Browse Articles

Real-world U.S. county-level analysis of erectile dysfunction diagnosis following radiation therapy for localized prostate cancer: The impact of rectal spacer utilization.

365 Background: Rectal spacers have been shown to reduce side effects of prostate radiotherapy (RT) in prostate cancer (PCa) patients in clinical studies. While rectal spacing may help preserve sexual function after RT, this association has not been explored in large-scale real-world data. This study evaluated the association between rectal spacer use and the prevalence of erectile dysfunction diagnosis among PCa patients receiving prostate RT at the U.S. county level. Methods: This study utilized Medicare 5% and 100% Standard Analytic Files to analyze county-level data. The population consisted of adult PCa patients receiving RT (IMRT, brachytherapy, SBRT, or proton therapy) between 2015 and 2022. The primary outcome was the county-level proportion of patients diagnosed with erectile dysfunction in any year between 2016 and 2023. The primary explanatory variable was the proportion of patients treated with RT using rectal spacer 1 to 5 years before erectile dysfunction diagnosis. Zero-inflated Poisson regression models assessed the association between rectal spacer use and erectile dysfunction diagnosis at county level, controlling for county-level PCa patients characteristics (average age and racial composition) and general population characteristics (median age, racial composition, and median household income). State-level fixed accounted for regional variation. Data for the general population were obtained from the Agency for Healthcare Research and Quality Social Determinants of Health Database 2020. Results: The study included 247,250 PCa patients receiving prostate RT during the study period across 3,132 U.S. counties. The average annual prevalence of erectile dysfunction diagnosis among PCa patients receiving RT at the county level was 1.3%. The proportion of patients receiving rectal spacers increased from 2.9% to 18.9% over the study period. After adjusting for confounders, counties with higher rectal spacer use 4-5 years prior had a significantly lower prevalence of erectile dysfunction diagnosis. A 10-percentage point increase in rectal spacer usage at the county level was associated with a 7.7% reduction in erectile dysfunction diagnosis after 4 years (p<0.001) and an 8.4% reduction after 5 years (p=0.006). Conclusions: In this first assessment of a real-world dataset, the county-level analysis suggests that increased use of rectal spacing among PCa patients receiving prostate RT is associated with a significantly lower prevalence of erectile dysfunction, with a time lag of 4 to 5 years. This finding supports the long-term benefit of rectal spacing in preserving sexual function in PCa patients undergoing prostate RT. Future research should evaluate the etiology of the longer than expected time lag between utilization and benefit.

Light-induced enhancement of alternating current poling quality and mechanical quality factor in ferroelectric single crystals

Alternating current poling (ACP) and light fields have been studied as domain engineering methods for regulating the domain structures and improving the physical properties of ferroelectric crystals because of their convenience, effectiveness, and economic advantages. In this study, we propose a LACP method (ACP under above-bandgap light illumination), by which the transparency and electro-optic properties of Mn- and Fe-doped KTa1−xNbxO3 single crystals were improved compared with only ACP. Furthermore, the mechanical quality factor (Qm = 538) of the sample poled using the LACP method increased significantly by 206% in contrast to that of the sample poled by the conventional high-temperature direct current poling method. The results reveal that the light-induced reorientation of defect dipoles is responsible for the enhancement of the ACP quality and Qm. This study provides an efficient and fast poling approach to the material design for multifunctional devices.

The effects of experimental conditions on extraction of polyphenols from African Nutmeg peels using NADESs-UAE: a multifactorial modelling technique

Clinical efficacy of enfortumab vedotin-pembrolizumab (EV-P) in locally advanced (LA) or metastatic urothelial carcinoma (mUC): A real-world retrospective study.

745 Background: The combination of EV-P therapy has recently been approved as first-line (1L) therapy for patients with LA/mUC based on the results of the EV-302 trial. Herein, we report the updated results from a cohort of patients with LA/mUC who received EV-P in real world clinical setting. Methods: This retrospective study included patients with LA/mUC (07/2022-08/2024) at the Mayo Clinic who completed at least one cycle of EV-P. The best overall response (BOR) was evaluated using radiographic imaging and was adjudicated as complete response (CR), partial response (PR), stable disease (SD), mixed response (MR), or progressive disease (PD). The median progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death, was estimated using the Kaplan-Meier method. Patients who had not experienced disease progression by their last follow-up were censored for the PFS analysis. Results: A total of 120 patients were included; 79 (65.8%) were males, 41 (34.1%) females, 109 (91%) White, and 119 (99%) were non-Hispanic/Latino. The median age was 72 years (IQR: 65-77). Of these, only 22 (18.3%) had locally advanced disease while the remaining had mUC; 62 (51.6%) had lower tract urothelial carcinoma (LUTC), 36 (30%) had upper tract urothelial carcinoma (UTUC). The median follow-up time was 7.1 months (IQR: 4.93-9.26). In terms of BOR, 56 patients (46.6%) experienced PR, 34 (28.3%) CR, 12 (10%) PD, 7 (5.8%) MR, and 8 (6.6%) experienced SD. 3 (2.5%) patients were not evaluable. The BOR across subgroups, LA and mUC, including LUTC and UTUC, is summarized in the table. Among the responders, the median number of treatment cycles to first response was 3 (IQR: 2.25–4). Within the follow-up, 28 patients (23.3%) experienced eventual radiographic disease progression; death was observed in 25 patients (20.8%). The median PFS was 12.7 months (95% CI: 9.8-NE), and OS was 25.1 months (16.3-NE). Conclusions: In real world setting, the combination of EV-P in LA/mUC demonstrated clinical efficacy compatible with the findings from the EV-302 trial. Our results showed comparable efficacy with EV-P in both UTUC and LUTC, highlighting it's broad therapeutic potential. However, clinical data at longer follow-up is required to fully evaluate overall survival and the durability of response. mUC LA Overall LUTC UTUC Total patients 98 62 36 22 BOR CR 23 (23.4%) 13 (20.9%) 10 (28.5%) 11 (50%) PR 49 (52.6%) 31 (50%) 18 (50%) 7 (31.8%) SD 6 (6.4%) 2 (3.2%) 4 (11.4%) 2 (9.0%) PD 10 (10.7%) 9 (15.5%) 1 (2.8%) 2 (9.0%) MR 7 (7.5%) 5 (8.6%) 2 (5.7%) 0 (0%)

Circulating tumor DNA as a prognostic biomarker to predict retroperitoneal histology in patients undergoing retroperitoneal lymph node dissection.

646 Background: Serum tumor markers (STM) are used in the management of patients with testicular cancer. However, a proportion have normal STM even with cancer present. Circulating tumor DNA (ctDNA) has shown promise in for detection of persistent disease. We sought to determine the utility of ctDNA for predicting retroperitoneal histology by comparing patients’ retroperitoneal lymph node dissection (RPLND) histology with their pre-operative ctDNA status. Methods: Patients undergoing primary (P-RPLND) or post-chemotherapy (PC-RPLND) from March 2023 to January 2024 had prospectively collected plasma ctDNA assay (Signatera, Natera Inc.) The association between ctDNA and RPLND histology was assessed. Sensitivity (SN), specificity (SP), and positive (PPV) and negative predictive values (NPV) were calculated for ctDNA to detect active cancer or teratoma alone in the RPLND histology. Results: Forty-six patients undergoing RPLND had pre-operative ctDNA collection with a median age of 33.5 (IQR:27-38.8). Plasma was collected on average, 8.6 days pre-operatively. Twenty (43.5%) patients underwent P-RPLND and 26 (56.5%) patients underwent PC-RPLND. ctDNA was positive in 23 (50%) patients. Two patients underwent P-RPLND for stage I disease and both had (-) ctDNA and histology. Eighteen patients underwent P-RPLND for stage II disease. Of these, 16 had active cancer, 1 had pure teratoma, and 1 had negative histology. ctDNA was positive in 15 of these patients all of which were found to have either teratoma or active cancer on pathology. Of the 3 patients with (-) ctDNA, 1 had negative histology, 1 had mixed, teratoma and seminoma, and 1 had pure seminoma. There were 26 patients who had ctDNA drawn prior to PC-RPLND. Of these, 4 had active cancer, 16 had pure teratoma, and 6 had necrosis on final RPLND histology. ctDNA was positive in 8 patients all of whom had either teratoma or active cancer on histology. Of the 18 PC-RPLND patients with a (-) ctDNA test, 1 had active cancer, 11 had teratoma, and 6 had necrosis. There were no false positive tests in the entire cohort. The SN, SP, PPV, and NPV were 85%, 77%, 74%, 87%, respectively for predicting active cancer. These numbers vary by primary or PC-RPLND patients (Table). Conclusions: To our knowledge, this is the first study evaluating test characteristics of ctDNA results in relation to RPLND histology. These findings suggest that ctDNA may be a useful adjunctive screening tool to predict active cancer or teratoma in the RP. Test characteristics of ctDNA stratified by primary or post-chemotherapy RPLND. Sensitivity Specificity PPV NPV P-RPLND GCT and/or Teratoma 88% 100% 100% 60% GCT only 88% 75% 93% 60% Teratoma only 100% 26% 7% 100% PC-RPLND GCT and/or teratoma 40% 100% 100% 33% GCT only 75% 77% 38% 94% Teratoma only 31% 70% 63% 39%

Peak Corticosteroid Dose for Immune-Related Adverse Events and Survival: Not the Whole Story

Clinical outcomes from a prospective study of comprehensive genomic testing in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

216 Background: In this prospective study at a community-based hospital, we conducted comprehensive genomic testing to identify pts with actionable variants. We previously showed that this resulted in identification of 38% of pts with a recommendation for treatment, predominantly with a PARP inhibitor (PARPI). We now report on the clinical outcomes of pts who received treatment based on this genomic testing. Methods: Pts with mCRPC had genomic testing with cfDNA using the PredicineCare NGS assay and germline and tissue (archival and metastasis) using the Northshore Expanded Cancer NGS Panel. Repeat cfDNA testing was done in pts when they showed cancer progression. Response to genomic-directed treatment (GDT) was evaluated by clinical or radiographic PFS (crPFS) and > 50% decrease in PSA from baseline (PSA50). Results: Of 138 enrolled pts, all had germline and cfDNA testing. Tumor tissue was obtained in 60 pts (archival 41%, metastasis 46%, both 13%). Repeat cfDNA testing was done in 25% of pts. Overall, 59 pts (43%) had a variant with a treatment recommendation. Testing with cfDNA alone identified 68% of which 28% were repeat. An HRR variant was detected in 57 pts (BRCA2 40%, ATM 14%, CHEK2 21%, CDK12 7%, other 13%). Of the 59 pts, 51% have received a GDT with a PARPI or pembrolizumab. Repeat cfDNA testing identified 27% of these pts. Reasons for no treatment included pts who had not yet received GDT as they were receiving effective treatment or pts with a poor performance status. The median crPFS was 4 months; 95% CI (1-11). There was no difference in PFS between pts with BRCA2 vs non-BRCA2 or repeat vs no repeat testing. A PSA50 was observed in 31% of pts (63% had a BRCA2). There was no difference between pts with BRCA2 vs non-BRCA2 or repeat vs no repeat testing. The median number of treatments for mCRPC prior to GDT was 2; 95% CI (1-6). There was a trend for longer PFS in pts receiving ≤ 2 vs > 2 prior treatments (5.3 vs 3.6 m; p=0.09). Of the pts receiving GDT, 57% had Group 4 or 5 Gleason, 37% had visceral metastasis, and 40% had > 10% weight loss. The median cfDNA fraction was 40.4%. Conclusions: In this prospective study done in a community setting, comprehensive genomic testing resulted in a relatively large number (43%) of pts with a treatment recommendation. Most of these pts (68%) were identified by cfDNA alone that also included repeat testing upon progression. Thus far, half of these pts have received a GDT with treatment available in the future for the others. The short PFS and low PSA50 are likely related to the pts being heavily pretreated and having a high tumor burden. This is expected in pts with late-stage mCRPC and corroborates the value of earlier use of GDT, although treatment in these pts still resulted in clinical benefit. Repeat cfDNA testing helped identify additional pts with a treatment recommendation, but further studies are required to define the validity of this testing.

Strong interface coupling for enhanced photoresponse in 1D BiInSe/2D WSe2 phototransistor

With the improvement of heterostructure preparation technology, research on the physical properties and device performance of mixed-dimensional heterostructures has been greatly developed. Numerous studies have focused on 2D/2D heterostructures, but research on 1D/2D heterostructures is comparatively limited, and the interface electron transfer mechanism needs to be further explored. In this study, we leverage the inherent band structure alignment characteristics of 1D Bi1.3In0.7Se3 and 2D WSe2 to create Bi1.3In0.7Se3/WSe2 heterostructure with Type-I band alignment. The results of PL, Raman, and KPFM prove the existence of a strong coupling effect at the heterostructure interface. The Bi1.3In0.7Se3 nanowire enhances the PL intensity and red-shifts the PL peaks of WSe2. This strong local electric field at the heterojunction interface improves the photoresponse performance of the Bi1.3In0.7Se3/WSe2 heterostructures devices. They achieve excellent photoresponce properties in a wide spectral range from solar-blind ultraviolet C (254 nm) to near-infrared (980 nm) region, with a large responsivity of 98 A/W, a high detectivity of 1.16 × 1013 Jones, and a fast photoresponse time of 500 μs. In addition, the optoelectronic performance of the device is controlled by modulating the Fermi level of the heterostructure by the applied gate electric field. Our work paves the way for the development of 1D/2D heterostructures for multifunctional optoelectronic applications.

Reconstruction of porous media pore structure and simulation effect analysis of multi-index based on SNESIM algorithm

Abstract The pore structure of porous media directly affects its permeability characteristics and fluid flow properties, making the accurate reconstruction of these structures of great significance. In recent years, multi-point statistics (MPS) methods have been widely used in pore structure modeling. Among them, the SNESIM algorithm, as an advanced MPS technique, has been extensively applied in the study of porous media pore structures. This paper aims to investigate the use of the SNESIM algorithm for reconstructing pore structures on 2D core slices with varying porosities, all taken from the same core. It also analyzes the effectiveness, limitations, and applicable conditions of the algorithm. This study utilizes CT scan images to construct digital core technology and applies the SNESIM algorithm to reconstruct pore structures of core slices with different porosities. By analyzing performance parameters such as porosity, pore throat ratio, average grain radius, coordination number, and permeability, the study shows that the reconstructed images(RI) from most samples maintain a trend similar to that of the training images(TI), demonstrating the good applicability and reliability of the SNESIM algorithm in pore structure reconstruction. However, the core slices used in this study were all taken from the same core. Effectively transferring the pore structures from the 2D plane to the 3D pore space and restoring the pore structures to the greatest extent still requires further research. In particular, when dealing with complex pore structures, the accuracy and performance of the SNESIM algorithm need further improvement. Future research will focus on optimizing the algorithm to handle more diverse pore structures and exploring 3D reconstruction methods to more comprehensively describe and analyze the pore characteristics in actual porous media.

Optimizing clear cell renal cell carcinoma tumor-infiltrating lymphocytes under controlled hypoxic conditions.

581 Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) represents a promising approach for advanced solid tumor treatment. Historically, the success of TIL therapy in clear cell renal cell carcinoma (ccRCC) has been limited by difficulty expanding cytotoxic functional TILs. Hypoxic conditions in the ccRCC tumor microenvironment have been associated with mixed tumor characteristics, including metabolic dysregulation and tumor progression. Given the significant role of hypoxia in ccRCC progression, we investigated TIL expansion under controlled hypoxic conditions and its impact on TIL cytotoxic functions. Methods: Fragments or tumor digests from 41 ccRCC patients were cultured with high-dose (6000IU/mL) IL-2 for four weeks. TIL expansion success was defined as at least one fragment expanding to a minimum of 2 wells. Primary TIL underwent rapid expansion protocol (REP) at 20% (normoxic) or 5% (hypoxic) O 2 levels. Cells were rested in post-REP media for 3–4 days in their respective conditions (20% or 5% O 2 ) and subsequently collected for downstream analysis. Reactivity to autologous tumor, expression of activation/co-inhibitory markers, and memory phenotype were analyzed with flow cytometry and co-culture assays. Results: TILs were successfully grown in 87.8% of samples (36/41). TILs secreted IFNγ in response to autologous tumors in 88.6% (31/35) of the samples. Both TIL expansion and reactivity occurred independently of tumor stage or grade. TIL REP under hypoxic conditions (5% O2) was successful, and these conditions salvaged more CD8+ TILs compared to normoxic conditions (p=0.0382). Hypoxic REP TILs showed increased IFNγ, TNFα, and Granzyme B release in response to autologous tumor compared to normoxic conditions. Additionally, hypoxic REP TILs expressed higher LAG3 and TIM3 markers (p<0.05), with significantly increased proportions of tissue-resident memory-like (TRM) CD8+ T-cells (CD69+CD103+) compared to normoxic conditions (18.2% CD69+CD103+ versus 2.6%, respectively, p<0.0001). These features have been associated with clinical responders TILs in melanoma. Conclusions: This study demonstrates the feasibility of expanding tumor-reactive TILs from ccRCC despite tumors harboring exhausted CD8+ T-cells. Exposing TILs to hypoxic conditions enhanced effector functions and promoted the acquisition of a TRM T-cell phenotype. These findings suggest that ccRCC TIL expansion under controlled hypoxia is feasible and could confer improvement to the clinical efficacy of TIL therapy for ccRCC.

Prognostic significance of tumor immune microenvironment dynamics in prostate cancer induced by androgen deprivation therapy.

398 Background: The dynamics of the prostate cancer microenvironment through androgen regulation are unclear. In this study, we analyzed the relationship between the dynamics of the immune microenvironment and prognosis after androgen deprivation therapy. Methods: We retrospectively reviewed the patients who underwent radical prostatectomy at our institution. Among them, 104 patients received prostate needle biopsy and neoadjuvant androgen deprivation therapy at the same institution. These cases were compared before and after androgen deprivation therapy. Immune cell infiltration in the cancer areas was assessed using multiplex fluorescent immunohistochemistry. Transcriptome analysis and gene panel analysis by next-generation sequencing were used to systematically and comprehensively analyze the expression and mechanisms of the immune microenvironment. Results: Few immune cells were detected in the needle biopsies before androgen deprivation therapy. After androgen deprivation therapy, prostatectomy specimens showed a significant change in various immune cells, including CD4 + T cells, CD8 + T cells, Foxp3 + regulatory T cells, CD204 + macrophages, and CD20 + B cells (P< 0.001). In particular, CD8 + T cells and CD20 + B cells were significantly increased compared to patients who did not receive androgen deprivation therapy followed by total prostatectomy (P<0.001). Clustering analysis allowed stratification into three groups: One group had a predominant increase in CD8 + T cells after androgen deprivation therapy, another group had a predominant increase in CD20 + B cells, and the third group had no significant increase. The group with increased CD8 + T cells had a significantly higher 5-year biochemical recurrence rate of 56 % (P=0.045). Differences in the mechanisms of androgen metabolism were observed among these cases. Conclusions: Differences in immune induction after androgen deprivation therapy have an impact on the prognosis of prostate cancer.

Clinicopathological characteristics of cancer of unknown primary (CUP) with renal profile using gene expression profiling (GEP) based cancer classification.

456 Background: CUP is a rare and heterogenous clinicopathologic syndrome with unidentifiable origin at time of diagnosis. Based on immunophenotyping, specifically PAX8 staining, CUP with Renal profile (RCUP) is emerging as a distinct clinical subset. In addition to clinical presentation and immunohistochemistry (IHC), molecular profiling for tissue of origin may aid defining CUP subsets. Precision in diagnosis impacts therapeutics given that cytotoxic chemotherapy options for CUP do not overlap with tyrosine kinase inhibitors or checkpoint inhibitors used for renal cell carcinoma. Methods: We retrospectively (2018-2022) evaluated patients with CUP composed of cases (renal profile, N=100, clear cell or papillary) or controls (non-renal, N=200) identified using the 92-gene assay (CancerTYPE ID), a validated classifier for predicting tissue of origin. Clinicopathologic data including IHC and molecular profiling results were collected using pathology specimens and reports. Results: Baseline characteristics (age, gender, tumor grade) of cases and controls were comparable, except for histology, wherein adenocarcinoma was less common with RCUP (27% vs 48%, p<0.001). Median number of IHC stains performed was 11 (range 0-30) vs 9 (0-29) (p=0.04) in RCUP vs non-renal cases, respectively. While PAX8 was tested in 64% vs 39% (p<0.001) of cases, it was found to be strongly or focally positive in 87.5% vs 21.8% (p<0.001), respectively. In contrast to non-renal CUP, RCUP patients were more likely to have bone biopsies (24% vs 11.5%, OR 2.4, p=0.007), less likely to have high-TMB (2.8% vs 28.2%, OR 0.07, p=0.001), and had a lower proportion of TP53 mutations (18.8% vs 89.2%, OR 0.028, p<0.001), KRAS mutations (13.3% vs 77.4%, OR 0.045, p<0.001) and BRAF mutations (0% vs 42%, OR 0, p=0.015). Conclusions: RCUP appears to be a distinct subset of CUP with variable diagnostic workup. Critical IHC markers may be omitted in a considerable number of cases and despite positivity, may still confer an uncertain diagnosis. Key molecular factors appear to be different and may require tailored therapeutic approaches. This study further supports the clinical utility of GEP-based cancer classification with the 92-gene assay to predict RCUP and may be an important adjunct to IHC to improve diagnostic accuracy for CUP and to guide treatment selection for better clinical outcomes. RCUP (N=100) Non-renal CUP (N=200) IHC Cases Tested (%)   Cases Positive (%)   Cases Tested (%) Cases Positive (%)   CK7  83  47  81 75* CK20  75  11 77 24* PAX8  64*  88* 39 22 Napsin  29  28* 25 8 RCC 26* 31 4 13 Vimentin  17  94 5.5 73 *Significantly (p<0.05) greater proportion of cases.

An open-label phase 1, window-of-opportunity study of ultrasound-guided long acting periprostatic neuraxial block with ethanol in patients with high-risk prostate cancer.

391 Background: Patients (pts) with high-risk prostate cancer (PCa) have an elevated risk of disease recurrence/progression after definitive therapy. These pts also exhibit increased levels of adrenergic nerve density on PCa histology. Pre-clinical evidence from murine models of PCa suggest that PCaNeurolysis of periprostatic adrenergic nerves inhibits cancer progression and metastasis by inhibiting angiogenesis, altering cancer metabolism, and inhibiting cell migration (PMC5783182). Pure Ethanol (>99%) injection for neurolysis is FDA-approved in chronic cancer pain and may have a survival benefit in late-stage cancers (PMC1242819). Ultrasound-guided (US) short-acting periprostatic neuraxial block with lidocaine is commonplace in urologic practice. Thus, PCaNeurolysis with ethanol may have both a protective effect in high risk PCa and be feasibly implemented. Methods: Pts with NCCN high risk PCa who were interested and eligible for surgery, and who did not have any prior PCa treatments received in-office US guided PCaNeurolysis with either 3mL or 5mL of pure ethanol 4 to 6 weeks prior to radical prostatectomy (surgery was not delayed for trial participation). Dose escalation was determined by keyboard design with 6 pts per group (dose limiting toxicity [DLT] period = 6 weeks; DLT ³ Grade 3 events). Results: Dose escalation: 12 pts, median age 68, were treated at 2 dose levels: 3/5mL (n=6/6) with no DLTs in either group, suggesting 5mL was maximal tolerated dose to use in future studies. Additionally, no off-target effects including no decrease in erectile function (Sexual Health Inventory for Men score), no increase in urinary symptoms (International Prostate Symptom Score), and no added difficulty (eg. Destruction of tissue planes) during prostatectomy were observed in any pts. 7 pts underwent prostatectomy (43% cT3a) and were included in secondary analysis: median decrease in adrenergic density on final pathology (35%), ≥pT3a (0%), 18month biochemical recurrence (14%). Conclusions: PCaNeurolysis with ethanol was well tolerated, and 5mL was the maximum tolerated dose to use in future studies. Histologically significant decrease in adrenergic nerve density was observed suggesting the intervention acts upon its intended target, and the intervention may have antitumor activity (43% pre-injection cT3a, but 0% ≥pT3a on final pathology after injection). These Phase 1 results encourage continued investigation of PCaNeurolysis in high risk PCa pts.

Heterostructure and interfacial engineering for low-resistance contacts to ultra-wide bandgap AlGaN

We report on the heterostructure and interfacial engineering of metalorganic chemical vapor deposition (MOCVD) grown reverse graded contacts to ultra-wide bandgap AlGaN. A record low contact resistivity of 1.4 × 10−6 Ω cm2 was reported on an Al0.82Ga0.18N metal-semiconductor field effect transistor by compositionally grading the contact layer from Al0.85Ga0.15N → Al0.14Ga0.86N with degenerate doping and proper interfacial engineering considering bandgap-narrowing-induced band offset between the channel and the contact layer. This represents orders-of-magnitude of lower contact resistivity than that obtained in similar MOCVD-grown structures. A detailed, layer-by-layer analysis of the reverse graded contact and TCAD simulation of the bandgap narrowing effect highlighted that the reverse graded contact layer itself is extremely conductive, and interfacial resistance due to bandgap-narrowing-induced barrier between contact and channel dominates the contact resistance.

Metabolomic profile of severe COVID-19 and a signature predictive of progression towards severe disease status: a prospective cohort study (METCOVID)

Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.

LBA18 Background: The Phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression-free survival (rPFS) for TALA + ENZA vs placebo (PBO) + ENZA as 1L treatment in pts with mCRPC unselected for homologous recombination repair (HRR) gene alterations (all-comers; cohort 1). Here we report final OS data, a descriptive update of rPFS, and extended safety follow-up in cohort 1. Methods: In cohort 1, pts were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive PC and HRR gene alteration status. Key eligibility criteria included asymptomatic or mildly symptomatic mCRPC, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC. The primary endpoint was rPFS by blinded independent central review. OS was an alpha-protected key secondary endpoint. For statistical significance at the final OS analysis, the stratified log-rank 2-sided P value needed to be ≤0.022 using a group sequential design with O’Brien-Fleming spending function. Results: Overall, 805 pts were randomized, 402 to TALA+ENZA and 403 to PBO+ENZA. At data cutoff (Sept 3, 2024), 211 pts (52%) in the TALA + ENZA arm and 243 pts (60%) in the PBO + ENZA arm had died; median follow-up was 52.5 and 53.0 months, respectively. Hazard ratio (HR) for OS with TALA + ENZA vs PBO + ENZA was 0.796 (95% CI, 0.661–0.958; 2-sided P =0.0155); median OS (95% CI), 45.8 months (39.4–50.8) vs 37.0 months (34.1–40.4 months), respectively. In prespecified subgroup analyses, OS favored TALA + ENZA vs PBO + ENZA in pts who were HRR-deficient (n=169; HR, 0.549; 95% CI, 0.364–0.826; P =0.0035) or HRR–non-deficient/unknown (n=636; HR, 0.878; 95% CI, 0.713–1.080; P =0.218). In exploratory analyses of pts with results available for both circulating tumor DNA and tumor tissue, OS favored TALA + ENZA vs PBO + ENZA in pts without BRCA1/2 alterations (n=439; HR, 0.749; 95% CI, 0.582–0.963; P =0.024) and in pts without HRR alterations (n=314; HR, 0.782; 95% CI, 0.582–1.050; P=0.101). Consistent with the primary analysis, updated rPFS data favored TALA + ENZA vs PBO + ENZA (HR, 0.667; 95% CI, 0.551–0.807; P <0.0001); median rPFS, 33.1 vs 19.5 months, respectively. Consistent with primary results, the most common grade ≥3 TEAEs with TALA + ENZA were anemia (49%) and neutropenia (19%). TEAEs were generally manageable; 86 pts (22%) discontinued TALA due to TEAEs. Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in OS vs standard-of-care ENZA as 1L treatment in pts with mCRPC unselected for HRR gene alterations. rPFS continued to favor TALA + ENZA. No new safety signals were identified with extended follow-up. Clinical trial information: NCT03395197 .

Evaluating the impact of a community-based prostate cancer screening program.

324 Background: One out of eight men in the U.S. will be diagnosed with prostate cancer during his lifetime. Early detection, often by routine screening, allows for more options for treatment and an increased chance of survival. Barriers to screening exist and may contribute to prostate cancer disparities, particularly among Black males and those who lack regular access to health care. Community based screening programs may be an effective way to overcome barriers to prostate cancer screening. Methods: An urban, NCI-designated cancer center collaborated with community partners and a national prostate cancer advocacy organization to provide free screening to males in our catchment area. Community partners identified the location of the screening and promoted the event. Participants completed a survey about their personal and family history of prostate cancer. A mobile screening team within the cancer center conducted the screenings, consisting of prostate specific antigen (PSA) tests. All participants received a letter with their PSA test results; males with an abnormal result (> 3 ng/mL) also received a phone call. Survey data was analyzed with descriptive statistics and bivariate analyses (ANOVA). Results: Two hundred and eighty-nine (n=289) males were screened at a community screening event. The mean age of males screened was 57.3 (SD=11.2) and the majority identified as Black (N=253, 84.9%). The mean PSA test value was 1.82 (SD= 2.70); 14% of males had an abnormal PSA test result. Black males had the highest PSA values of among all men who were screened. Conclusions: Disparities in prostate cancer, particularly among Black males, warrant interventions like community-based prostate screening events that reduce barriers of cost and access, bringing screening to those who would most benefit. Mean PSA test results by patient characteristics. N Mean PSA Level Sum of Squares, DF Between Groups Within Groups F p Full Sample 298 1.82 Race/Ethnicity 3; 19.62 271; 1876.18 0.94 0.42 Black 246 1.85 Hispanic 18 0.80 White 9 1.48 Other 2 1.59 PSA in the last 3 years, # tests 3; 19.43 260; 1861.65 0.91 0.44 0 121 1.62 1-3 133 1.82 4-6 6 3.40 7+ 4 2.08 Family history of PCa, # of relatives 2; 54.09 287; 2051.72 3.78 0.024* 0 215 1.78 1 63 1.50 2+ 12 3.84 Family history of PCa genetic risk, # of relatives 2; 11.75 287; 2094.06 0.81 0.45 0 229 1.71 1 52 2.24 2+ 10 1.96 Smoking status 4; 31.74 256; 1815.53 1.12 0.35 Current 26 2.19 Former, quit within 10 years 8 0.93 Former, quit within 11-19 years 8 1.46 Former, quit more than 20 years ago 20 2.75 Never 199 1.68 Diet, fat intake 2; 9.49 272; 1888.09 0.68 0.51 Low 60 1.65 Medium 186 1.71 High 29 2.29 Chemical Exposure 1; 2.80 257; 1824.87 0.39 0.53 Not exposed 210 1.72 Exposed 49 1.97 *Indicates significance (p <0.05).

Reply to: Peak Corticosteroid Dose for Immune-Related Adverse Events and Survival: Not the Whole Story

Survival impact of concomitant squamous differentiation in upper tract urothelial carcinoma patients receiving adjuvant chemotherapy.

729 Background: Adjuvant platinum-based chemotherapy after radical nephroureterectomy (RNU) was a strong recommendation for patients with pT2–4 and/or pN+ upper tract urothelial carcinoma (UTUC). However, the efficacy of adjuvant chemotherapy (AC) on UTUC with squamous differentiation (UTUCSD) remains unclear. This study was conducted to investigate survival impact of SD on UTUC patients receiving AC, and further assessed the efficacy of AC on UTUCSD. Methods: Data of 868 UTUC patients who underwent RNU at West China Hospital of Sichuan University from May 2003 to June 2021 were retrospectively included, and only patients with the history of postoperative adjuvant chemotherapy were further analyzed. The end points included overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Propensity score matching (PSM), Kaplan‒Meier curves and Cox proportional hazard model were utilized. Results: Overall, the prevalence rate of UTUCSD is 10.7% (93/868), and UTUCSD significantly tended to be locally advanced (pT>2), high grade and lymph node metastasis (LNM) disease. After PSM for tumor stage, grade, and LNM, 32 paired cohorts at a ratio of 1 to 3 among patients received chemotherapy (according to the presence/absence of SD) were derived. Compared with pure UTUC patients receiving AC, UTUCSD patients showed significantly inferior OS (HR 1.99, 95% CI 1.06-3.71) and CSS (HR 1.95, 95% CI 1.09-3.47) but comparable MFS (HR 1.33, 95% CI 1.0.71-2.50). Furthermore, AC could not bring significant survival benefit to patients with UTUCSD in terms of OS (HR 0.73, 95% CI 0.40-1.31) and CSS (HR 0.88, 95% CI 0.46-1.69). Conclusions: Concomitant SD acted as an inferior survival predictor among UTUC patients receiving AC. UTUCSD is less sensitive to chemotherapy and effective treatments need to be further studied.

Al2O3/<i>in situ</i> GaON gate dielectrics incorporated GaN MIS-HEMTs with stable VTH and significantly reduced interface state density

This work reports a metal–insulator–semiconductor High-Electron-Mobility-Transistor (HEMT) with Al2O3/in situ GaON bi-layer gate dielectric for improved threshold voltage (VTH) stability and reduced interface state density. With a combination of in situ GaON and large bandgap Al2O3 on top of the recessed gate region, normally-off HEMT was achieved with high On/Off current (ION/IOFF) ratio of 109, low VTH hysteresis less than 60 mV, and low-interface trap density (Dit) in the range of 4 × 1011–2 × 1012 cm−2·eV−1. Thanks to the sharp GaN/oxide interface with narrow distribution of lattice constant, uniform strain distribution and significantly reduced trap density were obtained. More importantly, our proposed bi-layer gate dielectric is perfectly compatible with the conventionally utilized gate recessing technique compared to the conventionally utilized in situ SiNx, demonstrating itself as a promising candidate in GaN power devices.