 95% CI CKD Group (n=1944) Enzalutamide (n=851): 35.2 monthsAbiraterone (n=1093): 30.5 monthsp < 0.001 0.835 (0.754 - 0.926) 0.849 (0.766 - 0.941) Non-CKD Group (n=8412) Enzalutamide (n=3660): 44.0 monthsAbiraterone (n=4752): 42.9 monthsp = 0.29 0.944 (0.899 - 0.998) 0.947 (0.899 - 0.998)

Ecological vulnerability and driving factors in the himalayan transboundary landscape under global climate change

PET imaging for metastatic castration sensitive prostate cancer (mCSPC) for patients with PSA response after systemic therapy: A multicentric ambispective analysis.

37 Background: PET imaging is not recommended for surveillance of mCSPC but it is used by some physicians. Little is known about surveillance for metastatic prostate cancer using PET imaging. The aim of this study was to assess the correlation between PSA response and PET imaging for mCSPC. Methods: An ambispective, multicentric, observational study, recorded PET imaging for patient’s treated with a minimum of 6 months of systemic therapy with androgen deprivation therapy (ADT) +/- androgen receptor pathway inhibitor (ARPI) +/- docetaxel for mCSPC with PSA < 0.2 ng/ml, normal CT scan and non progressive disease in bone scan. All of them had baseline evaluation with standard imaging. Results: Between August 2022 and September 2024, 57 patients (pts) with mCSPC were included, in 4 centres in France. Baseline characteristics at the time of metastatic disease were: median age of 65 years (range: 45-84), ISUP ≥4 for 63%, median PSA 22.1 ng/ml (1.6-5000ng/ml) with T≥3 in 53%. The majority of pts had low volume disease 56%, with synchronous metastatic disease for 67% and ≥ 4 bone metastases in 44%. Only 5 pts had visceral metastases. Pts were treated, by ADT + ARPI in 81%, ADT + docetaxel in 7% and triplet in 12% of cases. Patients had prostate radiotherapy (RxT) in 39% and RxT to metastatic bone lesion in 19%. The 8 months PSA was <0.2 ng/ml in 89% of pts. PET imaging was choline in 86%, PSMA in 14%. Median time between treatment initiation and PET imaging was 17 months and delay between PSA < 0.2 and PET imaging was 12 months (range: 0-32). A complete response was observed in 46 patients (81%). Non-complete responders (CR) were more frequently high volume disease (66%) and synchronous metastasis (100%), treated by ADT + ARPI alone (77%) or ADT + docetaxel (11%). Non CR were: 1 neuroendocrine progression, 1 lung cancer and 9 partial responders (2/9 progressed later). Conclusions: In patients with mCSPC, treated by ADT with ARPI and or docetaxel and with PSA < 0.2 ng/ml, a complete response is observed in 81 % when using PET imaging. The information given by PET imaging could be and additional surrogate measure to PSA response for intensification or de intensification the systemic and local treatment for mCSPC.

Evaluation of the impact on overall survival curves of patients with metastatic castration-sensitive prostate cancer staged with PET-PSMA and classified according to current prognostic criteria by volume and risk.

36 Background: The treatment of metastatic castration-sensitive prostate cancer (mCSPC) has evolved over the years. These therapies are guided by current volume (CHAARTED) and risk (LATITUDE) criteria, instituted based on conventional exams. The emergence of new imaging exams like PSMA PET, with its greater accuracy and early detection of metastatic disease, raises questions about the applicability of these criteria in this context. Methods: We conducted a retrospective, single-center study comparing patients staged with PSMA PET between August 2017 and February 2022 and classified as metastatic, after curative therapy or de novo metastatic. Patients with stage IVA, i.e., N1, were also included. Patients were stratified into high and low volume and risk, with the aim of comparing these prognostic factors with outcome of OS. Results: 48 patients with a median age of 66 years at diagnosis were selected: 81.3% had Gleason scores between 8 to 10, 57% had T classification greater than or equal to T3 and 32% were N1 by conventional exams. According to PSMA PET, 40% were de novo metastatic, with disease sites being bones (M1b - 52%), non-pelvic lymph nodes (M1a - 21%), pelvic lymph nodes (N1 - 17%), and viscera (M1c - 10%). 71% of them were low volume and 75% were low risk. With a median follow-up of 37.5 months and 7 deaths, at 36 months we had 64.6% of the high-volume population alive versus 96.6% of low-volume patients (p=0.054), 77.8% of high-risk patients alive compared to 89.9% of low-risk ones (p=0.739). There was a 67% increase in distant metastasis detection. When correlated with bone scintigraphy (BS), there was a 78.9% discordance between the number and/or location of bone lesions, and in 53.3% of cases, PSMA PET was positive for bone disease with negative BS at the same time. Conclusions: PSMA PET appears to be prognostic when applied to volume curves, despite p=0.054, which does not happen for risk, in addition to increasing the detection of metastatic disease compared to conventional exams and being more accurate in the detection of bone disease when compared to BS.

Prevalence of FGFR3 p.Arg248Cys mutation in lynch syndrome associated urothelial carcinoma: A single institution dataset.

858 Background: Patients with Lynch syndrome have an increased risk of developing UC and a relative risk in patient with MSH2 germline impairment of 3,6. In 2024, kinase-inhibitor erdafinitib has been approved in FGFR3 mutated locally advanced and metastatic UC. The aim of the study is to molecularly characterize Lynch-syndrome associated UC (LS-UC). Methods: Starting from a single-institution dataset of patients with Lynch syndrome, we identified 24 patients with LS-UC, of which 13 cases had available specimen for molecular analysis. A DNA NGS analysis was performed with a Cancer Hot-Spot Panel (Thermo Fisher Scientific) covering 50 genes, the detection of fusion transcripts was carried out by RNA-based Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific). Specimen, which didn’t pass internal quality control, were excluded. Results: Our case set was composed of 4 (31%) renal pelvis UC, 4 (31%) ureter UC and 5 (38%) bladder UC and germline pathogenetic variant (GPV) was detected in MSH2 in 7/13 (54%) patients, in MSH6 in 4/13 and in MLH1 in 2/13. Nine specimen provided evaluable material for molecular analysis. No gene fusions were detected in examined genes. The most frequent altered gene was FGFR3 in 6 (46%) cases. In one case, p.Glu368Lys mutation was observed, which is classified as variant of uncertain significance. In five cases (38%), we found the pathogenic variant p.Arg248Cys, which is set near the most frequent alteration in FGFR3 gene in sporadic UC (p.Ser249Cys) and is associated with a good response to erdafinitib. No differences were observed between cases with pathogenic FGFR3 mutation and other cases in term of GPV, tumor site, histologic grade and relapse. Among p.Arg248Cys FGFR3 mutated UC, 4/5 were upper tract UC and 1/4 was bladder UC, four carcinomas were high grade and one was low grade. At surgery time, 2/5 were locally advance with lymph node metastasis and both had a lymph node relapse within 24 months. Conclusions: Despite the small sample size, we confirmed a prominent relation between MSH2 germline mutation and the development of UC. Moreover, we observed a clear preponderance of p.Arg248Cys mutation in FGFR3 mutated LS-UC. These data shine a spotlight on druggable mutation in LS-UC, suggesting a role for molecular analysis in the therapeutic algorithm of these patients. Case Sex Pathogenic Variant Site FGFR3 mutation Other Pathogenic Mutation T N Grade 1 F MSH2 Renal Pelvis x x T1 NX LG 2 M MSH6 Bladder x x Ta NX LG 3 M MSH2 Ureter FGFR3 p.Glu368Lys (VUS) SMARCB1 T3 N0 HG 4 F MSH2 Bladder FGFR3 c.742C>T PIK3CA, TP53, RB1 pT1e NX HG 5 F MSH2 Renal Pelvis FGFR3 c.742C>T PIK3CA Ta NX LG 6 F MSH6 Bladder - TP53 T1 NX HG 7 M MLH1 Ureter FGFR3 c.742C>T - T2 N1 HG 8 F MSH2 Renal Pelvis FGFR3 c.742C>T ARID1A T3 N2 HG 9 F MSH6 Bladder x x T1 NX HG 10 M MSH2 Bladder x x T1 NX HG 11 F MSH2 Renal Pelvis - MSH2, BARD1, NF1, SMARCA4 T4 N0 HG 12 M MSH6 Ureter FGFR3 c.742C>T PIK3CA T1 N0 HG 13 M MLH1 Ureter - FBXW7, PTPN11 x x x

Comparative performance of multiple ensemble learning models for preoperative prediction of tumor deposits in rectal cancer based on MR imaging

Impact of testosterone recovery after androgen deprivation therapy on overall survival in patients with high-risk prostate cancer: Long-term data from a phase III trial.

310 Background: To determine the potential impact of persistent hypogonadism on overall survival (OS) after prolonged androgen deprivation therapy (ADT) in patients (pts) with high-risk prostate cancer. Methods: From 10/2000 to 01/2008, 630 pts were randomised to pelvic radiotherapy (RT) plus 36 (310 pts) vs. 18 months (320 pts) of ADT. Serum testosterone (T) was prospectively collected at baseline, then regularly. We defined T recovery as a return of T to within the normal range value of each participating institution, regardless of whether it was initially normal or abnormal. Excluded from the analysis were pts not receiving exactly 18 or 36 months of ADT (48), or had no T measured at baseline or during follow-up (67). We compared OS between patients recovering or not T to a normal level using the log rank test. Multivariable analysis to predict OS included recovered T to a normal level, age, Zubrod, comorbidities, baseline PSA, Gleason score, stage and ADT duration. Results: 515/630 pts had proper T data available (baseline and follow-up) and were retained for the analysis. The results are reported with a median follow-up of 17.4 years. Over a period of 22 years, 6587 T measurements were available. A total of 270/515 pts (52.4%) recovered T to normal level, 188/330 (57%) in the 18-month and 82/185 (44.3%) in the 36-month cohort, p=0.006. Pts not recovering T to a normal level were older, had higher clinical stage and diabetes. Among pts regaining T to a normal level, the median time to T recovery was 3.6 (IQR 2.9-4.9) years.10- and 15-year OS rates were 76% (71-81) and 44% (38-51) for pts recovering T vs. 55% (49-62) and 30% (24-36) for those who did not, p<0.001. A significant lower risk of death favoured pts recovering T when considering the global hazard ratio (HR) [HR (95% CI) = 0.54 (0.44-0.67), p<0.001]. Significant differences in HR for death are maintained for both 18-month [HR = 0.51 (0.39-0.66), p<0.001] and 36-month cohort [HR = 0.58 (0.40-0.84), p=0.004]. In multivariable analyses, the impact of T recovery remains significant for the risk of death [(HR = 0.69 (0.55-0.86), p=0.001], and also for the 18-month [HR = 0.70 (0.53-0.93), p=0.013] and the 36-month cohort [(HR = 0.61 (0.40-0.93), p=0.021]. In a multivariable model, among pts regaining T to a normal level, the time to T recovery had no impact on OS [HR = 0.97 (0.90-1.04), p=0.41]. Of note, there was no significant difference in the rate of death from prostate cancer between pts recovering or not T (11.9% vs. 13.5%, p=0.58). Competing risk analysis confirms this finding [sHR = 0.83 (0.51-1.35), p=0.57]. Conclusions: In high-risk prostate cancer treated with RT and long-term ADT, T recovery to normal level is associated with a significant improvement in overall survival. The increased death rate in pts not recovering T is likely due to causes unrelated to prostate cancer. Clinical trial information: NCT00223171 .

Comparison of digital pathology AI models, genomics classifier, and clinical variables in predicting progression free survival in TCGA prostate data set.

335 Background: Recent advances in AI have brought innovation to digital pathology problems with H&E whole slide images (WSI). Though some digital pathology AI (DPAI) models have been developed for survival analysis with TCGA data, there is a lack of understanding as to how DPAI models predict progression free survival (PFS) in the TCGA prostate dataset (PRAD). Nor is there a comprehensive comparison of DPAI models versus genomic or clinical models. Batch effects were also ignored in prior works. Methods: PRAD contains 392 patients with WSI and clinical data. WSI batch effect was first evaluated with HistoQC (1). We trained 4 different DPAIs to predict PFS in five-fold cross-validation (CV), controlling for the batch effects in the data splits. Such CV was repeated five times under different random splits. Each model’s performance was evaluated with mean C-index, whose confidence interval (CI) was approximated by the second smallest to the second largest value from the 25 splits. The same evaluation was used for the clinical or genomic model trained with regularized Cox regression. The clinical-only model used variables of age, Gleason group, and adverse pathology features. The genomic model was trained using expression of five prognostic genes from Mou et al. 2022. Multi-modal models using clinical variables with expression and/or DPAI features were evaluated in the same way. Results: Substantial WSI batch effects were discovered across the PRAD dataset; we excluded 9 patients whose WSIs were generated with a distinct scanner. With the remaining 383 patients, the clinical-only model achieved a mean C-index of 0.73 (0.63, 0.84) in the cross-validations, compared to that of 0.72 (0.58, 0.88) by the expression-only model. The clinical-genomic model achieved a better performance of 0.79 (0.65, 0.90). Among the DPAI models, CLAM attention model (2) initialized under the UNI foundation model (3) achieved best mean C-index of 0.68 (0.57, 0.82). Combining this DPAI model with clinical variables achieved a modestly larger C-index of 0.71 (0.59, 0.83). Interestingly, adding gene expression to this multi-modal model didn’t further improve performance. We also observed that ignoring batch effects during data-splitting consistently worsens performance. Conclusions: To the best of our knowledge, this is the first deep dive into PFS prediction on PRAD comparing DPAI with clinical or expression-based models. All modalities of data yielded similar C-indices with overlapping CIs, while the clinical-genomic model performed best. Controlling batch effects is important for DPAI models; future research is needed to explore if batch effect correction on WSI can bring DPAI’s performance closer to clinical-genomic models. Larger sample size is needed to adequately compare data modalities or build proper multi-modality models. 1. Janowczyk et al. 2019. 2. Lu, et al. 2020. 3. Chen, et al. 2023.

KIM-1 as a circulating biomarker in metastatic RCC: Post-hoc analysis of JAVELIN Renal 101.

594 Background: Kidney injury molecule-1 (KIM-1) is a circulating biomarker for renal cell carcinoma. The JAVELIN Renal 101 trial established avelumab and axitinib as a standard treatment regimen for advanced renal cell carcinoma (aRCC). In this post-hoc analysis, we evaluated whether baseline plasma KIM-1 and KIM-1 change on treatment are associated with outcomes in JAVELIN Renal 101. Methods: Patients with aRCC were randomized to avelumab plus axitinib (Av/Ax) or sunitinib (Sun), as previously described. KIM-1 was measured in plasma at baseline (C1D1) and at C3D1 using a Luminex microbead-based assay and an MSD electrochemiluminescence-based assay. KIM-1 values were categorized into high and low according to an optimized cutoff based on the maximum log-rank Q-statistic for PFS. Cox regression analyses were performed for OS and PFS and adjusted for baseline clinical characteristics. Associations between KIM-1 levels and clinical and transcriptomic data were evaluated using the Wilcoxon rank-sum test. Results: Plasma for analysis was available from 612 patients (69% of the ITT population), including 323 treated with Av/Ax and 289 with Sun. 57% of patients had high KIM-1 at baseline. In all patients, lower circulating KIM-1 at baseline was associated with longer progression-free survival (PFS) and overall survival (OS) (Table). Baseline KIM-1 levels were significantly lower in angiogenic (1-2) vs immune (4-5) transcriptomic clusters (p=0.002), responders vs non-responders (p=0.01), and exceptional vs intermediate responders (p=0.0015). In paired analyses, circulating KIM-1 decreased from baseline to C3D1 (p<0.0001) in both arms. Decrease in KIM-1 from baseline to C3D1 was associated with longer PFS and OS (Table). Luminex and MSD antibody-based assays had good concordance for distinguishing higher vs lower KIM-1 when measured in the same samples (Spearman’s ρ = 0.737), but absolute values of KIM-1 differed between the two assays (p<0.0001). Conclusions: This is the first study to evaluate circulating KIM-1 among patients with aRCC receiving immune checkpoint inhibitor and VEGF tyrosine kinase inhibitor combination therapy. Lower baseline plasma KIM-1 and decrease during treatment were associated with better prognosis. The distribution of circulating KIM-1 is assay-dependent and standardized cutoffs are needed before KIM-1 can be used in clinical decision making. Association of baseline KIM-1 and KIM-1 change on treatment with outcomes. Entire CohortHR (95% CI) SunitinibHR (95% CI) Avelumab + AxitinibHR (95% CI) PFS(KIM-1 low vs high) 0.76 (0.58–0.99) 0.67 (0.47–0.95) 0.88 (0.61–1.28) OS(KIM-1 low vs high) 0.58 (0.38–0.88) 0.46 (0.26–0.81) 0.79 (0.43–1.47) PFS(KIM-1 decrease vs increase) 0.65 (0.46–0.87) 0.66 (0.46–0.96) 0.79 (0.48–1.30) OS(KIM-1 decrease vs increase) 0.58 (0.39–0.88) 0.79 (0.46–1.35) 0.45 (0.46–0.89) HR: hazard ratio; CI: confidence interval.

Prediction of COVID-19 cases by multifactor driven long short-term memory (LSTM) model

A phase 1, first-in-human, open label, dose escalating study of B440, an oral cancer vaccine using a WT1-expressing <i>Bifidobacterium</i> , in patients with advanced urothelial cancer.

TPS883 Background: B440, an oral cancer therapeutic vaccine, is based on an innovative oral vaccine platform utilizing gut microbiota ( B. longum; Bifidobacterium longum ) that can efficiently deliver the heterogeneous antigen protein to dendritic cells (DCs) in Peyer's patches in gut-associated lymphoid tissue (GALT). B440 is a lyophilized powder of inactivated B. longum 440, a recombinant B. longum expressing a partially modified human WT1 tumor-associated antigen protein (amino acids 117-419 with a single amino acid substitution at 236 from M to Y to enhance immunogenicity). In preclinical studies, B440 showed superior anti-tumor activity to the WT1 peptide vaccine (WT1 126-134 peptide, human HLA-A02 or mouse H-2Db restricted CD8 epitope) due to the large length of the WT1 117-419 protein, including multiple CD8 and CD4 epitopes without HLA restriction, and its ability to internalize into DCs (1, 2). Furthermore, our extensive preclinical studies showed that B440 alone or as an adjunct to an anti-PD1 antibody can induce potent WT1-specific cellular immunity and anti-tumor activity in several mouse syngeneic tumor models (urothelial cancer (3), prostate cancer (4), and renal cell carcinoma (5)). Methods: This first-in-human, multicenter, open-label, single-arm, investigator-initiated phase 1 study will evaluate the safety and initial efficacy of B440 monotherapy in patients with advanced urothelial cancer who are refractory to all standard therapies, including chemotherapeutic agents, PD-1/PD-L1 inhibitors and antibody-drug conjugates (ADCs). A total of 12 patients will receive B440 orally once daily for 5 consecutive days followed by a 2-day rest for a total of 20 doses for 4 weeks. The study consists of 2 escalating doses of 6 patients each; the low dose group will receive 800 mg (4 capsules) per dose and the high dose group will receive 1,600 mg (8 capsules) per dose. One enteric capsule contains 200 mg of B440, equivalent to 2X10 10 colony forming units (cfu) of B. longum 440. The primary endpoint is the determination of dose-limiting toxicity (DLT) with an assessment period of 4 weeks during treatment. Secondary endpoints are safety as assessed by adverse events (AEs) using CTCAE 5.0 and efficacy as assessed by best overall response and progression-free survival (PFS) using RECIST ver1.1. In addition, the immunological response to B440 will be evaluated by enzyme-linked immunosorbent assay (ELISPOT). The study was registered with the Japan Registry of Clinical Trials under the number jRCT2051220143 on December 27, 2022. Patient enrollment was completed in September 2024. Research Sponsor: Immunorock Co., Ltd., Grant: the Japan Agency for Medical Research and Development (AMED); 23ym0126081h0002. Clinical trial information: jRCT2051220143 .

The impact of neoadjuvant therapy on the formation of tertiary lymphatic structures and the distinct prognosis in prostate cancer.

411 Background: This study aims to investigate the characteristics and prognostic predictive efficiency of tertiary lymphoid structures (TLS) in prostate cancer (PCA). We also perform experiments to explore the effects of neoadjuvant hormone therapy (NHT) on TLS formation and immune infiltration in PCA. Methods: We retrospectively collected paraffin-embedded tumor tissue samples from 27 patients who didn`t receive NHT and underwent radical prostatectomy for PCa, and these patients were categorized as Cohort 1. We Additionally retrospectively collected 28 PCa tumor samples, from 14 NHT treated and 14 NHT naive patients, which are categorized as Cohort 2. We prospectively collected prostate biopsy tissue samples, as well as corresponding radical prostatectomy tumor specimens, from 21 patients who all received NHT and are categorized as Cohort 3. We performed HE staining and Multiplex immunohistochemical (mIHC) staining for ki67, panCK, CD21, CD4, CD8, and CD20 to evaluate TLS characteristics and immune infiltration level in different cohorts. We enrolled two GEO cohorts to evaluate the difference of TLS signature between NHT treated PCA and NHT-Naive PCA patients, and between pre-NHT and post-NHT tumor paired samples. We developed an immunocompetent orthotopic prostate cancer mouse model based on CRISPR-Cas9 gene editing technology. In in vivo experiments, we utilized flow cytometry to investigate the difference of CD4 and CD8 immune cell infiltration level in tumor tissues of mice treated or not with androgen deprivation treatment. Results: We found most of the NHT-naive PCa tissues were TLS positive (93%), and the majority of TLSs are located within the tumor region. Patients with positive mature TLSs, SFL-TLSs and higher intra-tumor TLSs density had significantly longer PFS duration. Compared with that in patients received no NHT, TLSs maturity grade and density were higher in NHT treated patients. A matched analysis using biopsy and paired post-NHT tumor samples revealed that NHT significantly increased the positive detection rate of tertiary lymphoid structures (TLSs) within the tumor, the maturity grade of TLSs, and the level of CD8+ T cell infiltration within the TLSs. Transcriptome analysis revealed elevated TLSs signature expression and CD8+ T cell infiltration in NHT treated tumor samples. In vivo experiments also show elevated CD3+ and CD8+ T cells infiltration level after NHT treatment. Conclusions: This study comprehensively characterizes TLSs in PCa and highlights the heterogeneity among patients. Our clinical cohort data, transcriptome sequencing analysis, and in-vivo experiment data confirm that neoadjuvant hormone therapy promotes immune cell infiltration, as well as the formation and maturation of TLSs within PCa tissues. Combining endocrine therapy with immunotherapy is a potential treatment approach for promoting prostate cancer prognosis.

Neoadjuvant combined chemotherapy and immunotherapy for upper tract urothelial carcinoma: Preliminary results from a phase II study.

812 Background: Upper Tract Urothelial Carcinoma (UTUC) presents a challenging prognosis even after Radical Nephroureterectomy (RNU). The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain.This phase II study aims to investigate the efficacy and safety of a combination of chemotherapy (Gemcitabine/Cisplatin/Carboplatin) and PD-1 inhibitor (Toripalimab /Tislelizumab/Nivolumab) as neoadjuvant treatment (NT) in UTUC patients. Methods: We planned to enroll 34 UTUC patients with either cT1N0M0 (high grade) or cT2-3N0M0, confirmed by ureterorenoscopy biopsy and imaging. The treatment regimen included three or four cycles of NT (Gemcitabine, 800mg/m 2 , days 1 and 8/Cisplatin or Carboplatin, 60mg/m 2 , day 1/Toripalimab or Tislelizumab or Nivolumab, 240mg, day 1 of a 21-day cycle), followed by RNU and pelvic lymphadenectomy. The primary outcome was the pathological complete response (pCR) rate, with secondary outcomes including significant downstaging (≤pT1) rate, disease control rate (DCR), and safety. Results: To date, 30 patients have been accrued since August 1st, 2020, and recruitment is ongoing. Twenty-seven patients have completed treatments and were preliminarily analyzed, with three patients still undergoing treatment. The median age was 65.0 years, with 55.6% being male. The majority of patients had unifocal tumors, with a median maximum diameter of 3.3cm (0.7-7.5). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating four T2 and twenty-three T3 patients. Ureterorenoscopy biopsy revealed twenty-five high-grade and two low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twenty patients completed 4 cycles, five underwent 3 cycles and two underwent 2 cycles. The median interval time from initiation of NT to RNU and from the end of NT to RNU was 17.3 (11.4-28) weeks and 6.8 (2.3-22) weeks respectively. The pCR rate was 29.6% (8/27), the ≤pT1 rate was 63.0% (17/27), and the DCR was 100%. No grade 4-5 chemotherapy-related adverse events were recorded, but 41% (11/27) experienced grade 2 myelosuppression, 29.6% (8/27) grade 3, and 7.4% (2/27) grade 4. Four patients experienced immune-related adverse events after 4 cycles, including hypothyroidism (grade 2) and adrenal insufficiency (grade 2). No surgery-related complications or readmissions within one month were reported. With a median follow-up of 14.1months, all patients remained alive and tumor-free. Conclusions: Preliminary analyses suggest that the combination of chemotherapy and a PD-1 inhibitor as NT exhibits promising pCR rate for UTUC. The treatment was manageable in terms of safety, with immune-related adverse events potentially leading to prolonged treatment periods. Clinical trial information: NCT04099589 .