Browse Articles

Evaluating RSPO2 activation and its association with outcomes and potential role as a driver in double-negative prostate cancer (DNPC).

236 Background: Several aggressive tumor variants have emerged since the broad use of 2nd generation androgen therapies for metastatic prostate cancers (mPCs). Close to 20% of mPCs are double negative prostate cancers (DNPC) that lack androgen receptor (AR) and do not exhibit histopathological features of neuroendocrine prostate cancer (NEPC). Our study focused on the R-spondin family of genes ( RSPO1/2/3/4 ), which are secreted proteins classified as WNT regulators. In mPCs, we examined their genomic alterations, impact on clinical outcomes, interaction with CTNNB1 (master regulator of WNT signaling), or other genes associated with DNPC and epithelial-mesenchymal transition (EMT). Methods: Alterations in RSPOs , CTNNB1 , and APC were examined with respect to survival using data from the TCGA Pan Cancer Atlas (n=10967) and a non-redundant set of prostate tumors from cBioPortal (n=2510). Kaplan-Meier and log-rank tests were used to evaluate survival. Alphafold2 was used to model the protein structures in silico . Differential gene expression, Algorithm for Linking Activity Networks (ALAN), and Gene Set Enrichment Analysis (GSEA) were used to model gene expression and determine enriched pathways. Proliferative effects of RSPO2 and CTNNB1 were analyzed in AR+ (LNCaP) and AR- (PC3) cell lines. Results: Pan cancer RSPO2 amplification rates (5%) were greater than CTNNB1 mutations (4%) but less than APC loss (8%). In mPC, RSPO2 amplifications (22%) were greater than CTNNB1 mutations or APC loss (9%, 8%). RSPO1/3/4 alterations were of low prevalence. Pan cancer, RSPO2 and CTNNB1 alterations were associated with poor disease-free survival (HR=1.578, 1.448, 95%CI=1.17-2.13, 1.06-1.964, p<0.001 respectively), whereas APC loss or RSPO1/3/4 alterations were not prognostic. In primary prostate cancer, RSPO2 amplifications were associated with worse survival (HR=1.63, 95%CI=1.05-2.54, p<0.05). In silico protein structure modeling indicated stark differences between RSPO2 and RSPO1/3/4 . Using RNA-seq data from 208 mPCs, our gene-gene interaction analysis and GSEA indicated that RSPO2 expression was robustly associated with DNPC driver genes FGFR1/2 , the Hallmark EMT pathway, and EMT transcription factors ZEB1 , SNAI1/2 , TWIST1/2 , while being anti-correlated with expression of AR, AR co-factors ( FOXA1 , HOXB13 ), and Hallmark androgen signaling. Unlike RSPO2 , CTNNB1 was associated with Hallmark EMT and Androgen response. Finally, RSPO2 overexpression promoted proliferation in the two PC cell lines regardless of AR expression. Conclusions: RSPO2 has unique features from RSPO1/3/4 in which amplifications are associated with worse outcomes in prostate and other cancers. Relative to CTNNB1 , RSPO2 exhibits unique signaling properties that imply RSPO2 has oncogenic functions other than WNT signaling, which may explain how it promotes growth of cell lines without AR expression.

Classifying COVID-19 hospitalizations in epidemiology cohort studies: The C4R study

Rationale Robust COVID-19 outcomes classification is important for ongoing epidemiology research on acute and post-acute COVID-19 conditions. Protocolized medical record review is an established method to validate endpoints for clinical trials and cardiovascular epidemiology cohorts; however, a protocol to adjudicate hospitalizations for COVID-19 among epidemiology cohorts was lacking. Objectives We developed a protocol to ascertain and adjudicate hospitalized COVID-19 across a meta-cohort of 14 US prospective cohort studies. This report describes the first three years of protocol implementation (October 1, 2020—October 1, 2023) and evaluates its repeatability and performance compared to classification by administrative codes. Methods The protocol was adapted from cohort approaches to clinical cardiovascular events ascertainment and adjudication. Potential COVID-19 hospitalizations and deaths were identified by self-/proxy-report and, in some cases, active surveillance. Medical records were requested from hospitals and adjudicated for COVID-19 outcomes by clinically trained personnel according to a standardized rubric. Inter-rater agreement was assessed. The sensitivity and specificity of discharge diagnosis codes was compared to adjudicated diagnoses. Measurements and main results The study obtained medical records for 1,167 potential COVID-19 hospitalizations, which underwent protocolized adjudication. Adjudication confirmed COVID-19 infection was present for 1,030 (88%) events, of which COVID-19 was not the cause of hospitalization for 78 (8%). Of 952 hospitalizations determined by adjudicators to be caused by COVID-19, 319 (34%) participants were critically ill and 210 (22%) died. Pneumonia was confirmed in 822 (86%) and acute kidney injury in 350 (37%); other cardiovascular and thrombotic complications were rare (2–5%). Interrater reliability among adjudicators was high (kappa = 0.85–1.00) except for myocardial infarction (kappa = 0.60). Compared to adjudication, sensitivity of discharge diagnosis codes was higher for pneumonia (84%) and pulmonary embolism (81%) than for other complications (48–70%). Conclusions Protocolized adjudication confirmed four out of five COVID-19 hospitalizations in a US meta-cohort and confirmed cases of pneumonia, pulmonary embolism, and other conditions that were not indicated by discharge diagnosis codes. These results highlight the importance of validating health outcomes for use in research on COVID-19 and post-COVID-19 conditions, and some limitations of claims-based data.

Spin-dependent thermoelectric properties of a hybrid ferromagnetic metal/quantum dot/topological insulator junction

Abstract The thermoelectric properties of hybrid system based on a single-level quantum dot coupled to a ferromagnetic metallic lead and attached to the surface states of a three-dimensional topological insulator are theoretically investigated. On the surface of a three-dimensional topological insulator, massless helical Dirac fermions emerge. We calculate the thermoelectric coefficients, including electrical conductance, Seebeck coefficient (thermopower), heat conductance, and the figure of merit, using the nonequilibrium Green’s function technique. The results are analyzed in terms of the emergence of new effects. The calculations are performed within the Hubbard I approximation concerning the dot’s Coulomb interactions. Additionally, the spin-dependent coupling of the quantum dot to the ferromagnetic lead lifts the spin degeneracy of the dot’s level, which influences the transport properties of the system. We incorporate this effect perturbatively to obtain the spin-dependent renormalization of the dot’s level. We also consider the case of finite spin accumulation in the ferromagnetic electrode, which leads to spin thermoelectric effects.

Concordance of circulating tumor DNA and imaging surveillance in patients with urothelial carcinoma and renal cell carcinoma post-immunotherapy.

597 Background: Early detection of recurrence in urothelial carcinoma (UC) and renal cell carcinoma (RCC) may improve patient outcomes. Conventional imaging techniques may not identify early molecular relapses that precede clinical relapse. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for the early detection of disease relapse. This study aims to evaluate the concordance of molecular relapses by ctDNA and radiographic progression in patients with UC and RCC who are off immunotherapy due to intolerance of side effects or completion of treatment. Methods: We conducted a retrospective study of locally advanced/advanced UC and RCC patients who were treated at The Ohio State University James Cancer Hospital from November 2021 to September 2024. Patients who completed planned immunotherapy followed by imaging and ctDNA surveillance were included. ctDNA levels were measured using the Signatera tissue informed assay at intervals of 4 to 12 weeks. Imaging surveillance schedules were at the treating physician discretion. Patient demographics, clinical characteristics, and ctDNA levels were recorded and analyzed. Results: A total of 36 patients were included: muscle-invasive bladder cancer (MIBC, n = 10), metastatic urothelial carcinoma (mUC, n = 10), locally advanced RCC (n = 4), and metastatic RCC (mRCC, n = 12). The median follow-up was 39.5 weeks (range: 1–138 weeks), with a median age of 67.5 years (range: 41–83 years), and 72.2% were male. At the time of immunotherapy discontinuation, ctDNA was negative in all patients except one mRCC patient (ctDNA 0.95 MTM/mL). During surveillance, 9 patients (25%) - 5 mUC and 4 mRCC - became ctDNA-positive, of which, eight showed radiographic progression, while one mRCC patient (ctDNA 0.15 MTM/mL) did not. None of the 27 patients (75%) that continued to have negative ctDNA had radiographic progression. For the 8 patients with progression, the median time from stopping immunotherapy to ctDNA relapse was 17.5 weeks (range: 11–42 weeks). The median time from ctDNA relapse to imaging-confirmed progression was 22 weeks (range: 13–43 weeks). At progression, ctDNA levels ranged from 0.08 to 136.49 MTM/mL (median: 2.33 MTM/mL). Six of the 20 metastatic patients (30%) relapsed despite negative ctDNA at immunotherapy discontinuation. Conclusions: ctDNA positivity occurs much earlier and is highly concordant with radiographic progression in patients with locally advanced/advanced UC and RCC under post-immunotherapy surveillance. These findings suggest that ctDNA is a promising tool for early disease relapse detection in these patients. Further studies are warranted to validate these results and establish standardized ctDNA surveillance protocols.

Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgement. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard-of-care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only). PURPOSE To provide evidence-based guidance for clinicians who treat patients with stage I-III anal cancer. METHODS A systematic review of the literature conducted by the Minnesota Evidence-based Practice Center provided the evidence base for this guideline. An ASCO Expert Panel reviewed this evidence and came to consensus on a set of evidence-based recommendations. RESULTS The systematic review contained three randomized controlled trials and three nonrandomized studies of interventions that were relevant to the guideline topic and informed the recommendations. RECOMMENDATIONS Mitomycin-C (MMC) with a fluoropyrimidine (fluorouracil [FU] or capecitabine) is recommended as the radiosensitizing component of chemoradiation (CRT) for anal cancer; the Expert Panel recognizes that capecitabine is often used as an orally administered alternative to FU and is currently being used in ongoing clinical trials. Cisplatin with FU is an additional chemotherapy combination that may be recommended as radiosensitizing chemotherapy. Because of the myelosuppression associated with MMC, the preferable regimen for patients with immunosuppression is cisplatin and FU. Cisplatin is not recommended for patients with renal dysfunction, significant neuropathy, or hearing loss, and there is no evidence to recommend substituting carboplatin for cisplatin. Dose and schedule options for recommended chemotherapy agents are included within the full text of the guideline. Routine induction chemotherapy before CRT and additional chemotherapy after CRT are not recommended for patients with localized anal cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Survival of patients with metastatic renal cell carcinoma with or without brain metastases.

476 Background: Brain metastasis (BM) is an adverse prognostic indicator and associated with poor survival for patients with metastatic renal cell carcinoma (mRCC). Although immune checkpoint inhibitor (ICI) therapy has significantly improved survival in patients with metastatic renal cell carcinoma, the prognostic significance of BM in the ICI era is unclear. Methods: We performed a retrospective cohort study of patients diagnosed with clear cell RCC (ccRCC) between 2012-2023 at the Yale Cancer Center. We examined the association between brain metastasis and overall survival among patients by treatment type (with or without ICI in any line of therapy). We compared overall survival (mOS) using Kaplan-Meier analyses and multivariable Cox proportional hazards models. Results: We identified 338 patients diagnosed with metastatic ccRCC between 2012 and 2023, of whom 96 (28.4%) had BM, 39 of which were detected by screening versus 57 detected by symptoms. BM detected on screening MRI were smaller than those identified for cause (mean 13.9 versus 20.8 mm, respectively, p=0.002). The mOS from the time of metastatic ccRCC diagnosis was 54.0 months (95%CI 41-76) in patients without BM versus 37.0 (27-52) months in patients with BM (p=0.03). Among patients who received ICI therapy, mOS was 66 months (95% CI, 50-91) in those without BM versus 37 months (95% CI, 29-63) in those with BM (p=.01). In patients who did not receive ICI therapy, mOS was 31.5 months (95% CI, 23-80) in those without BM versus 17 months (95% CI, 14-NR) in those with BM (p=0.4). Among patients with BM, the mOS from the development of BM was 17.0 months (95% CI, 13-30). Median overall survival was 62 (95% CI: 17-NR months) versus 12 months (95% CI: 5-25 months) from the time of metastatic cancer diagnosis for those who underwent screening versus those who did not (p=0.0001). Conclusions: In our ccRCC population, there is a higher prevalence of brain metastases than previously thought. Overall survival for patients with metastatic ccRCC and brain metastases has improved in the era of ICI therapy. Brain metastases remain associated with poor prognosis and were frequently detected during asymptomatic screening. Patients with brain metastases discovered on screening had improved overall survival compared to those with brain metastases discovered because of symptoms.

MAP1LC3C repression reduces CIITA- and HLA class II expression in non-small cell lung cancer

In the last decade, advancements in understanding the genetic landscape of lung squamous cell carcinoma (LUSC) have significantly impacted therapy development. Immune checkpoint inhibitors (ICI) have shown great promise, improving overall and progression-free survival in approximately 25% of the patients. However, challenges remain, such as the lack of predictive biomarkers, difficulties in patient stratification, and identifying mechanisms that cancers use to become immune-resistant (“immune-cold”). Analysis of TCGA datasets reveals reduced MAP1LC3C expression in cancer. Further analysis indicates that low MAP1LC3C is associated with reduced CIITA and HLA expression and with decreased immune cell infiltration. In tumor cells, silencing MAP1LC3C inhibits CIITA expression and suppresses HLA class II production. These findings suggest that cancer cells are selected for low MAP1LC3C expression to evade efficient immune responses.

Association between rheumatoid arthritis and interstitial lung disease and impact of serologic status: a large-scale longitudinal study

Targeting the soluble epoxide hydrolase (sEH) enzyme to relieve painful docetaxel-induced peripheral neuropathy.

126 Background: Docetaxel is an important chemotherapeutic agent used for the treatment of several cancers, including metastatic prostate cancer. Unfortunately, it shares the side effect profile of other taxanes, including causing painful chemotherapy-induced peripheral neuropathy (CIPN). The pain of CIPN is notoriously difficult to treat, can lead to discontinuation of life-prolonging cancer treatments and can become a debilitating, chronic condition. Notably, African American (AA) cancer patients have increased (2-3-fold) risk and increased severity of CIPN. The enzyme soluble epoxide hydrolase (sEH) functions as a master regulator of inflammation, by converting epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding inactive or pro-inflammatory diols. As sEH inhibition has demonstrated efficacy in several models of neuropathy, here we assessed its potential to relieve and/or prevent docetaxel-induced CIPN specifically. Methods: We established a model of docetaxel-induced painful neuropathy in male Sprague Dawley rats, by administering 3 doses of docetaxel (10 mg/kg intraperitoneally, once weekly, for 3 doses). We tested the efficacy of the small molecule sEH inhibitor EC5026 (EicOsis, Inc, Davis, CA) both (1) as a single dose administered via oral gavage and (2) via chronic administration (1 mg/kg/day) in the drinking water started 1 week prior to and continuing during the period of docetaxel treatments. To examine the analgesic efficacy of EC5026, the rats were assessed for responses in nociceptive (von Frey assay and cold plate assay) and functional (open field test) behavior assays. Tail vein blood was sampled, and the blood concentration of docetaxel (measured by mass spectrometry) was compared between vehicle-treated and EC5026-treated cohorts. Results: Oral dosing of the sEH inhibitor EC5026 dose-dependently relieved docetaxel-induced painful neuropathy. Additionally, chronic treatment with EC5026 via the drinking water blocked both tactile allodynia and cold sensitivity compared to vehicle-treated rats. The open field assay revealed that EC5026 has no negative effect on motor skills. Moreover, EC5026 did not affect the blood levels of docetaxel in rats. Conclusions: sEH is a novel target for achieving pain relief in our CIPN model. Our results indicate robust response to therapeutic treatment of the CIPN model and additionally improved outcomes with prophylactic administration of the sEH inhibitor EC5026 in docetaxel-induced painful CIPN, without effect of EC5026 on animal motor skills or docetaxel pharmacokinetics.

Influence of MRIs performed in a 6-week interval on the histopathological detection of prostate cancer with different PIRADS classifications: A real-world data analysis.

334 Background: In the early phases of MRI-guided prostate biopsies, it was often necessary to perform an additional in-house multiparametric MRI after an external MRI to accurately assess lesions for biopsy. This study aims to evaluate the consistency of lesion identification and the associated clinical and histological outcomes at a high-volume tertiary care center performing over 500 biopsies annually. Methods: This analysis included real-world data from 111 patients treated between 2018 and 2022. Each patient underwent two multiparametric MRI scans of the prostate at different institutions, with a median interval of 42 days [32–52] between scans. An MRI-fused biopsy followed 7 days [4–10] after the second MRI. Data were analyzed using the Chi-square test. Results: The PIRADS scores for index lesions on the in-house MRI were as follows: PIRADS V in 33.3% (n=37), PIRADS IV in 49.5% (n=55), PIRADS III in 12.6% (n=14), and PIRADS II in 4.5% (n=5) (Table 1). Most lesions were located in the peripheral zone of the prostate (68.8%, n=75). Cancer detection rates for randomized and/or targeted biopsies were 91.9% (n=34) for PIRADS V, 65.5% (n=36) for PIRADS IV, 21.4% (n=3) for PIRADS III, and 20% (n=1) for PIRADS II. Clinically significant prostate cancer (ISUP > 1) was detected in 91.9% (n=34) of PIRADS V, 60% (n=33) of PIRADS IV, and 21.4% (n=3) of PIRADS III lesions. Overall, malignant histology was found in 64.9% (n=72) of targeted lesions and 59.5% (n=66) of randomized biopsies. A median of 7 [5.5–8.5] biopsies were taken per lesion, with an additional 13 [11–15] randomized biopsies. In the initial external MRI, 18% (n=20) of patients were assigned a higher PIRADS category, while 10.8% (n=12) were had a lower score (p<0.001). The biopsy plan was adjusted for 57 patients (51.4%) based on the findings of the second MRI. However, given the cancer detection rates in both targeted and randomized biopsies, it is likely that all cancers would have been detected regardless of these adjustments. Conclusions: Although PIRADS classifications varied slightly between the two MRI scans performed six weeks apart, and biopsy plans were adjusted in about half of the cases, all cancers would likely have been identified. The six-week interval between MRI scans does not appear to significantly affect biopsy accuracy. PIRADS classification comparison of internal and external MRI. External MRI PIRADS II PIRADS III PIRADS IV PIRADS V All Internal MRI PIRADS II 0 40% (2) 40% (2) 20% (1) 5 PIRADS III 0 28.6% (4) 57.1% (8) 14.3% (2) 14 PIRADS IV 0 9.1% (5) 81.8% (45) 9.1% (5) 55 PIRADS V 0 2.7% (1) 16.2% (6) 81.1% (30) 37 All 0 12 60 39

Intra-patient comparison of urinary radioactivity after ¹⁸ F-piflufolastat and ¹⁸ F-flotufolastat PET in men with low PSA biochemical recurrence of prostate cancer who have had radical prostatectomy.

TPS272 Background: Prostate-specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceuticals enable early detection of metastatic and recurrent prostate cancer (PCa). High urinary radioactivity of some PSMA-PET agents can affect interpretation of scans in the pelvic region (prostate/prostate bed [PB]; pelvic lymph nodes [PLN]). 18 F-Piflufolastat and 18 F-flotufolastat are FDA-approved, mainly renally cleared, diagnostic PSMA-PET agents; data suggest 18 F-flotufolastat has lower urinary radioactivity than 18 F-piflufolastat, but no clinical differences have been confirmed by head-to-head intra-patient studies. The present study will directly compare the urinary radioactivity of 18 F-piflufolastat with 18 F-flotufolastat in men with low prostate-specific antigen (PSA) biochemical recurrence (BCR) of PCa after radical prostatectomy (RP). Methods: This multicenter, prospective, intra-patient comparator study will include men (≥ 18 years old) with low PSA (≤ 0.5 ng/mL) BCR of PCa who have had RP ≥ 6 months before enrollment (with undetectable PSA post surgery) and are due to have routine 18 F-piflufolastat PET. Men who have had prior 18 F-piflufolastat PET or salvage therapy, or with conditions affecting urinary output, will be excluded. Eligible patients will undergo 18 F-piflufolastat PET followed by 18 F-flotufolastat PET ≥ 24 hours but ≤ 10 days later. No diuretic will be administered for scanning purposes. Each radiopharmaceutical will be administered as a single intravenous bolus per approved US prescribing information (USPI). Scanning (with the same scanner for both scans) will start 50–90 minutes post injection of 18 F-piflufolastat and 50–70 minutes post injection of 18 F-flotufolastat. Each patient will be their own control. The primary endpoint will be difference in mean standardized uptake value (SUV mean ) between 18 F-piflufolastat and 18 F-flotufolastat as assessed in volumes of interest drawn on the urinary bladder. Secondary endpoints for both agents will include detection rates: at the patient level (overall; by baseline PSA); for local recurrences in PB subregions; and for PLN lesions. For secondary endpoints, PET scans will be interpreted per product-specific USPI by 2 specially trained, blinded, central readers (a third reader will adjudicate disagreements). Safety will be monitored until 24 hours after the second scan. Around 60 men will be screened and ≥ 52 with evaluable PET scans for both agents will be included in the primary analysis. The primary endpoint will be assessed for normality and a difference in SUV mean will be tested using 2-sided paired tests (Wilcoxon signed-rank test [non-normal]; t-test [normal]). All further endpoints, including safety, will be summarized descriptively. The trial has been open for enrollment since 10/24. Clinical trial information: NCT06604442 .

Assessment of public awareness and perspectives towards adverse drug reaction reporting system in Karachi, Pakistan

Background Public involvement in reporting adverse drug reactions (ADRs) generates a broader database on drug safety. Underreporting remains a hindrance to implementing an effective pharmacovigilance system that ultimately affects public health. Hence, it is critical to appraise the public’s awareness of ADR reporting and pharmacovigilance to address the gaps for the enhancement of ADR reporting rate. Objectives The current study explored public knowledge and attitudes toward ADR reporting in Karachi, Pakistan. Methods A quantitative cross-sectional study was conducted from 3rd Jan 2022 to 30th Nov 2022 using a forty-item questionnaire to evaluate public insights regarding the ADR and its reporting. Descriptive analysis was executed to determine frequencies and percentages for the respondents’ baseline characteristics and the responses toward ADR reporting. The chi-square test (χ2) was applied to determine the association between the dependent and independent variables considering a p-value < 0.05 as statistically significant. Results The response rate of the present study was 78.3%. More than 80% of the respondents deemed that ADR occurs only with high doses of medicines and over-the-counter medications do not cause any ADR. More than 75% of the respondents did not know that the ADR reporting form is available on the Drug Regulatory Authority of Pakistan (DRAP) website; the response varied significantly with the education (p = 0.002) and social status (p = 0.0001) of the respondents. More than 50% of the participants refused to ever report an ADR to health professionals. Physicians (n = 364; 47.7%) and pharmacists (n = 253; 33.1%) were the respondents’ professed most reliable sources to whom ADR can be reported; responses varied significantly with their education (p = 0.003) and age (p = 0.001). Conclusions The study has provided insight into the challenges and gaps needed to improve ADR reporting in Pakistan. The outcomes revealed that the public is aware of the benefits of reporting ADRs; however, they do not realize their role and the potentially significant impact on the healthcare system by contributing to ADR reporting. Therefore, it is a need of time to educate the public on the value of reporting ADRs and implement user-friendly and accessible ADR reporting systems in patient care areas to facilitate easier reporting.

Author Correction: Memory reactivation generates new, adaptive behaviours that reach beyond direct experience

Survival outcomes of de novo mHSPC based on hemoglobin A1C and ARPI therapy.

139 Background: While there has been no prospective studies, enzalutamide (enza) has better overall survival, fewer adverse events, risk of progression, and PSA response compared to the abiraterone (abi) in real-world treatment of metastatic prostate cancer with androgen receptor pathway inhibitors (ARPI)s. Diabetes (T2DM) is a major comorbidity in elderly patients, with worse glycemic control as a risk factor for and worse cancer outcomes. Studies analyzing the role of ARPIs in patients with diabetes have found enza associated with longer survival, less frequent acute hospitalizations, and likelihood of developing T2DM, compared to abi. However, there is little data in hormone sensitive population (mHSPC), where ARPIs are most commonly used. This study analyzed the association between use of APRI treatment and survival in patients with controlled versus uncontrolled diabetes based off hemoglobin A1C (hgbA1C). Methods: 1591 Patients with de novo mHSPC diagnosed between 2017-2023, treated with abiraterone or enzalutamide with 4 months of ADT, and hgbA1C within 1 year prior and up to 3 months after cancer diagnosis were retrospectively identified. Additional variables included age, BMI, base-line prostate specific antigen at diagnosis, Charlson Comorbidity Index score (CCI). Kaplan-Meier method was used to compare overall survival months based on hgbA1C and diabetes diagnosis. Cox proportional hazard modeling was performed to assess the relationship when adjusting for confounding variables. Results: The cohort included 1591 patients with de novo mHSPC, 1,196 who received abiraterone and 395 who received enzalutamide. Veterans treated with enza were older (mean 74.4 years vs. 73.0, p<0.001) with higher CCI (mean 2.6 vs. 2.0, p<0.001). Veterans with hgbA1C>6.5 were more likely to be prescribed enzalutamide (31.1% vs. 21.6%, p<0.001). Veterans with hgbA1C<6.5 had significantly longer survival compared to veterans with hgbA1C>6.5 (41.5 vs. 33.3 months, HR 0.79 95%, CI 0.68-0.91). Patients treated with abiraterone had a significant difference in survival based on hgbA1C (41.5 vs. 31.1, HR 0.79, CI 0.67-0.93). In patients treated with enzalutamide, there was no significant difference in survival (40.7 vs. 38.0, HR 0.80 95%, CI 0.60-1.07). A1C remained predictive of mortality (HR 1.27, 95CI 1.10-1.48) when controlled for PSA, BMI, ARPI, and age. Conclusions: In veterans with mHSPC who are treated with abiraterone, elevated hgbA1C is associated with shorter survival. No differences were seen in veterans treated with enzalutamide; however, these analyses may be underpowered. These results may help in treatment selection and support glycemic control when treating patients with mHSPC and comorbidities. ARPI A1C Median OS (months) HR 95 CI Abiraterone <6.5 41.5 0.79 0.67-0.93 6.5+ 31.1 overall 39.2 Enzalutamide <6.5 40.7 0.80 0.60-1.07 6.5+ 38.0 overall 39.4

Biomarker testing patterns among patients newly diagnosed with prostate cancer in a community oncology network.

229 Background: Prostate cancer guidelines recommend that clinicians order biomarker testing for patients with metastatic prostate cancer. In addition, testing is recommended to determine patients’ eligibility for clinical trials and to identify potential actionable mutations that can inform appropriate treatment strategies. The aim of this study was to evaluate biomarker testing patterns among patients newly diagnosed with prostate cancer who received care in a large community oncology provider network. Methods: A retrospective database analysis, using several sources that include iKnowMed (EMR), Ellkay CareEvolve (Genetic HL7 interface), and the Molecular Data Warehouse and covers approximately 1.7 million distinct patients, was conducted on patients newly diagnosed with prostate cancer between Jan 1, 2018, and Jun 30, 2022, and receiving care in a large oncology network in West South-Central United States. Baseline demographics and clinical characteristics were analyzed descriptively and the proportion of patients who received biomarker testing was determined. Results: Data on 18,743 patients with prostate cancer (mean age at diagnosis, 71 years; 46% White, 13% Hispanic, 7% Black, 1% Asian, 33% other/unknown) were abstracted. The proportion of patients who received biomarker testing was 14% overall and 23% among those with Stage IV disease. Of all biomarker tests performed, roughly 6% was single gene testing, 49% was broad panel testing, 25% was both single gene testing with broad panel testing, and approximately 20% of the tests were unknown. The average time from first biomarker testing to disease diagnosis was approximately 5 months. Less than 10% of the patients who tested positive with an actionable mutation received targeted therapy. Hormone therapy (32%) was the most common treatment received, followed by supportive care (7%). Conclusions: These findings provide insights into the frequency of biomarker testing among patients newly diagnosed with prostate cancer who receive care in a large community practice setting. Advancement in targeted therapies is predicated on improved testing rates, and this study suggests opportunities exist for interventions and increased education among healthcare providers based on observed time to testing and the rate of testing. Biomarker testing patterns in patients with prostate cancer. Parameter Patients with prostate cancer(N=18,743) Received biomarker testing All patients, n (%) 2,585 (14) Patients with metastatic Stage IV disease, n/n (%) 941/4,168 (23) Received targeted therapy after positive biomarker testing indicating actionable mutation, n/n (%) 36/450 (8) Mean (standard deviation) days from ordering biomarker test to: Disease diagnosis 156 (545) Receiving results 52 (213) Treatment initiation 113 (525)

Improving health related quality of life (HRQoL) assessment and immune related adverse event (irAE) classification with novel tools in renal cancer.

525 Background: HRQoL tools and adverse event criteria were designed around outdated therapies and require re-evaluation in the era of immune checkpoint inhibitors (ICI). Attempts have been made to create a novel HRQoL tool (Bergerot et al) but this has not been validated in prospective data sets. To our knowledge no attempts have been made to re-evaluate current toxicity grading systems. Data from PRISM, a randomized ph2 trial which explored scheduling of 1 st line ipilimumab/nivolumab in advanced renal cell carcinoma (RCC), was used to validate these novel tools. Methods: HRQoL (EORTC QLQ-C30 & FKSI-19) and irAE data graded using common terminology criteria for adverse events (CTCAE) were analysed in treatment naïve patients with advanced RCC recruited to PRISM. Patients were randomised 2:1 to 4 doses of ipilimumab 12-weekly (modified) or 3-weekly (standard) in combination with nivolumab. The novel QoL tool, created with patient engagement and expert input, was prospectively tested and compared with scores for FKSI-19 (0-76) and QLQ-C30 (0-100). irAEs (graded 1-5 CTCAEv5) were reclassified by patient advocates into 3 groups; life changing (LC), significant (S), non-significant (NS). These were further classified into short term (ST) or long term (LT). Results: In PRISM 192 patients were randomised 2:1 (128 modified, 64 standard schedule). HRQoL scores were available for 157 patients at baseline, week 13 and 25. Baseline scores were comparable across all 3 (QLQ-C30, FKSI-19, novel tool) tools. IMDC good risk patients had higher QOL scores at baseline across all three questionnaires compared to intermediate/poor risk (FSKI 64 vs 58, QLQC-30 86 vs 77, novel tool 59 vs 53, p <0.05). Only the novel tool showed significantly improved QoL (57 v 51, p >0.05) at 13 weeks. There was no correlation between occurrence of grade 3/4 irAEs and reduction in QOL as reported in PRISM. QoL scores in patients with progressive disease were worse across all tools (FSKI 52.3 v 58.9, QLQC-30 60.3 v 75.2, novel tool 48 v 56.4, p <0.02). 1158 irAEs were reported and reclassified. All grade 1 irAEs were deemed NS. The table shows the frequency of significant or life changing toxicity as perceived by patients. Incidence of life changing and significant toxicity was 15% and 24% respectively, which was associated with reduction in HRQoL across all tools. Conclusions: Here we describe the frequency of significant or life changing toxicity associated with ICI which will help clinicians in describing risk/benefit ratios to patients. Refining these tools facilitates more accurate future data collection in trials which better reflects the patient experience. irAE Life changing (LC) Significant short term (SST) Significant long term (SLT) Non-significant (NS) Grade 2n=281 17 (6%) 17 (6%) 10 (4%) 237 (84%) Grade 3n=122 14 (12%) 53 (43%) 9 (7%) 46 (38%) Grade 4n=8 2 (25%) 4 (50%) 1 (12.5%) 1 (12.5%)

Role of the platelet-lymphocyte ratio as a prognostic indicator in patients with intracranial hemorrhage: A systematic review and meta-analysis

Background The prognostic value of platelet-lymphocyte ratio (PLR) in ischemic stroke had been investigated in previous studies. However, the results of studies on PLR in patients with intracranial hemorrhage (ICH) are inconsistent. We aimed to conduct a meta-analysis to determine the prognostic value of PLR in predicting functional outcome and mortality in patients with ICH. Methods We searched the databases of PubMed, Embase, the Cochrane Library, and CNKI for relevant studies up to 10th June 2024. The Newcastle Ottawa Quality Assessment Scale (NOS) was applied to evaluate the quality of the included studies. We calculated the pooled odds ratios (OR) with 95% confidence intervals (CI) between PLR and both functional outcome (as measured by the modified Rankin Scale, mRS) as well as mortality. Poor functional outcomes were defined as mRS > 2. Results A total of 6 studies with 2992 patients were included. The random effects meta-analysis demonstrated that elevated PLR exhibited an association with poor functional outcome in patients with ICH (OR = 1.69; 95% CI [1.39–2.07]; P<0.0001; I2 = 24%). Similarly, elevated PLR was associated with mortality in patients with ICH (OR = 1.65; 95% CI [1.12–2.43]; P = 0.01; I2 = 31%). Conclusion This study suggested that elevated PLR was significantly associated with poor functional outcome (mRS>2) and increased mortality, indicating that elevated PLR could serve as a reliable a prognostic factor for unfavorable clinical outcomes in patients with ICH. It is advisable to conduct extensive prospective investigations across diverse ethnic backgrounds to verify the accuracy of this correlation prior to its utilization in clinical settings.

A prosperous and thorough analysis of gravity profiles for resources exploration utilizing the metaheuristic Bat Algorithm

Analysis of distinct genomic, transcriptomic, and immune landscapes driven by alterations in androgen production, uptake, and conversion (APUC) genes in metastatic prostate cancers.

209 Background: Prostate cancer (PC) progression is driven by aberrant activity of the androgen receptor (AR) or its associated ligands - androgens. Dysregulation of genes that regulate androgen production, uptake, and conversion (APUC) may impact the efficacy of hormone therapies for PC. In our recent study of primary (n=2593) or metastatic PC (n=4490) biopsies, 6 APUC genes ( HSD3B1 , HSD3B2 , CYP11A1 , CYP11B1 , CYP17A1 , CYP3A43 ) showed strong clustering in prostate adenocarcinoma. Tumors with high APUC expression (APUC-6 high) had low AR alterations/signaling activity and showed prolonged overall survival. Here we examined the genomic, transcriptomic, and immune cell-fraction compositions in APUC-6 high versus AR-high tumors. Given improved outcomes in APUC-6 high tumors, we hypothesize reduced features of tumor aggressiveness or a favorable immune milieu in these specimens. Methods: Metastatic PC samples in the SU2C/PCF dataset (n=208) were annotated as APUC-6 high or AR-high based on gene expression quartiles, with the upper quartile defining “high” status. Additional stratification was performed to ensure that no samples classified as both APUC-6 high and AR-high were included in either group. This stratified two groups of tumors (n= 41, each). Transcriptomic, genomic, and clinical features between the two groups were compared. Gene Set Enrichment Analysis was used to identify upregulated gene-expression hallmark pathways, and CIBERSORT was used to infer fractions of 22 immune cell types. Results: APUC-6 high tumors exhibited fewer AR genomic alterations, AR gene expression, and AR-V7 detection. APUC-6 high and AR-high groups harbored significant differences in mutation alteration frequencies of 4 genes: AR, EDN2, EDA2R, and OPHN1 (q < 0.05). There were no differences in the frequency of poor-prognosis mutations such as in TP53, PTEN, or RB1. APUC-6 high tumors were enriched in several hallmark inflammatory pathways and epithelial to mesenchymal transition (EMT) (NES>1.5, FDR<0.05). APUC-6 high tumors contained a higher fraction of naïve CD4 T-cells (224-fold, q = 0.0226), and also exhibited numerically higher levels of activated natural killer cells and neutrophils (1.35-fold and 2.11-fold, q = 0.081, 0.051, respectively), relative to AR-high tumors. Conclusions: APUC-6 high tumors, characterized by a favorable prognosis, are associated with upregulation of inflammatory pathways and EMT, and a distinct immune cell repertoire despite no difference in aberrations of canonical drivers of aggressiveness, such as TP53, PTEN , or RB1 status. The more inflamed tumor microenvironment observed in APUC-6 high tumors warrants further exploration of distinct clinical approaches to this distinct phenotype. Validation of these findings in larger cohorts is ongoing.

Detection of mutations in homologous recombination repair (HRR) pathway genes using liquid biopsy in metastatic, castration-resistant prostate cancer (mCRPC) patients without tumor tissue availability.

98 Background: Accurate detection of mutations in HRR pathway genes among patients with mCRPC is essential for selecting patients who would benefit with poly (ADP-ribsose) polymerase (PARP) inhibitor therapies. Traditional tissue-based detection methods can be associated with practical challenges as acquisition of specimens can involve significant risk or high costs. For prostate cancer patients, obtaining adequate tissue samples can be even more difficult, considering the unique characteristics of the disease. This study aimed to evaluate the real-world performance of liquid biopsy using circulating tumor DNA (ctDNA) in detecting mutations in HRR genes, among mCRPC patients who did not have tissue available for genomic evaluation. Methods: Blood samples (20ml of whole blood) were collected from 760 mCRPC patients in 10 Asian countries. Samples were collected once for each patient, regardless of treatment type or cycles as long as the patients were followed up for their mCRPC. All patients included were confirmed from each participating site to have no tissue available for genomic analysis. Blood samples were analyzed using a next-generation sequencing (NGS) based ctDNA assay, covering 15 genes in the HRR pathway ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) . Results: ctDNA NGS testing was successfully performed in all 760 mCRPC patients. Any mutations in the HRR pathway genes were detected in 63.7% of the included patients and deleterious or suspected deleterious HRR pathway gene mutations were detected in 32.5% with the assay. Deleterious/suspected deleterious BRCA1/2 mutations were detected in 68/760 (8.95%) of the cases. Other detected deleterious/suspicious deleterious mutations included mutations in CDK12 , detected in 59/760 (7.76%) patients, followed by ATM mutation in 39/760 (5.13%), and CHEK2 in 31/769 (4.08%) by frequency. Conclusions: ctDNA testing for HRR gene mutations offers a practical tool for therapy selection in mCRPC patients. This non-invasive approach enables testing for patients who were not eligible for evaluation by tissue-based methods and can expand access to adequate targeted therapies.