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Management of metastatic castration-resistant prostate cancer (mCRPC) at the Veterans Affairs Healthcare System (VAHCS): A real-world assessment of patient characteristics and treatment across lines of therapy.

60 Background: With the emergence of several newly approved therapies for mCRPC, data on the optimal treatment sequence are limited. The aim of this study is to understand the treatment patterns of mCRPC patients who received at least one androgen receptor pathway inhibitor (ARPI) or taxane at the VAHCS, an equal-access healthcare system. Methods: This is a retrospective, observational study utilizing VAHCS claims data from patients diagnosed with mCRPC between January 1, 2018 and February 29, 2024 nationwide. Patients with mCRPC who received first-line (1L) therapy of ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide; [ARPI cohort]) or a taxane (docetaxel or cabazitaxel; [taxane cohort]) were included; 1L therapy was defined as the first prescription for ARPI or taxane after prostate cancer diagnosis. Thus, though the 1L treatment could have been for metastatic castration-sensitive prostate cancer or mCRPC, all patients ultimately progressed to mCRPC. Patients who received radiation within 6 months or any other chemotherapy prior to 1L therapy, or who were diagnosed with any other cancers (excluding non-melanoma skin cancer) prior to mCRPC were excluded. Results: In total, 2982 patients with mCRPC who met the inclusion criteria were identified, which included a large cohort of African American patients (25%). Although most patients received an ARPI in the 1L (2828 patients, 95%), 154 patients (5%) received 1L taxane. Patients in the ARPI cohort were significantly older than those in the taxane cohort (median 74 vs 68 years; p<0.001). Patients in the ARPI cohort received mainly 1L abiraterone or enzalutamide with a similar frequency (both 48%), and docetaxel was the most common treatment for patients who had received 1L taxane (97%). Overall, 1223 patients (41% of all patients) received second-line (2L) therapy. Taxanes were more frequently used in 2L treatment (16%) compared with 1L; however ARPI, especially abiraterone (27%) and enzalutamide (42%), remained the most frequent choices for 2L treatment. Back-to-back ARPI use in 1L and 2L was the most common treatment sequence, with 74% of patients who received 2L abiraterone having been treated with 1L enzalutamide, and 87% of patients who received 2L enzalutamide having been treated with 1L abiraterone. Few patients (11% of all patients) received third-line (3L) treatments. Conclusions: In the VA equal-access healthcare system, back-to-back ARPIs remained the most common treatment sequence for the management of patients with mCRPC with few patients receiving 3L treatment. Further research is planned to investigate clinical outcomes, adverse events, and healthcare resources utilization associated with these treatment sequences to hopefully identify an optimal mCRPC management.

THERATEST: A multi-centre observational cohort feasibility study of de-escalation therapies for stage II seminoma.

TPS651 Background: Standard of care (SOC) for stage II seminoma involves primary orchidectomy with combination chemotherapy or external beam radiotherapy, and yield high survival rates but with significant toxicities. Three cycles of Carboplatin AUC10 or robotic retroperitoneal lymph node dissection (rRPLND) with or without adjuvant chemotherapy are promising de-escalation strategies to minimise treatment associated toxicities whilst maintaining oncological outcomes. However, they are not widely adopted due to a lack of comparative data in prospective clinical trials. Therapy De-escalation for Testicular Cancer (THERATEST) aims to assess the feasibility of recruitment for de-escalation strategies for stage II seminoma. Methods: Thirty participants will be recruited over 12 months and treated with either Carboplatin AUC10 or rRPLND with or without adjuvant treatments based on whether the institution offers this treatment as a de-escalation strategy. If participants decline or are not eligible, they will be offered SOC but remain within the study. Both cohorts will be followed up for 2-years. Data collection includes recruitment and retention rates, disease status, surgical outcomes, adverse events and patient-reported outcomes using validated questionnaires which are EORTC QLQ-TC26, EORTC QLQ-C30, the Brief Male Sexual Function Inventory (BMSFI) and additional enquiries on anejaculation. Results: THERATEST has recently commenced recruitment at Barts Health and the Royal Marsden Hospital NHS Trusts. Conclusions: THERATEST is the first endeavour to prospectively evaluate Carboplatin AUC10 and rRPLND as de-escalation strategies for stage II seminoma in a single study. Feasibility of recruitment and retention as well as qualitative and quantitative outcomes data will inform a large-scale multicentre trial. Clinical trial information: ISRCTN61007118 .

CONVERGE-01: Dosimetry, randomized dose optimization, dose escalation, and efficacy of ac-225 rosopatamab tetraxetan in participants with PSMA-positive castration-resistant prostate cancer.

TPS289 Background: Prostate specific membrane antigen (PSMA) is a validated target in metastatic castration resistant prostate cancer (CRPC). Use of an alpha emitter as a radionuclide and a high affinity monoclonal antibody for protein targeting in PSMA-targeted radiopharmaceutical therapy (TRT) offer the promise of improved precision and potency as compared to alternative approaches. Ac-225 rosopatamab tetraxetan (CONV01-ɑ, formerly Ac-225-J591) has been evaluated for safety and efficacy in sequential investigator-initiated trials (Tagawa et al. JCO 2024, Nauseef et al . AACR 2023) with encouraging results in patients with and without prior exposure to PSMA-directed Lu-177-small molecule-based TRT. The phase II CONVERGE-01 trial is the first industry-sponsored study of CONV01-ɑ and will further advance the understanding of safety and efficacy in patients with progressive PSMA PET-positive CRPC. Methods: The study is being conducted in three parts. Part 1 (P1) is a lead-in to evaluate the biodistribution of CONV01-ɑ using In-111 rosopatamab tetraxetan. Each of these patients will then proceed to Part 2 or Part 3. Part 2 (P2) randomizes 1:1 between 45 and 60 kBq/kg in patients with CRPC without prior exposure to Lu-177-PSMA (-617 or -I&T). Part 3 (P3) is a Bayesian Optimal Interval (BOIN) design dose-escalation protocol (45, 55, and 60 kBq/kg, with optional dose expansion) for patients with metastatic CRPC and prior exposure to Lu-177-PSMA. Key study-wide inclusion criteria include PSMA PET-positive (via VISION criteria) progressive CRPC. Metastatic disease on conventional imaging (CT, MRI) is not mandated in P2 (stratification factor: conventional imaging M0 v M1). All patients will have prior exposure to at least 1 androgen receptor signaling inhibitor and have adequate performance status (ECOG 0-1) and organ function (platelets ≥150 k/uL, ANC ≥1.5 k/uL, CrCl ≥60 mL/min). Key study-wide exclusion criteria include: superscans on Tc-99 bone scintigraphy, prior platinum-based chemotherapy or PARP inhibitor use, and prior PSMA-targeted non-TRT use. Additional P2-specific exclusions are: prior chemotherapy for CPRC and radiopharmaceuticals. Treatment: CONV01-α (P2/P3) will be given in a single cycle of two fractions on days 1 and 15. Primary endpoints: biodistribution of radiolabeled CONV01-α (P1), safety and tolerability (P2, P3), determination of RP2D (P3 only), efficacy via PSA50 response (P2, P3 at RP2D). Secondary endpoints: biodistribution and pharmacokinetic profile (P2, P3), characterization of Ac-225 radiation dosimetry (P2), biochemical PFS (P2), PSA50 (P3, all patients treated). Exploratory endpoints include: rPFS, ORR, and DOR via RECIST v1.1 (PCWG3-modified where appropriate), genomic and imaging biomarker nomination. Enrollment began in August 2024. Clinical trial information: NCT06549465 .

Comparison of PSA-based <i>g</i> -rate and conventional PSA metrics in veterans with metastatic prostate cancer (mPC).

188 Background: While PSA is routinely used for monitoring in clinics for pts with mPC, it is not a surrogate endpoint for survival or benefit in the majority of cases for specific interventions. However, a novel tumor growth rate ( g -rate) method that can estimate tumor growth ( g ) and decay ( d ) rates using PSA values while on treatment, has the potential to serve as such. This has been validated to show a robust inverse correlation with overall survival (OS) using 13 clinical trials and real-world data from the US Veterans in mPC regardless of type of treatments. We now compare its prognostic utility to currently used PSA metrics. Methods: We have created a comprehensive database to assess drug efficacy in mPC by collecting data from the VA nationalized data warehouse using VA Informatics. Details such as age, race, serial PSA values, reason for treatment, castrate sensitive (mCSPC) or resistant (mCRPC) setting, line of therapy, and survival were collected. g and d rates are calculated using PSA values while on treatment via the TUMGr package for R. Results: We collected PSA values on 38,929 treatment records from 25,023 unique pts getting novel hormonal therapies (abiraterone, enzalutamide, darolutamide, apalutamide), chemotherapies (docetaxel, cabazitaxel) or olaparib. Of this, 17383 had achieved a nadir followed by an increase in PSA, 10738 had the last available result as their lowest, and 10808 had a PSA rise only while on treatment. Nadir-based PSA metrics, such as 50% decrease in PSA (PSA50), absolute PSA nadir, percent PSA nadir can be applied to 28,121 (72%) of records. PSA50 response rate was noted in 1780/2390 (84%) mCSPC and 16796/36539 (65%) mCRPC pts. Only 487 (20%) and 155 (6.5%) of mCSPC and 2038(5.6%) and 508 (1.4%) of mCRPC achieved PSA of 0.2 and 0.02 at 6 months(mo), respectively. For pts with PSA rise only, PSA doubling time(DT) of &lt; 3 mo was noted in 5843 (54%). However, g -rate was calculated in 36124 (93%) of pts regardless of treatment type, treatment setting, and rise or fall in PSA while on treatment. 22,800 pts had at least 3 PSA values within the first 3 mo of starting treatment, and we could calculate either g or d values in 19,465 (85%) of pts. Linear regression testing of both log g and log percent PSA nadir revealed a robust inverse correlation with OS, with R 2 of 0.98 and 0.99, respectively. Conclusions: PSA decline with absolute 6 mo PSA &lt; 0.2 or PSA increase with DT of &lt; 3 mo was noted in only 26% and 54 % of pts, respectively, noting limitation of current validated PSA metrics. In contrast, we can calculate the g -rate in 93% of pts on treatments and g values can be calculated or imputed as early as 3 months. It has a robust inverse correlation with OS demonstrating its superiority over PSA kinetics alone. The g -rate method can potentially replace all current PSA-based metrics regardless of decline or increase in PSA for assessing treatment response in mPC in both research and clinical settings.

Perception of four intellectual and developmental disabilities based on search engine and news portrayal

Background For people with intellectual and developmental disabilities, other’s perceptions of them based on their condition often begin before birth and go on to impact relationships, opportunities, and self perception across the life course. Search engine results and news media, which may portray these conditions stereotypically or in poor light, are often a key source in these perceptions. Our purpose was to understand how search engine results and available news media can shape perceptions on certain intellectual and developmental disabilities. Methods We developed an online Likert-scale survey to measure differences in perceptions based off first available search engine results, images, and news headlines of four intellectual and developmental disabilities: cerebral palsy, Down syndrome, Prader-Willi syndrome, and Angelman syndrome. These four conditions were selected to compare less prevalent (Prader-Willi and Angelman) and more prevalent conditions (Down syndrome and cerebral palsy). Perception questions addressed general impression and aspects of the disability experience expected to be impacted by perception from others. We recruited via multiple social media platforms, flyers posted in the Boston area, and word of mouth to local communities and friends. Findings 229 individuals opened the survey, and 125 responses were used in analysis. Mean responses to Prader-Willi syndrome were significantly more negative than responses to cerebral palsy, Down syndrome, and Angelman syndrome across all variables. Responses to Angelman syndrome were also more negative than responses to Down syndrome. Significant differences between conditions found when treating the data as continuous were confirmed when treating the data as ordinal. Conclusion Lesser-known intellectual and developmental disabilities, such as Prader-Willi syndrome and Angelman syndrome, are subject to more negative portrayal in media, leading to more negative perception, which may impact social opportunity and quality of life. Combined with our finding that the perception of Prader-Willi syndrome follows the ideals of the medical model of disability more closely than the social model, a need for social model of disability training and education for physicians and other medical providers is clear.

Optimization of toilet bowl ventilation technology for odor control and energy efficiency enhancement in public toilet

Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of clinically advanced penile squamous cell carcinoma (CAPSCC).

824 Background: CAPSCC is a challenging disease with significant need for improvements in effective systemic therapies for patients with surgically incurable disease. Methods: 373 cases of CAPSCC underwent comprehensive genomic profiling to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system. Results: 13 (3.5%) of the CAPSCC cases featured a positive HRDsig status (HRDsig+). The PSCC HRDsig+ patients were older than the PSCC HRDsig+ patients (median ages 67 vs 62; NS). The GA/tumor frequencies were higher in the PSCC HRDsig- cases (5 v3 3; NS). Genomic ancestry distribution was similar with 68-77% of patients featuring EUR ancestry. 9.4% of PSCC HRDsig- featured AFR ancestry compared with 0% PSCC HRDsig+ (NS). MSI-high status was extremely low in both HRDsig- vs HRDsig+ PSCC groups (1.4% vs 0.0%; NS). Although the median TMB was higher in the HRDsig+ (6.3 vs 3.8; NS); the frequency of TMB &gt; 10 mutations/Mb was similar in both groups (13.3% vs 17.7%; NS). Trinucleotide mutational signature distribution was similar in both cohorts. PD-L1 low (1-49% TPS) expression was similar in both groups and ranged from 43% to 52%. Only 1 (7.7%) of the 13 PSCC HRDsig+ cases featured a BRCA1 inactivating mutation and 0 (0%) had a BRCA2 mutation. In the HRDsig- group, 66.7%/75.0% of BRCA1 / BRCA2 mutated CAPSCC were mono-allelic likely non-driver GA respectively. Other HRD associated mutations in the PSCC HRDsig+ cases included 2 (15.4%) ATM and 1 (7.7%) PALB2 mutation. The PALB2 mutation was a bi-allelic homozygous deletion which has been linked to prolonged benefit from PARP inhibitor-based treatments. GA in both TERT (51.1% vs 0.0%; P=.009) and TP53 (53.3% vs 23.1%) were more frequent in the PSCC HRDsig- cases whereas GA in MAP2K1 (15.4% vs .0%; P=.025), KRAS (15.4% vs 1.1%); NS) and NF1 (15.4% vs 1.4%; NS) were more frequent in the PSCC HRDsig+ cases. NOTCH1 GA were similar in both groups (range 16.4% to 15.4%). There was no difference in the frequencies of HPV+ status between the 2 groups. Conclusions: With a 3.5% frequency, HRDsig+ status is a relatively uncommon biomarker in CAPSCC. However, HRDsig+ status appears to occur in PSCC in the absence of BRCA1 / 2 mutations and may include homozygous deletions in HRD-associated genes such as PALB2 that been associated with substantial benefit from PARPi regimens in other tumor types. These findings may impact the future development of PARP inhibitor-based treatment regimens for PSCC patients.

Avelumab in combination with axitinib (Ave + Axi) for first-line (1L) treatment of advanced renal cell carcinoma (aRCC): A systematic literature review (SLR) of real-world effectiveness and safety.

491 Background: Ave + Axi combination is an approved option worldwide for 1L treatment of patients with aRCC based on the results of the JAVELIN Renal 101 phase 3 trial. The results of the final analysis (data cutoff: Aug 31, 2023) confirmed the long-term efficacy and manageable safety profile of this immunotherapy (IO)/tyrosine kinase inhibitor combination with the longest follow-up (≥68 months in all patients). The aim of this SLR was to summarize the real-world effectiveness, safety, and tolerability of Ave + Axi in aRCC and compare with outcomes from JAVELIN Renal 101. Methods: A SLR was conducted using 3 online databases (MEDLINE, Embase, and Cochrane) to identify publications (to Jul 29, 2024) and recent conference abstracts of Ave + Axi real-world studies reporting outcomes for 1L treatment of aRCC, with no geographical or observational study-type restrictions. Results: A total of 9 studies met the inclusion criteria; most were retrospective (7/9), including multicenter, single-center, or database/registry studies relying on secondary data sources. Studies were conducted in the UK (4/9), Japan (3/9), USA (1/9), and Russia (1/9). Median age was 61.5-70 years; most patients were male (68%-90.5%), had an ECOG performance status of 0-1 (60%-94%), and had metastatic tumors with clear cell histology (66.7%-100%). High attrition between lines of treatment was noted, with only 35% of patients receiving second-line treatment after disease progression (most commonly with cabozantinib monotherapy, 52.2%). Median progression-free survival (PFS) ranged from 9.1-15.3 months (vs 13.9 months in JAVELIN Renal 101). Landmark 1-year PFS and overall survival rates from Ave + Axi start were 27%-68.2% and 15%-98.8%, respectively. Overall response rate was numerically higher in International Metastatic RCC Database Consortium (IMDC) risk favorable- (70.5%) vs intermediate- (64.7%) or poor-risk (39%) subgroups (reported in 1 UK study). Rates of grade ≥3 adverse events (AEs; 17%-36%) and discontinuation due to AEs (10%-27%) were low. Conclusions: Overall, findings from global real-world studies of Ave + Axi in 1L aRCC align with those of the JAVELIN Renal 101 trial, validating the long-term efficacy and safety of this combination. The high rate of attrition between lines of therapy supports the use of the most effective IO-based treatments upfront. Despite the limited number of studies and data heterogeneity, results from this SLR of real-world studies conducted in the IO era in several countries provide a good representation of Ave + Axi use in an evolving treatment landscape. Additional prospective data (eg, the ongoing multi-country AVION study; NCT04941768) and extended follow-up are required to inform the optimal use of Ave + Axi in patient subgroups, such as those with IMDC favorable-risk disease.

Osteonecrosis of the jaw (ONJ) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with denosumab in a randomized phase III trial comparing 4 vs. 12 weekly administration (REDUSE, SAKK 96/12).

163 Background: While reducing skeletal-related events in patients (pts) with bone metastases (BM), bone protecting agents such as DN have adverse events. One major adverse event is osteonecrosis of the jaw (ONJ), which can significantly impact quality of life. The risk of ONJ increases with treatment duration and reaches cumulative rates of up to 9%. We report ONJ rates in a randomized phase III non-inferiority trial investigating the optimal dose schedule of denosumab (DN). Methods: Pts with BM from mCRPC were randomized 1:1 to receive DN every 4 weeks (q4w; arm A, standard arm) versus every 12 weeks (q12w; arm B, experimental arm) after a 16-week induction phase with q4w therapy for both arms. The primary endpoint of the study is time to first symptomatic skeletal event (SSE) while the incidence of ONJ is an important secondary endpoint. Since the differentiation between ONJ and tooth abscess (the term according to CTCAE v5.0 is tooth infection [TI]) can be difficult, we report these two outcomes separately as well as combined (in case both events were reported for one patient, the timepoint of earlier event was counted). An oral inspection at baseline as well as before each application of DN was mandatory. In patients with risk factors for ONJ, a prophylactic dentist visit prior to treatment start was recommended. Data from patients who received at least one dose of DN and who were randomized at least one year before data cut-off (December 11, 2023) were included in this interim safety analysis. As this is an interim analysis, only descriptive analyses were performed without formal statistical comparison between the arms. Results: 546 pts from 39 centers with a median follow-up time of 2.4 years were evaluated for ONJ. The median number of administered DN-doses was 16 doses in arm A and 8 doses in arm B, the treatment duration was 64 weeks in arm A versus 72 weeks in arm B. Rates of ONJ, tooth infection, and the combined rates are given in the table. Time to first ONJ and time to first ONJ or TI was in favor of arm B with HRs 0.63 (95% CI 0.33 - 1.21) and 0.71 (95% CI 0.43 – 1.16), respectively. Conclusions: Administration of DN q12w reduces the risk of ONJ. This risk reduction of ONJ or TI is clinically relevant with an overall absolute difference of 1.6% for all grades and 1.9% for ≥3 after a median follow-up of 2.4 years. Efficacy data for time to first SSE (the primary endpoint of this trial) is not yet mature and will be reported later. Clinical trial information: NCT02051218 . Term Induction phase Arm A (q4w) Arm B (q12w) ONJ, all grades (G) 1/546 (0.2%) 21/242 (8.7%) 15/233 (6.4%) TI, all G 7/546 (1.3%) 13/242 (5.4%) 13/233 (5.6%) ONJ or TI, all G 8/546 (1.5%) 31/242 (12.8%) 26/233 (11.2%) ONJ ≥ G3 0/546 (0%) 12/242 (5.0%) 8/233 (3.4%) TI ≥ G3 1/546 (0.2%) 4/242 (1.7%) 1/233 (0.4%) ONJ or TI, ≥ G3 1/546 (0.2%) 14/242 (5.8%) 9/233 (3.9%)

Chimeric RNA landscape in the Chinese population and the role of <i>SFT2D2-TBX19</i> in prostate cancer progression.

406 Background: Specific gene fusions and their fusion products (chimeric transcripts and proteins) have served as ideal diagnostic markers and therapeutic targets for cancer. However, few systematic studies for chimeric transcriptome have been conducted in prostate cancer (PCa), and none in the Chinese populations. Methods: We analyzed raw RNA-seq data from PCa patients in the Chinese Prostate Cancer Genome Epigenome Atlas (CPGEA) to predict chimeric RNAs using the Eriscript. Fluorescence-activated cell sorting (FACS) was employed to isolate tumor cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and T cells from fresh clinical specimens. Cellular functional assays, western blotting, FISH, electron microscopy, RNA pull-down, and immunofluorescence were employed to elucidate the underlying mechanisms by which the chimeric SFT2D2-TBX19 regulates prostate cancer progression. Results: Over 100,000 chimeric RNAs have been predicted in CPGEA. After several rounds of screening, we identified 301 of them with differential expression between cancerous and adjacent normal tissues, and 101 out of them were validated in clinical samples. About 20% showed prognosis correlation, indicating their potential biomarker values. Further experiments found differential expression of those chimeras among cancer epithelial cells, CAFs, TAMs, and T cells. We further examined the effect of these chimeric RNAs, and found examples of chimeric RNAs directly regulates the growth and motility of tumor cells, and regulate communications between tumor cells and their microenvironment, which jointly facilitate tumor progression. An important chimeric RNA, SFT2D2-TBX19 , was identified as encoding the TBX19-202 protein. Both TBX19-202 and its parental TBX19, which share homologous amino acid sequences, enhance prostate cancer cell proliferation, migration and invasion. Additionally, SFT2D2-TBX19 also can work as a lncRNA which could interact with the ATP synthase F1 subunit ATP5F1A, increasing ATP5F1A phosphorylation, which stabilizes the interaction between ATP5F1A and ATP5F1B. The region spanning 1801-2400bp of SFT2D2-TBX19 and the intermediate structural domain of ATP5F1A are crucial functional areas. This stabilization of ATP5F1A and ATP5F1B enhances mitochondrial ATP synthase activity and ATP production, thus maintaining prostate cancer cell proliferation. Conclusions: These findings established the atlas of chimeric transcriptome in PCa from the Chinese populations, and provided a large list of validated chimeric RNAs that have the potentials of becoming novel biomarkers and/or treatment targets. Our research provides comprehensive evidence that the SFT2D2-TBX19 promotes prostate cancer progression by encoding the TBX19-202 protein and stabilizing mitochondrial ATP synthase through ATP5F1A phosphorylation.

Outcome of COVID-19 in patients with idiopathic inflammatory myopathy during the Omicron wave in China: A longitudinal observational study

Objective The coronavirus disease pandemic brought unknown challenges to patients with idiopathic inflammatory myopathy, who are often heavily immunosuppressed and have comorbidities. We aimed to investigate the outcomes and risk factors of coronavirus disease in Chinese patients with idiopathic inflammatory myopathy during the Omicron wave. Methods This observational study included patients with idiopathic inflammatory myopathy who visited the China-Japan Friendship Hospital. Data on baseline characteristics and coronavirus disease-related information were collected through medical records and surveys, and subsequently analysed. Results Overall, 204 patients with idiopathic inflammatory myopathy were identified; dermatomyositis was the most common idiopathic inflammatory myopathy subtype. Data were collected from 185 patients with idiopathic inflammatory myopathy who tested positive for severe acute respiratory syndrome coronavirus 2 via polymerase chain reaction or antigen tests; of these, 20 experienced a severe course of the disease, and 9 died. All patients with severe coronavirus disease had idiopathic inflammatory myopathy-associated interstitial lung disease, and the most common antibodies observed in patients with mortality were anti-aminoacyl tRNA synthetase and anti-MDA-5 antibodies. Furthermore, 45.0% of patients in the severe disease group took &gt; 15.0 mg of prednisone daily before infection, a significantly higher proportion than that in the non-severe disease group. Advanced age, mechanics’ hands, dyspnoea, chronic cough and fever during the course of myositis, low lymphocyte count, low serum albumin level, and high D-dimer and ferritin levels before infection were prominent in patients with severe coronavirus disease. Albumin levels below 35.0 g/L and ferritin levels above 306.8 ng/mL were independent risk factors of severe coronavirus disease. Conclusion Omicron did not worsen the overall outcomes of coronavirus disease for patients with idiopathic inflammatory myopathy; however, specific risk factors were identified, highlighting the need for targeted management strategies.

CaV2.3 channels in the mouse central medial thalamic nucleus are essential for thalamocortical oscillations and spike wave discharges

Characteristics and clinical outcomes of metastatic testicular cancer in a distinct demographic.

620 Background: Testicular cancer is the most common malignancy among adolescent and young adult (AYA) males (15 – 40 years). While the median age at diagnosis is 33 years, testicular cancer also occurs in older aged males (&gt;40 years). Though it is less frequent in this population, it is important because outcomes of metastatic testicular cancer in this population are unknown. We examined the inpatient characteristics and outcomes for older patients with a diagnosis of metastatic testicular cancer. Methods: In a retrospective cohort analysis using the NIS database from 2008 to 2021, admitted patients with metastatic testicular cancer were identified using ICD codes. Descriptive analyses were conducted to compare sociodemographic, hospital-level and clinical characteristics between the older population and the AYA. Multivariate logistic and linear regression models were used to examine the association between the age groups and mortality, length of stay (LOS), and total hospital charges (THC). Results: There were 57,366hospitalizations with metastatic testicular malignancy. Of these, 14,733 (25.7%) were in the older male cohort. The mean age was 51 years in the older group and 27.3 years in the AYA group (P &lt; 0.001). There was a higher proportion of non-Hispanic White patients in the older group compared to the AYA group (73% vs 53%, P &lt; 0.001) but a lower distribution of Hispanic patients (11% vs 31%, P &lt; 0.001). Most of the patients in both cohorts had private insurance (54% vs 47%, P&lt;0.001). Both groups had most admissions in teaching (75.7% vs 84%, P &lt; 0.001), urban (95.2 vs 97.2%, P&lt;0.001), andlarge-sized hospitals (65.5 vs 70%, P=0.001). HIV comorbidity was higher in the older population (0.5% vs 0.2%, P = 0.02). The mortality rate was higher in the older population compared to the AYA population (6.2% vs 2.8%, P &lt; 0.001). The older group had over two-fold higher odds of mortality relative to the younger adult group (aOR: 2.25, 95% confidence interval [CI]: 1.84-2.75, P &lt; 0.001). On subgroup analysis, black patients had 70% higher mortality relative to non-Hispanic White patients (aOR: 1.7, 95% CI 1.15-2.5, p=0.008). There was a longer LOS in the older group (β coefficient: 0.49, 95% CI: 0.15-0.84, P = 0.005). THC were similar between the two cohorts (β-Coefficient: 1,238, 95% CI: -4,080–6,555, P = 0.65). The older group were less likely to have retroperitoneal lymph node dissection (aOR: 0.57, 95% CI: 0.48-0.67, P&lt;0.001). Conclusions: This is the largest epidemiological study to date on metastatic testicular cancer hospitalizations in older adults. Older males with metastatic testicular cancer have higher odds of mortality relative to younger patients. Racial disparities were evident, with Black patients having higher mortality. Our findings underscore unique characteristics and outcomes that could guide patient selection for future clinical trials and enhance the development of novel therapies for this population.

Implementing precision oncology in renal cell carcinoma (RCC): Prospective identification of clinical, tissue-based, and circulating factors to refine outcome prediction and support therapeutic choices (SIGNS-RCC TRIAL).

TPS617 Background: At diagnosis, 55% of RCC are localized, and 25% are locally advanced/metastatic (aRCC); an additional 30% develop metastases during follow-up. Prognosis is highly variable in both resectable and advanced disease. All patients’ stratification tools are based on clinical risk scores. For resected patients, only pembrolizumab has demonstrated OS benefit in the adjuvant setting. For metastatic disease, first-line combos (IO-IO and IO-TKI) have dramatically improved outcomes in intermediate/poor-risk patients but have shown no additional OS benefit over TKI in good-risk patients. Methods: We designed a multicentric trial to identify novel prognostic/predictive biomarkers to refine current therapeutic algorithms for systemic therapy in both early-stage and aRCC in three different cohorts of patients. Cohort (A) includes patients who underwent radical surgery for RCC (resected, rRCC). Cohort (B) is a retrospective cohort that reclutes aRCC treated with VEGFR TKI monotherapy in I line. The prospective cohort (C) enrolls aRCC patients who are candidate to receive current I-line IO-TKI combos. In the first part, we will correlate patient- and tumor-related factors with the risk of recurrence after surgery for rRCC and progression-free survival and overall survival for aRCC. Tissue-based signatures will be obtained using IHC (PD-L1 expression, tumor immune microenvironment - TiME - composition), an NGS custom panel (mutational profiling), and FISH (for recurrent RCC alterations, such as 9p loss). Multiplex IHC and RNA-ISH will assess cytokine production by specific TiME components. Correlations between the obtained signatures and clinical outcomes will be calculated. In cohort C, the prognostic role of circulating factors (serum cytokine levels and mononuclear cell subpopulations, focusing on MDSC and TReg) will also be evaluated in addition to clinical and tissue-based factors. Blood samples will be collected before and during I-line treatment at pre-planned timepoints. Biomarkers will be quantitatively analyzed to evaluate their relationship with outcomes. Enrollment is ongoing.

The role of circulating kidney injury molecule-1 (KIM-1) in metastatic renal cell carcinoma (mRCC): A biomarker analysis of Tide-A, a phase 2 study of first-line avelumab (ave) plus intermittent axitinib (axi).

584 Background: KIM-1 was evaluated as plasma circulating biomarker of microscopical residual disease, disease recurrence after nephrectomy, and potential benefit from adjuvant immunotherapy (IO). No data are available about its role in the metastatic setting. Tide-A is a phase 2 trial showing the feasibility of a de-intensified strategy of VEGFR-TKI interruption and IO-maintenance in mRCC pts treated with ave+axi. We investigated whether plasma KIM-1 was a prognostic biomarker in the prospective cohort of Tide-A. Methods: Treatment-naïve mRCC pts with prior nephrectomy, and no symptomatic/bulky/liver disease received ave+axi, and interrupted axi after 36 weeks in case of disease response. We performed a proteomics analysis with the aptamer-based technology SomaScan 7K (Somalogic, USA) to characterize the plasma expression levels of ≈7000 proteins. Levels of KIM-1 SomaScan aptamers (uniprot accession number Q96D42, aptamer ID:9021-1) were evaluated in available baseline samples and normalized by Adaptive Normalization by Maximum Likelihood (ANML) to integrate samples and correct for batch-effects. KIM-1 cut-off (10.456 relative fluorescence units [RFU]) was determined by Maximally Selected Rank Statistics using the maxstat R package, with Van der Waerden test and log-rank scores methods. Outcomes in pts with high vs. low KIM-1 levels at baseline were analyzed in the overall population, and adjusted for IMDC groups and for the duration of ave-maintenance. Results: Of 79 pts enrolled in Tide-A, data for KIM-1 analysis at baseline were available for 69 pts, of which 9 (13%) were KIM-1-high and 60 (87%) KM-1-low. KIM-1-high status was significantly associated with shorter OS (mOS 24.2 months [95%CI 21.1–NR] in KIM-1-high vs. not reached (NR) in KM-1-low; p=0.0019). The 2-yOS rate was 90% in KIM-1-low vs. 56% in KIM-1-high (p=0.002). Significant correlation between KIM-1 levels and OS was retained when adjusted for IMDC (table). No significant correlation was observed between KIM-1 levels and progression-free survival (mPFS 22.9 vs. 29.9 months in KIM-1-high and low, respectively; p= 0.4). Of the 29 pts that discontinued axi, KIM-1 data were available for 28 pts; the median duration of ave-maintenance was 15.9 wks in 25 pts with KIM-1-low and NR in 3 pts with KIM-1-high, (p=0.19). Conclusions: High baseline plasma KIM-1 level is an independent negative prognostic factor in metastatic RCC pts treated with VEGFR-TKI+IO combination, regardless from IMDC. KIM-1 seems not to have a key role in the selection of pts more likely to benefit from a TKI-intermittent strategy. Additional analyses are ongoing to identify predictive biomarkers to improve a tailored management of pts. 2-year OS rate according to IMDC. 2-year OS KIM-1 High KIM-1 Low P value IMDC Favourable 80% 95% 0.045 IMDC Int/Poor 25% 86% 0.006

Outcomes with multi parametric MRI (mpMRI) compared to diagnostic transurethral resection of bladder tumor (TURBT) in patients (pts) with suspected muscle-invasive bladder cancer (MIBC): A pilot study.

TPS881 Background: TURBT is a standard diagnostic procedure to determine the depth of bladder tumor invasion into the bladder wall, particularly whether the muscularis propria layer is involved by tumor. This is crucial in order to distinguish between non-MIBC and MIBC, providing accurate tumor staging and determining appropriate therapy. However, TURBT may be associated with multiple complications such as pain, infection, need for Foley catheters, blood loss requiring transfusions, hospitalization, and a small mortality risk. A proportion of pts end up with a superficial resection out of concern for bladder perforation, where the muscularis propria layer is absent from the surgical specimen, and require a repeat TURBT that is typically performed 4-6 weeks following the initial procedure. Further, TURBT scheduling requires coordination with urology and operating room availability. These factors may cause delays in initiation of cancer-directed therapy. Recent data suggests that mpMRI may accurately predict the degree of invasiveness of bladder tumors by generating a Vesical Imaging-Reporting and Data System (VI-RADS) score. mpMRI is not commonly associated with complications and can be performed quickly by radiology. Methods: This is an IRB-approved, single-institution, prospective, single-arm, phase 2 pilot study, which aims to compare two diagnostic modalities for bladder cancer - TURBT versus mpMRI. Pts are identified based on tumor appearance during initial routine cystoscopy, if MIBC is suspected. If eligible for the study, pts then proceed with an mpMRI and a diagnostic TURBT. Primary study endpoint is incidence of concordance between VI-RADS score 4 and 5 bladder tumors on mpMRI, which represent “likely” and "very likely" muscularis propria invasion, and pathologic muscularis propria invasion on TURBT. Secondary study endpoints include time from initial cystoscopy to performing each diagnostic test, time from performing each diagnostic test to initiation of cancer-directed therapy, incidence of repeat TURBT, patient-assessed quality of life with each diagnostic test, incidence of adverse events related to each diagnostic test, progression free survival, and financial toxicity of each diagnostic test. Based on prior literature, the rate of detecting muscularis propria invasion with TURBT is about 90%. We hypothesized that diagnostic accuracy of mpMRI would be non-inferior to TURBT, within a 10% difference. Power calculations for this study were based on a one-sided, one-proportion exact test, with a power of 80% at a significance level of 0.05 using a non-inferiority design. Out of 30 anticipated pts, 11 have been enrolled to date. Clinical trial information: NCT06335667 .

Adolescent weight management counseling: The effectiveness of an online training program for primary healthcare professionals in Indonesia

Background Overweight and obesity are growing public health concerns globally for which innovative prevention and care delivery efforts are required. We recently developed a web-based training program to improve the quality of health professionals’ weight management counseling of adolescents in Indonesia. Having previously confirmed its acceptability, this study aimed to measure the effectiveness of the program through a randomized controlled trial. Methods We recruited 64 primary healthcare professionals from 17 provinces across Indonesia who were randomized to participate in a 4-week online training program (intervention group [IG, n = 32] or a waitlist control group [CG, n = 32]). Using active learning approaches, the training program focused on adolescent development, psychosocial assessment, motivational interviewing (MI), and parent engagement. Participants in each arm were asked to record two counseling sessions with adolescents. These were objectively rated by trained psychologists using a validated tool, and also by qualitative assessment of counseling quality. In both groups, the first recorded counseling session occurred before the training. The second recording took place after the training for IG participants, but not for CG participants. Results IG participants demonstrated significant improvements in their knowledge and counseling skills (p&lt;0.001, t-test). This included improvements in introductory remarks, quality of psychosocial assessment, and MI skills. There was no change in the extent of parental involvement. The MI training successfully oriented the counseling sessions towards a more collaborative and participatory conversation for supporting behavioral change. Conclusion This novel online training program improved the knowledge and counseling skills of Indonesian primary healthcare professionals. Greater emphasis on engaging parents and more guidance on conducting telehealth counseling may improve parental involvement in future iterations.

Advanced and hybrid machine learning techniques for predicting compressive strength in palm oil fuel ash-modified concrete with SHAP analysis

Breaking language barriers: ‘Not being fluent in English is often viewed as being an inferior scientist’

Domain-specific large language model for predicting prostate cancer treatment plan.

428 Background: Prostate cancer management presents a significant healthcare burden, with the need to efficiently triage patients for treatment. Our objective is to leverage large language models to predict physician-recommended treatment plans from unstructured clinical notes. By accurately predicting treatment plans, we aim to risk stratify and triage patients effectively, thereby optimizing the allocation of physician resources. Methods: 448 unstructured initial urology consultation patient notes following first positive prostate cancer biopsy were identified. The recommended and final treatments received were manually annotated to establish ground truth labels (Table 1). The dataset was split 80:20 for training and testing, preprocessed to remove plan sections and formatted into question-answer (QA) format. A domain-specific large language model (LLM) inspired by GPT and a specialized tokenizer (PCa- LLM) for prostate cancer terminology were developed. QA models were built using the PCa-LLM and compared with those using GPT-2 as the backbone to predict recommended and final treatments. Results: For the physician-recommended treatment plans, our LLM (PCa-LLM) showed superior performance with higher AUROC scores for curative vs. non-curative treatments (0.78 vs. 0.65), chemo-hormonal vs. other non-curative treatments (0.89 vs. 0.65), and surveillance vs. all other treatments (0.72 vs. 0.70), while both models achieved the same high AUROC of 0.99 for chemo-hormonal vs. all other treatments. For final treatments, PCa-LLM demonstrated better AUROC for curative vs. non-curative treatments (0.77 vs. 0.74) and chemo-hormonal vs. other non-curative treatments (0.71 vs. 0.66), while GPT2 outperformed PCa-LLM for surveillance vs. all other treatments (0.78 vs. 0.70). Both models achieved an AUROC of 0.99 for chemo-hormonal vs. all other treatments. Conclusions: PCa-LLM accurately predicted most treatment categories better than GPT2, with higher AUROC scores, and can be utilized to triage prostate cancer patients using initial consultation notes. Task Physician -Recommended Treatment Plan Final Treatment Received Curative Prostatectomy/Radiation 228 230 Non-Curative Focal Therapy 22 15 Active Surveillance 40 45 Chemo-hormonal 30 30 Model Predictions (AUROC) GPT2 PCa-LLM GPT2 PCa-LLM Curative vs. non-curative 0.65 0.78 0.74 0.77 Chemohormonal vs. other non-curative 0.65 0.89 0.66 0.71 Chemohormonal vs. all other 0.99 0.99 0.99 0.99 Surveillance vs. other non-curative 0.64 0.60 0.67 0.59 Surveillance vs. all other 0.70 0.72 0.78 0.70