Browse Articles

Understanding health inequalities based on socio-economic factors and geographical location in renal cell carcinoma: A large-scale national cohort study in England.

464 Background: Kidney cancer is 7 th most common cancer in England with renal cell carcinoma (RCC) accounting for about 80% of all cases of kidney cancer. It has well established that the incidence and mortality rates of RCC are strongly associated with four main risk factors, including family history, lifestyle, environment, and occupation. In addition, unequal access to improvements in RCC cancer treatment and limited access to screening and diagnosis, significantly contribute to the difference observed in survival rate. Methods: We aim to assess the association between area-level measures of socioeconomic deprivation, from the 20% most deprived of the population (quintile 1) to the 20% least deprived (quintile 5), or geographical regions in England, with both the diagnosis and treatment of RCC, over five years from April 2019 to March 2024. This study utilized patient-level data for primary and metastatic renal cancer (ICD-10: C64) by organisation, procedure, ethnicity, age group and deprivation quintile from Hospital Episode Statistics (HES). Results: Among 54,535 included patients, 9,935 (18.2%) came from the most deprived quintile and 11,330 (20.8%) from the least deprived quintile with a mean age of 62 years across all patients. Of included patients, 43,290 (79.3%) were Caucasian (white) and the remaining 14,235 patients came from other ethnic groups. In total, 61.0% of patients were middle aged (aged from 45 to 74), with 35.0% elderly (75 and above) and 5.4% classed as young (below 45). Caucasian populations have higher rates of metastatic disease (34.6%) vs non white (29.6%). Prevalence of metastatic disease increases with age (24.1% vs 33.3% vs 34.6% in young, middle aged and elderly respectively). Higher deprivation is associated with lower rates of nephrectomy (42.3% in most deprived vs 43.6% in least deprived). Patients in areas of higher deprivation are on average younger than those in least deprived areas (57 years in most deprived vs 64 in least deprived) while non-white renal cancer patients are also typically younger (57 non-white vs 64 white). The Midlands (central England) region is associated with the highest rates of metastatic cancer (37.4%) while North East & Yorkshire (30.8%) and London (31.1%) has the lowest metastatic disease rates. Conversely, total nephrectomy rates are highest in North East & Yorkshire while they are lowest in the South West region and London (46.6% vs 42.8% vs 43.0% respectively). Conclusions: This study presents the most recent and extensive RCC data from England, exploring the impact of socioeconomic status and geographical location in diagnosis and management of RCC. These findings could facilitate targeted initiatives to improve health inequity across regions in England.

<i>NECTIN4</i> RNA expression and clinical outcomes with first-line (1L) platinum-based chemotherapy (PBC) and avelumab 1L maintenance in locally advanced or metastatic urothelial carcinoma (la/mUC): Exploratory analyses from JAVELIN Bladder 100.

827 Background: Nectin-4 is widely expressed in UC tumors, although protein expression levels vary between patients. Prior analyses have suggested that low overall Nectin-4 expression based on immunohistochemistry may be associated with worse outcomes in patients with advanced UC irrespective of treatment. We report exploratory biomarker analyses from the JAVELIN Bladder 100 phase 3 trial evaluating response to 1L PBC and survival outcomes with avelumab administered as 1L switch-maintenance treatment in subgroups defined by tumor NECTIN4 RNA expression. Methods: In JAVELIN Bladder 100 (NCT02603432), patients with unresectable la/mUC without progression after 4-6 cycles of 1L PBC were randomized to receive avelumab 1L maintenance + best supportive care (BSC) or BSC alone. Whole-transcriptome profiles in tumor samples (primary tumors in ≈75%) were generated using RNA sequencing, and transcript levels were quantified using Personalis ACE technology. NECTIN4 RNA expression was assessed as a continuous variable for subgroups defined by response to 1L PBC, and as a dichotomous variable (median split) for survival analyses. Results: In biomarker-assessable patients enrolled in JAVELIN Bladder 100, no significant differences were observed in tumor NECTIN4 RNA expression in patients who had complete response (n=149), partial response (n=261), or stable disease (n=150) to 1L PBC (Kruskal-Wallis p=0.192). In subgroups with high or low NECTIN4 RNA expression, overall survival (OS) and progression-free survival (PFS) improvements with avelumab + BSC vs BSC alone were consistent with improvements observed in the overall study population (Table). No significant differences in OS and PFS were observed between subgroups with high or low NECTIN4 RNA expression within the avelumab + BSC (p=0.26 and 0.89) and BSC alone (p=0.34 and 0.94) arms. Limitations include ad hoc exploratory analysis and potential selection bias. Conclusions: Exploratory analyses from JAVELIN Bladder 100 suggest that NECTIN4 RNA expression was not prognostic or predictive of level of response to 1L PBC or survival with avelumab 1L maintenance treatment in patients with la/mUC without progression after 1L PBC. Clinical trial information: NCT02603432 . Avelumab + BSC BSC alone High NECTIN4 RNA expression n=139 n=140 Median OS (95% CI), months 22.0 (18.2-30.9) 14.8 (12.9-19.4) Median PFS (95% CI), months 5.65 (4.60-9.00) 3.29 (1.97-3.75) Low NECTIN4 RNA expression n=145 n=136 Median OS (95% CI), months 30.0 (21.4-35.2) 18.7 (13.7-25.5) Median PFS (95% CI), months 5.65 (3.81-9.95) 2.20 (1.91-3.71)

Prostate cancer risk groups by PSMA-PET PROMISE (PPP): Results from an international multi-center registry study.

266 Background: We previously established prognostic nomograms of PSMA-PET standardized by Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria in a large single-center cohort. Now, we reassess the PSMA-PET PROMISE (PPP) prognostic nomograms in a large international multi-center registry study with overall survival follow-up. Methods: We included patients with histologically proven prostate cancer who underwent PSMA-PET at 20 hospitals in Germany, Italy, Sweden, Netherlands, Belgium, Slovakia, Austria, United States and Australia between 2014 and 2021. PSMA-PET was standardized by molecular imaging TNM (miTNM). Total tumor volume in L, PSMA expression score and overall survival follow-up were obtained. The cohort was randomly split 2:1 into development and validation cohorts. In the development cohort we assessed PPP predictors and created visual and quantitative PPP nomograms based on Cox regression models with least absolute shrinkage and selection operator penalty for overall survival. Performance of both nomograms was measured in the validation cohort using Harrell´s C-index and calibration plots. Head-to-head comparison to the NCCN risk score was examined by ROC-curves. Results: We analyzed 6128 male patients (4075 development and 2053 validation) across all disease stages with 1915 (31.2%) reported deaths and median follow-up of 4.77 years [IQR 3.38-6.44]. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases [M1a], bone metastases [M1b; oligometastatic disease, disseminated or diffuse marrow involvement], and organ metastases [M1c]), PSMA expression score and total tumor lesion count. Predictors in the reassessed quantitative PPP nomogram were distant metastases (M1a, M1b, and M1c), tumor volume and PSMA expression score. C-indices (95% CI) in the validation cohort were 0.812 (0.794; 0.830) for the visual and 0.821 (0.805; 0.837) for the quantitative nomogram, respectively. For three-tier stratification (high, intermediate, low risk), accuracy of both PPP nomograms was superior when compared to the NCCN risk score (n=3638, visual: AUC 0.828 vs. 0.756; p&lt;0.0001 and quantitative: AUC 0.837 vs. 0.756; p&lt;0.0001). Conclusions: PSMA-PET PROMISE nomograms in an international multi-center study accurately stratify high vs. intermediate vs. low-risk groups for overall survival across all stages of prostate cancer and yield superior accuracy compared to the NCCN risk score. Follow-up continues in the PROMISE Registry (NCT06320223, promise-pet.org).

Impact of specimen type on digital histopathology-based multimodal artificial intelligence (MMAI) biomarker risk score: Whole slide image vs tissue microarray.

400 Background: The ArteraAI Prostate Test (v1.2), a digital pathology-based multimodal artificial intelligence (MMAI) biomarker, was developed and validated using clinical data (age, T stage, PSA) and whole slide images (WSI) from prostate biopsies to prognosticate risk of 10-year distant metastasis for men with localized prostate cancer (PCa). This study aimed to apply the MMAI biomarker to prostatectomy (RP) tissue microarray (TMA) samples and, for the first time, explore the impact of using RP TMA in place of RP WSI on MMAI scores. Methods: The analysis cohort included men with localized PCa who had undergone RP. Black men were matched in a 4:1 ratio to White men with similar baseline characteristics. MMAI scores were generated using digitized TMA and WSI from each patient’s RP specimen. The normality of score distribution was examined using the Shapiro-Wilk (SW) test. Wilcoxon signed rank (WSR) test and Spearman rank coefficients were used to compare TMA-derived and WSI-derived scores. Analyses were performed in the entire cohort and Black or White subgroups. Results: Paired MMAI scores were generated for 98 men with a median age of 58, PSA 5.4 ng/mL, the majority were Gleason grade groups 1-2 (84%), 82% were Black. The distribution of TMA-derived scores (SW test, P=0.04) was more skewed than that of WSI-derived scores (SW test, P=0.39). The median MMAI score was significantly higher for WSI images than for TMA images in all men and in Black men (WSR test, P&lt;0.01). There was no notable variation in either set of scores by race (Table). The correlation coefficient was 0.496 (0.519 for Black men). Using pre-specified cutoffs in MMAI scores (high, intermediate, low), 30/98 (31%) men were classified into lower risk groups by TMA than WSI scores (23/80 [29%] Black men). Conclusions: In this application of the MMAI biomarker to RP samples within this cohort of primarily Black men, we found WSI-derived and TMA-derived MMAI scores to be significantly different but moderately correlated. Given that TMA represents only a portion of WSI and sampling location may impact the results, TMA may be insufficiently reliable for MMAI score generation. MMAI biomarkers that are robust across different specimen preparation methods have potential for clinical and research utility; these hypothesis-generating results support further research along these lines. Continuous MMAI scores and categorical MMAI risk group distribution using WSI- and TMA-derived images by subgroup. WSI-derived score TMA-derived score Patients Continuous 1 Low 2 Int 2 High 2 Continuous 1 Low 2 Int 2 High 2 All 0.47(0.44-0.53) 0(0%) 69(70%) 29(30%) 0.37(0.33-0.42) 6(6%) 87(89%) 5(5%) Black 0.47(0.45-0.51) 0(0%) 58(73%) 22(27%) 0.37(0.33-0.43) 4(5%) 73(91%) 3(4%) White 0.48(0.43-0.54) 0(0%) 11(61%) 7(39%) 0.37(0.32-0.41) 2(11%) 14(78%) 2(11%) 1 Presented as median (IQR). 2 Presented as n (%).

Oxygen impurities in AlN and their impact on optical absorption

Oxygen is a common impurity in AlN samples. Using hybrid density functional calculations, we investigate the role of substitutional oxygen (ON) in the optical absorption. We construct configuration coordination diagrams for ON and related complexes. Our results indicate that an optical transition involving ON− (a DX center) gives rise to an absorption band peaked at 2.22 eV, suggesting it is a source of the absorption band with an onset at ∼ 2 eV observed in oxygen-containing samples. We also propose that neutral ON–DX complexes can form, which would give rise to absorption peaking at 3.06 eV. In addition, we find that oxygen, in spite of its DX character, may behave as an “optically shallow donor” and be involved in optical transitions from deep defect states to the conduction band. This observation provides an alternative physical mechanism for the optical absorption bands observed in AlN samples in the visible and ultraviolet (UV) region.

The accuracy of capture per unit effort in predicting density of a cryptic snake was more sensitive to reductions in spatial than temporal coverage

A critical component of monitoring wildlife populations is understanding changes in population size or abundance. However, for most populations a complete census is not possible; thus, trends or abundance need to be estimated through alternative means, such as indexes. An important aspect of using indexes, such as capture per unit effort (CPUE), is validating them as accurate or precise predictors of population trends or abundance. We completed such analyses using data collected from visual surveys and trapping for brown treesnakes (Boiga irregularis) within a 5-ha enclosure that was undergoing a continuous population decline. During a ~ 6-year period, we censused and marked the snake population to fully enumerated the population, with new individuals resulting from births and removals resulting only from mortality (natural or experimental). From trapping and visual surveys, we were also able to calculate CPUE as a function of trap nights or km surveyed and used regressions to forecast snake density (snakes/km) in the enclosure from CPUE. We also rarefied the true dataset to measure whether reductions in sampling intensity, either temporally or spatially, affected the accuracy or precision in predicting snake density from CPUE. We found that trap CPUE demonstrated no statistical relationship to density based on our study methods. CPUE during visual surveys did predict actual density, with sufficient spatial and temporal sampling intensity. CPUE from visual surveys was relatively robust against reductions in temporal sampling when spatial intensity remained high. However, reductions in the spatial area covered to less than 50% of the enclosure rapidly reduced the accuracy and precision in using CPUE to forecast density. Our results indicate that visual surveys are a relatively accurate measure of true density for brown treesnakes, given sufficient spatial sampling effort. The spatial area of coverage required for CPUE to accurately predict changes in abundance was, however, intense with &gt; 50% of the spatial area required to be sampled on a given sampling night. Our results indicate that CPUE is only reliable as an index of abundance or population trends for cryptic snakes, if sampling effort covers most of the landscape over which populations are being estimated.

Magnetic surgical marker navigation for excision of non-palpable ultrasound visible breast lesions: first 200 cases in a French cancer center

Efficacy and safety of fexagratinib (Fexa) in Chinese patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) harboring FGF receptor (FGFR) genetic alterations.

790 Background: Fexagratinib (former AZD4547), a selective and potent oral inhibitor of FGFR1-3, has shown promising efficacy and safety in phase I trials among solid tumor pts with FGFR1-3 alterations, including mUC. This study (NCT05086666) aimed to assess efficacy and safety of Fexa in previously treated Chinese mUC pts with FGFR alterations. Methods: Pts with mUC harboring FGFR3 alterations (including activating mutations or fusion detected via NGS panel) who failed at least 1 prior therapy or were platinum- ineligible, were enrolled. Pts received continuous oral Fexa 80mg BID until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST v1.1. Results: As of data cutoff (14 Jun 2024), a total of 35 pts were enrolled, of those 80% were male with a median age of 66 years (range 41-86). Most pts (85.7%) had ECOG PS≤1, 43% had a creatinine clearance &lt;60 mL/min, 66% had received ≥ 1 prior therapies, 66% had been treated with PD-(L)1. The primary tumor site was reported in the upper tract in 40% of pts, and 25.7% had liver metastases. The best overall responses assessed by IRC was 34.4% (95% CI, 18.6%-53.2%) in 32 evaluable pts, including 9 confirmed partial responses (cPRs), 2 unconfirmed PRs. Ten (37.0%) of 27 evaluable pts harboring FGFR3 mutation achieved at least one PR. Among 15 pts who experienced progression after PD-(L)1 treatment, 5 pts (33.3%) achieved cPRs. Median PFS by IRC was 3.6 (2.8, 6.1) months. Most common treatment-related adverse events (TRAEs) were anemia (40.0%), nail disorder (40.0%), hyperphosphatemia (37.1%) and hyponatremia (34.3%). Grade ≥3 TRAEs were reported in 54.3% of the pts, incidence &gt;5% included pneumonia(5.7%), anemia (5.7%) and hand-foot syndrome (5.7%). Conclusions: Fexa was generally well tolerated in previously treated Chinese mUC pts, with no new safety signals identified. The efficacy observed was consistent with that previously reported in western populations, with notable benefits seen in pts with FGFR alterations who had experienced disease progression following PD-(L)1 treatment. Clinical trial information: NCT05086666 .

PRO-XL: A phase II study of zanzalintinib (XL092) in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on lutetium-177 (177Lu)-PSMA-617.

TPS285 Background: 177Lu-PSMA-617 has been approved for patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy after demonstrating improvement in overall survival (OS) in the phase III VISION trial (PMID: 34161051). However, the tumor eventually develops resistance to 177Lu-PSMA-617 and progresses, and therefore, therapies are needed to treat 177Lu-PSMA-617 refractory mCRPC. Prior studies have demonstrated a significant VEGF expression in LNCaP tumors and locally recurrent prostate cancer after radiotherapy. Also, tumor recurrence largely depends on new vessel formation through angiogenesis when radiation inhibits angiogenesis. Zanzalintinib is a novel, potent, orally bioavailable small molecule multi-targeted inhibitor of kinases, including the receptor tyrosine kinases (RTKs), VEGFR2, MET, and TAM kinases AXL, and MER, which have been shown to be overexpressed in radiation-resistant tumors. Therefore, zanzalintinib is expected not only to inhibit tumor angiogenesis but also to mitigate resistance to antiangiogenic therapy over time. We initiated a phase 2 trial of zanzalintinib in pts with mCRPC after progression on 177Lu-PSMA-617. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 30 patients. Zanzalintinib will be administered orally at 100 mg once daily. Eligibility criteria: ≥ 18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, progression on or after prior treatment with 177Lu-PSMA-617, ECOG performance status ≤ 2, and adequate organ function. Any number of prior therapies will be allowed. Primary Endpoint: Proportion of participants with non-progressive disease at 16 weeks of treatment with zanzalintinib as assessed by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1. Thirty patients will ensure that the disease control rate can be estimated via a 95% confidence interval with a margin of error &lt;0.20. Secondary Endpoints: safety, tolerability, PSA 50% response rate, and OS. Tissue and blood samples will be collected for correlative studies. Clinical trial information: NCT06568562 .

Germline DNA repair gene variants in patients under active surveillance for low-grade bladder cancer: Implications for risk stratification.

849 Background: The growing interest in de-intensifying therapeutic strategies for low-grade bladder cancer (BC), including active surveillance (AS), highlights the imperative need for precise patient stratification criteria. The major clinical challenge is the identification of patients at risk for progression to high-grade disease. To address this unmet need, we investigated the role of germline pathogenic variants (PVs) and variants of unknown significance (VUS) in DNA repair genes (DRG) to refine patient selection for AS. Methods: This ongoing prospective study includes patients with bladder cancer who have been enrolled in an AS protocol for a minimum of 12 months. Whole-exome sequencing was performed to screen for PVs and VUS in DRG (including TM, ATR, MRE11A, BAP1, BARD1, BRCA1, NBN, BRCA2, PALB2, BRIP1, CHEK2, RAD51C, FAM175A, RAD51D, GEN1, XRCC1, and the mismatch repair genes MLH1, PMS2, MSH2, and MSH6). The inclusion criteria for AS include suspicious recurrence at follow-up cystoscopy following a histopathologically confirmed diagnosis of low-grade pTa/pT1a NMIBC, with a maximum of five suspicious lesions, each no larger than 1 cm in diameter, absence of gross hematuria, and negative urinary cytology (UC). The primary endpoint was to describe the prevalence of PVs and VUS in AS patients. Patients with high-grade NMIBC and muscle-invasive bladder cancer (MIBC) were included as positive controls and screened for the same set of genes. This study is funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under Protocol ICH-2812, code IG 2020-ID-25027. Results: From January to June 2024, a total of 15 patients under AS were tested. The median duration of surveillance at the time of testing was 16 months. All patients had a history of low-grade bladder cancer, with a median interval of 23 months between initial diagnosis and entry into the active surveillance protocol. None of the patients in the AS cohort harbored pathogenic variants in the targeted genes analyzed. In the positive control group, consisting of 10 patients with HG-NMIBC and 16 with MIBC, a total of 18 variants were identified, including 17 VUS and 1 PV. The distribution of variants was as follows: ATM (N=4), ATR (N=3), BARD1 (N=3), PMS2 (N=2), with one variant each in BRCA2, MSH6, NBN, PALB2, and GEN1. The single risk variant was detected in the CHEK2 gene. Conclusions: Our study indicates that none of the patients under AS with NMIBC harbored PVs or VUS the targeted genes. On the contrary, in the positive control group (NMIBC and MIBC), multiple VUS and one risk variant were identified, suggesting that germline DNA repair gene analysis may be more relevant in higher-risk bladder cancer cohorts. These findings underscore the need for further investigation into the utility of genetic screening, which might play a crucial role in refining patient selection for AS protocols in the future.

A real-world clinicogenomic study of androgen receptor mutations and co-mutations in prostate cancer: Clinical implications.

73 Background: While most prostate cancer (PCa) patients (pts) initially respond to androgen deprivation therapy, resistance commonly develops, resulting in castration-resistant PCa. In certain patients, androgen receptor ( AR ) mutations permit tumor cells to proliferate despite the absence of circulating androgens. This study leverages real-world clinicogenomic data to investigate the prevalence and clinical implications of AR mutations and co-mutations. Methods: We analyzed 3,753 pt records with PCa who underwent next-generation sequencing (NGS) from January 1, 2014 to October 1, 2024. NGS was ordered by &gt;400 physicians from &gt;180 community-based oncology clinics across the Sarah Cannon Research Institute network, and results were collated with pt medical records in the software platform, Genospace. Pts were stratified into AR -mutated ( AR m; 306 pts), AR -amplified ( AR amp; 231 pts), and AR wild-type ( AR WT; 3,216 pts) cohorts. Pts with multiple primary cancers were excluded. Results: AR mutations were detected in 306 pts (8%), with a higher detection rate in plasma- versus tissue-based NGS (15% vs 2%; p&lt;0.01). AR mutations were more common in older pts, with 68% of AR m pts &gt;70 years old compared to 53% of AR WT pts (p&lt;0.01). The most common AR mutations included L702H (51%, 156 pts), T878A (38%, 115 pts), H875Y (23%, 70 pts) and W742C (8%, 25 pts), and over half of AR m pts reported multiple AR mutations (51%, 156 pts). Several genes were more frequently mutated in AR m versus AR WT pts, including TP53 (43% vs 32%), PTEN (10% vs 6%), BRCA2 (9% vs 4%), RB1 (5% vs 2%), and BRCA1 (4% vs 1%; p&lt;0.01 for all). AR m pts reported a higher frequency of microsatellite instability (MSI) compared to AR WT pts (11% vs 2%; p&lt;0.01). Within the AR m cohort, MSI was more frequently detected by tissue- versus plasma-based NGS (26% vs 7%; p&lt;0.01). Specific AR mutations were enriched in MSI versus microsatellite stable (MSS) pts, including H875Y (50% vs 20%) and V716M (31% vs 2%; p&lt;0.01 for both). Additionally, BRCA1/2 mutations were more common in AR m/MSI pts versus AR m/MSS pts ( BRCA1 : 15% vs 3%; BRCA2 : 35% vs 6%; p&lt;0.01 for both). Pts in both the AR m (3.3 yrs) and AR amp (2.1 yrs) cohorts exhibited shorter overall survival from metastatic staging compared to the AR WT cohort (9.0 yrs; p&lt;0.01 for both). Neither specific AR mutations nor MSI status correlated with survival outcomes. Conclusions: AR mutations are frequently detected by plasma-based NGS in the real-world setting, possibly due to test selection at disease progression and/or sampling of tumor heterogeneity. However, plasma-based NGS may miss other critical alterations, such as MSI status. The high co-occurrence of MSI in AR -mutated PCa suggests potential for combination therapies involving immunotherapy and novel AR degraders. These findings emphasize the need for tissue- and plasma-based genomic profiling to guide therapeutic decisions and optimize treatment strategies for advanced PCa.

Low-frequency noise and DC I–V characterization of gamma-ray irradiation-induced degradation and trap behaviors in a-IGZO TFTs

This work reports the impact of gamma-ray (γ-ray) irradiation-induced degradation based on the trap behaviors in amorphous indium-gallium-zinc-oxide (a-IGZO) thin-film transistors. By employing multiple measurement configurations via low-frequency noise and direct current I–V characterization, we quantitatively investigated the energetic distribution of subgap density-of-states in the a-IGZO channel and the spatial distribution of oxide traps (Not) in the gate insulator, respectively. Also, the qualitative analysis was performed to determine the oxygen-related defects after γ-ray irradiation using x-ray photoelectron spectroscopy. Furthermore, the validity of our results was additionally confirmed by measuring the breakdown voltage and applying positive-bias stress to the fabricated devices exposed to radiation for accelerated tests.

Metarhizium mendonceae sp. nov.: An important biological control agent for insect pests

The Metarhizium anisopliae complex consists of 34 formally described phylogenetic species. Metarhizium anisopliae sensu lato has been used for decades in Brazil as a biological control agent for controlling spittlebugs in sugarcane plantations. We investigated the identities of the Metarhizium isolates used in mycoinsecticide formulations through multilocus phylogenetic analyses and morphological characterization for species delimitation. A well-supported clade containing only isolates from this study formed a sister group with species of M. anisopliae sensu stricto, which we described as a new taxon, M. mendonceae sp. nov. Isolates URM 8144 and URM 8145 are used in the formulation of various brands of biological insecticides; however, they have always been referred to as M. anisopliae. According to the antibiosis assay, all the isolates of this new species were able to colonize and kill Mahanarva spectabilis nymphs. Therefore, M. mendonceae has been used in the formulation of mycoinsecticides for several decades under the name M. anisopliae.

Profiling difenoconazole and flusilazole resistance, fitness penalty and phenotypic stability in Venturia inaequalis

The nature of progression on long term active surveillance for confirmed Gleason grade group 1 prostate cancer in the modern era.

360 Background: Gleason Grade Group 1 (GG1), or Gleason 3+3, prostate cancer (PCa), are considered low-risk, and unlikely to lead to major adverse outcomes such as metastasis or PCa-specific mortality. However, initial diagnoses of GG1 can upgrade over time, and balancing the need for monitoring with concerns about overtreatment of GG1 has led to the emergence of active surveillance (AS) as the standard of care for GG1 PCa. There has been a recent controversy regarding whether the label of cancer should be removed from GG1 tumors; proponents argue that such a change would dramatically reduce patient anxiety and overtreatment of GG1 PCa, while detractors argue that this could lead to failure to follow such patients and a missed opportunity for cure in those who might benefit. We sought to describe the nature of progression of GG1 disease in the modern era for confirmed GG1 patients after multiparametric prostate MRI-targeted biopsy in a large, well-annotated AS cohort. Methods: The Urologic Outcomes Database (UODB) at the University of California San Francisco (UCSF) was queried for men with cT1-2N0/xM0/x, PSA &lt;20ng/ml, GG1 PCa with ≤33% biopsy core positivity with a minimum of 2 biopsies on AS with at least one multiparametric prostate MRI-targeted biopsy. Clinicodemographic factors and pathology data at diagnosis and at subsequent biopsies were obtained. Outcomes were any upgrade (≥GG2), major upgrade (≥GG3), increase in percentage of positive cores to &gt;33%, and progression to active treatment. Life-table estimates and Kaplan-Meier analyses were used to describe major outcomes variables. Results: 803 men met inclusion criteria. Median (IQR) follow-up for the cohort was 114 (75-157) months. CAPRA score at diagnosis was low risk and intermediate risk in 749 (93%) and 54 (7%) patients, respectively. Median (IQR) PSA at diagnosis, any upgrade, and major upgrade was 5.0 (3.8-6.7) ng/mL, 6.9 (4.5-9.9) ng/mL, and 7.8 (5.5-11.8) ng/mL, respectively. At 5 and 10 years, any upgrade rate was 28% and 61%, major upgrade rate was 5% and 17%, rate of increase in core positivity from ≤33% to &gt;33% was 22% and 37%, and active treatment rate was 15% and 33%, respectively. Patients with both upgrade to GG2 and increased core positivity and major upgrade were more likely to progress to active treatment compared to patients with either upgrade to GG2 or increased core positivity alone (Log-rank p&lt;0.01). Conclusions: Men with confirmed GG1 PCa on AS with at least one MRI-targeted biopsy have high rates of minor upgrade, moderate rates of increased core positivity and progression to active treatment, and low rates of major upgrade on subsequent biopsy, and are more likely to progress to treatment if they experience major upgrade or both upgrade to GG2 and increase in core positivity. These findings highlight heterogeneity of outcomes in patients with confirmed GG1 PCa in the modern era and highlights the critical need for continued monitoring with AS in such patients.

A phase 2/3 multicenter trial evaluating safety and efficacy of a new mucoadhesive gemcitabine suspension for ablation of upper tract urothelial carcinoma.

TPS889 Background: Patients with large, multifocal, or frequently recurrent low-grade (LG) upper tract urothelial carcinoma (UTUC) often require nephroureterectomy to effectively manage their disease, despite the low oncologic risk of progression. There is a need for safer, more effective nephron-sparing treatments. Intraluminal therapies are underdeveloped and limited by the short dwell time of drugs in the collecting system. Intravesical gemcitabine has shown efficacy and minimal toxicity in treating bladder urothelial carcinoma, suggesting a similar potential for UTUC. The investigational drug (ST-02) is a novel mucoadhesive gemcitabine suspension designed for pyelocaliceal instillation. It changes from a liquid to a mucoadhesive gel in the collecting system once in contact with water, thereby facilitating prolonged exposure to gemcitabine. This trial aims to demonstrate that intraluminal administration of ST-02 can effectively and safely ablate LG UTUC. Methods: This is a prospective, multicenter, single-arm, open-label phase II/III clinical trial (NCT06124976) designed to enroll 70 patients with biopsy-confirmed LG UTUC. The study employs a two-stage design with early stopping rules, where the trial will be halted if there are 8 or fewer complete responses (CR) among the first 30 participants (phase II). Eligible patients must have tumors measuring 5-15 mm at treatment initiation. ST-02 will be instilled via retrograde or antegrade catheterization weekly for 6 weeks. The primary endpoint is the CR rate, assessed by ureteroscopic evaluation 6 weeks after the last instillation. Maintenance therapy with ST-02 will be offered to participants with ongoing CR at 3, 6, 9, 12, and 15 months. Secondary objectives include evaluating the durability of CR at 12 months, objective response rates based on tumor size, event-free survival, and safety. The trial includes a safety lead-in phase with pharmacokinetic evaluation in the first 10 patients. An independent Data Monitoring Committee will oversee safety and efficacy assessments. Clinical trial information: NCT06124976 .

A multi-centre review of the use of adjuvant pembrolizumab for renal cell carcinoma.

484 Background: In patients with increased risk of recurrence after surgical resection of renal cell carcinoma (RCC), adjuvant treatment with pembrolizumab has been shown to reduce recurrences and improve overall survival. This treatment is now offered as standard of care in England. In the KEYNOTE 564 trial 96.3% of patients who received pembrolizumab experienced at least one adverse event and 32.4% of patients experienced an adverse event of grade 3-5. 38.9% of trial patients discontinued treatment early; 21.3% due to adverse events and 10.5% due to disease recurrence. 7.4% of patients who were treated with pembrolizumab were treated with high dose systemic steroids (≥40mg prednisolone per day). Aims: To evaluate how real world data compares to the findings of KEYNOTE 564, in UK centres. Methods: This was a retrospective review of 182 patients treated with adjuvant pembrolizumab following surgery for RCC across 7 centres in the UK between 2022-2024. Toxicity, discontinuation, use of steroids, and recurrences were assessed. Results: 182 patients were started on adjuvant pembrolizumabbetween 2022-2024. Median FU is 8.4 months. Overall, 18 patients (9.9%) have experienced recurrence, and 15 (83.3%) of these occurred during treatment. 82 (45.1%) patients are currently undergoing treatment, and 41 (22.5%) patients completed the full 12-month course. 59 (32.4%) patients did not complete the full course, 44 (24.1%) due to toxicity and 15 (8.2%) due to recurrence. Mean number of cycles completed for patients discontinuing treatment was 3.4 (range 1 – 8). Toxicity was varied with endocrine (24%), skin (23%) &amp; colitis (12%) being the most common toxicities of all grades. 24 (13.2%) and 3 (1.6%) patients experienced grade 3 and grade 4 toxicities respectively. The commonest toxicity leading to treatment discontinuation was colitis (27.3%). The number of patients requiring steroids for toxicity management was 59 (32.4%) with 34 (18.6%) requiring high dose steroids and 7 (3.8%) requiring additional immunosuppressive agents (methotrexate (3), infliximab (3) and MMF (1)). 26 (14.2%) patients required hospitalisation for management of toxicity. There was 1 treatment-related death due to complications from colitis and nephritis. Conclusions: In our group of patients, discontinuations of Pembrolizumab due to toxicity and recurrence rates were similar to data from KEYNOTE 564. A larger proportion of patients in our real world data were treated with high dose steroids (19%) compared to the trial (7.4%).

TP53 Y220C mutations in advanced urothelial bladder cancer (UBC): A genomic landscape study.

821 Background: TP53 is the most frequently altered gene in human cancers. Novel agents targeting the pathogenic TP53- Y220C mutation and p53-based cancer therapy have attracted significant interest. Evaluation of TP53- Y220C mutation and co-occurrent alterations in UBC is needed. Methods: FFPE tissue from 11,224 UBC patients (pts) underwent hybridization capture and comprehensive genomic profiling. A total of 324 cancer related genes including selected introns of 31 genes frequently rearranged in cancer were evaluated for genomic alterations (GA). We obtained an average sequencing depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were estimated using next-generation sequencing. TMB-high was defined as ≥10 mutations/Mb. PD-L1 expression was measured by IHC (DAKO 22C3). Comparisons were performed using the χ 2 method with Yates correction. Results: TP53 Y220C mutation (Y220C+) was identified in 73 UBC (0.65%). Age/gender were comparable between TP53 Y220C negative (Y220C-) and TP53 Y220C+ pts; 8.4% of TP53 Y220C+ and 8.2% of TP53 Y220C- UBC cases exhibited ≥1 GA. In TP53 Y220C+ UBC, the frequency of co-occurring GA was significantly lower for FGFR3 (8.2% vs 18.3%; P = .038), MTAP loss (13.3% vs 25.1%; P = .035), CDKN2A (26% vs 37.8%; P = .05), and CDKN2B (19.2% vs 30.2%; P = .05) vs TP53 Y220C- UBC. BRCA1 GA was significantly higher in TP53 Y220C+ UBC (8.2% vs 2.0%; P &lt; .0001). In TP53 Y220C+ UBC, trends were observed with numerically higher GA frequency in ERBB2 (20.5% vs 17.6%; not significant [NS]), RB1 (24.7% vs. 21.4%; NS) and numerically lower GA frequencies in TERT (61.1% vs 76.1%; NS), PIK3CA (15.1% vs 21.6%; NS). No significant differences in other GA frequencies: TSC1 (8.2% vs 9.0%, NS), ERBB3 (6.8% to 6.2%, NS), BRCA2 (4.1% to 3.2%, NS), FGFR2 (2.7% to 1.1%, NS), or in MSI / TMB status were detected between groups. PD-L1 low expression (1-49%) was observed in 7.3% of TP53 Y220C+ UBC. Conclusions: The TP53 Y220C mutation is rare in advanced UBC (&lt; 1% of cases). In our study, this mutation was associated with specific co-occurring GA, notably with a significantly lower frequency of FGFR3 and higher BRCA1 GA. TP53 Y220C mutation warrants further clinical investigation in basket trials, including UBC, e.g. NCT04585750. TP53 Y220C+ UBCn=73 TP53 Y220C- UBCn=11,151 p value BRCA1 8.2% 2% &lt;.0001 FGFR3 8.2% 18.3% .038 MTAP 13.3% 25.1% .035 CDKN2A 26% 37.8% .05 CDKN2B 19.2% 30.2% .05 MSI-high 0% 0.7% NS TMB-high 34.2% 34.1% NS

Direct measurement of thermal Knudsen forces in rarefied gas environments

At micro- and nanoscales, momentum transfer between surfaces is influenced by various physical mechanisms, including quantum fluctuations, electromagnetic interactions, electric charges, and the dynamics of (rarefied) gases. Under non-isothermal conditions, rarefied gases give rise to thermal Knudsen forces whose magnitudes strongly depend on the gas species and surface characteristics. Knudsen forces are particularly relevant in nanotechnology, optical manipulation, and aerospace systems, where gas rarefaction occurs due to highly confined geometries, sub-micrometer length scales, and reduced particle densities. Despite their significance, predictive modeling of Knudsen forces is limited by a lack of comprehensive experimental data across diverse materials and surface morphologies. In this work, we present a highly sensitive and adaptable measurement platform capable of directly quantifying Knudsen forces using a suspended, interchangeable micro-cantilever within controlled rarefied helium and nitrogen environments. The system integrates optical fiber interferometry to precisely capture out-of-plane displacements at sub-micrometer resolution, driven by Knudsen forces. From the empirical data, we derive a robust correlation linking the magnitudes of Knudsen forces to energy accommodation coefficients, offering deeper insights into the underlying gas–surface interaction mechanisms.

Effects of outdoor play on body composition and physical performance in children: the Yamanashi Adjunct study of the Japan Environment and Children’s Study

Introduction Childhood is a pivotal developmental stage that substantially affects lifelong habits. Recent research has emphasized the vital role of outdoor play in children’s mental and physical well-being. Despite the World Health Organization recommending 1 hour of daily physical activity for children, a knowledge gap exists regarding the specific link between children’s physical performance, body composition (evaluated through bioelectrical impedance analysis [BIA]), and outdoor play habits. Methods Utilizing data from the Japan Environment and Children’s Study, a national birth cohort study, this study included 494 eight-year-old participants. The assessment included body composition (height, weight, body fat percentage, predicted muscle weight, and phase angle using BIA) and physical performance (50 m sprint, standing long jump, 20 m shuttle run, and handgrip strength). Parents provided information on children’s outdoor playtime. Results The group with more outdoor play demonstrated superior sports test results, particularly among boys. Girls engaged in increased outdoor play exhibited higher predicted muscle weights, whereas boys showed greater phase angles in the lower limbs. Handgrip strength correlated with phase angle and predicted muscle weight. Notably, the association between body composition and sports test results was more pronounced in boys than in girls, with phase angles exhibiting stronger links to running and jumping. Conclusion This pioneering study explored the relationship between outdoor play, body composition, and physical performance in children. Outdoor play positively correlated with improved sports performance, revealing sex disparities in body composition changes. Unlike previous studies focusing on general physical development, this study scrutinized specific physical functions, uncovering correlations between phase angle and muscle quality. Findings suggest that outdoor play positively impacts muscle quality, especially in boys, contributing to enhanced physical performance in children. Understanding these effects on body composition and physical activity is imperative for promoting children’s health.