Browse Articles

Potential Impact of the Medicare Prescription Payment Plan for Medicare Part D Beneficiaries With a Cancer Diagnosis

PURPOSE To address high out-of-pocket (OOP) medication costs among Medicare Part D beneficiaries, the 2022 Inflation Reduction Act introduced the Medicare Prescription Payment Plan (M3P), a voluntary program that allows beneficiaries to spread OOP costs over the calendar year. We examined M3P's potential impact among beneficiaries with cancer, who frequently incur substantial early-year Part D medication costs. MATERIALS AND METHODS We evaluated a 2022 5% random sample of Medicare beneficiaries with a cancer diagnosis and ≥1 fill for a cancer-indicated Part D medication. We estimated 2025-adjusted annual true OOP spending and median monthly beneficiary OOP payment obligations with and without M3P enrollment. Subgroup analyses were performed by demographics, nonadherence status in 2022, and Part D benefit phase. RESULTS Among 168,480 beneficiaries with cancer, most were diagnosed with breast (47.6%), dermatologic (17.6%), or prostate (13.3%) cancers. Overall, 46.7% were projected to reach catastrophic coverage in 2025, with 32.4% doing so in January. Breast (29.7%), prostate (21.20%), and hematologic (20.0%) cancers were most common among those reaching catastrophic coverage. Overall, 43.0% were nonadherent to cancer-indicated Part D medications, with 31.5% reaching catastrophic coverage in January 2025. M3P reduced beneficiary payment obligation variability, especially among those reaching the catastrophic phase in January (IQR, $1,798 US dollars [USD] no M3P v $118 USD M3P). Of those reaching catastrophic coverage with a cancer-indicated drug (58.6% overall), 89.2% did so in January. CONCLUSION Early-year entry into catastrophic coverage is common among beneficiaries with certain high-cost cancers. M3P may most effectively reduce financial burden when enrollment occurs before January. Targeted outreach from cancer care teams and Part D plans to nonadherent patients and those considering costly therapies could maximize program impact and improve treatment outcomes.

Discrete element study on mechanical properties of layered sand-cobble strata under unloading stress path of shield construction

Autoantibody (AAb) profiling in metastatic cisplatin-ineligible metastatic urothelial carcinoma (mUC) treated with ipilimumab (IPI), nivolumab (NIVO), and sacituzumab govitecan (SG).

863 Background: We previously reported that the combination of IPI-NIVO plus SG shows high efficacy with 83.3% objective response rate (ORR) as first-line treatment for cisplatin-ineligible mUC patients in a Phase I/II trial (NCT04863885). However, two grade 5 immune-mediated myocarditis events attributed to IPI-NIVO occurred, leading to early trial termination after accruing 25 patients. We evaluated serum autoantibodies (AAbs) to predict response and immune-related adverse events (irAEs) in patients receiving IPI-NIVO + SG on this trial. Methods: Using a customized 96-antigen NavigAID panel potentially linked to heart, muscle, autoimmune myositis, myasthenia gravis (MG) and checkpoint inhibitors (CPI)-induced irAEs in mUC, IgG AAbs were measured via SeroTag in pre- and post-treatment serum from mUC patients enrolled in NCT04863885. Comparative analyses included baseline vs. healthy controls, association with irAEs, best overall response (BOR), and time to progression (TTP). Top associated AAbs were selected by |log2 fold change| > 1 and |ΔMFI| > 500 between groups. P-values were calculated post-hoc using logistic regression risk modeling, ANOVA or SAM analysis. Results: Risk model analysis showed moderate evidence linking cardiac and muscle-related antigens L1CAM (OR 4.43, p = 0.08) and KCNJ8 (OR 4.31, p = 0.086) to myocarditis. KCNJ8 (KIR6.1) mutation has been previously associated with cardiac arrest. While no clear association was observed between total AAb burden and specific irAEs or response types, individual AAbs such as HMGCR (p = 0.66/0.22), TRIM28 (p = 0.43/0.058), and MYL4 (p = 0.44/0.61) showed potential predictive value for BOR/TTP. TRIM28 (TIF1β) and HMGCR AAbs are myositis-specific AAbs (MSA). HMGCR AAbs are a marker for necrotizing autoimmune myopathy (NAM), a rare but severe muscle disease. MYL4 is expressed in adult cardiac atrial tissue. Treatment-induced AAb variation was higher in responders (CR/PR). The most prominent post-treatment changes in AAbs were observed for anti-TONSL (p = 0.07). AAbs to several tumor associated antigens were elevated in mUC vs. controls including CTAG1B (NY-ESO-1) (p = 0.03) and BCL2L1 (p = 0.02). Conclusions: In patients with mUC receiving first-line IPI-NIVO+ SG, pre-treatment AAbs to cardiac and muscle-related antigens L1CAM and KCNJ8 showed a trend for association with immune myocarditis, while AAbs to HMGCR, TRIM28 and MYL4 were associated with better outcomes with the treatment. Together, these observations support further exploration of AAb profiling as a biomarker to predict efficacy and toxicities in those receiving CPI based therapies.

Reactive Carbide‐Based Synthesis and Microstructure of NASICON Sodium Metal All Solid‐State Electrolyte (Adv. Mater. 16/2026)

Intrinsically Thermally Robust Nanocrystals for High‐Flux Photonics

ABSTRACT High‐brightness photonic platforms driven at high currents self‐heat beyond 400 K; under such conditions, colloidal emitters (II–VI, III–V, I–III–VI 2 , group‐IV semiconductors, and both leaded and lead‐free halide perovskite nanocrystals) typically lose efficiency and drift in color. Extrinsic passivation offers limited thermal gains with trade‐offs such as organic‐matrix degradation or oxide‐shell phonon bottlenecks. Here we establish a lattice‐encoded chemical strategy that imparts intrinsic thermal resilience to colloidal nanocrystals via defect–phonon–exciton coupling in a zero‐dimensional Sb 3+ ‐doped Cs 3 LnCl 6 lattice. A controlled‐ramp synthesis co‐modulates site occupancy and defect chemistry, creating rigid, low‐phonon [BX 6 ] 3− octahedra that localize lattice expansion and suppress multiphonon relaxation. Ångström‐scale engineered deep traps (∼0.6–1.2 eV) recycle thermally activated carriers, enabling trap‐compensated anti‐thermal quenching and stabilizing emission through Ln 3+ 4f cascade coupling. Tunable from deep violet to ultra‐narrow green and yellow, these nanocrystals show enhanced photoluminescence at elevated temperatures (Cs 3 LnCl 6 :Sb 3+ reaches 160% intensity at ∼410 K while retaining >93% photoluminescence quantum yield). High‐power devices retain >90% luminous flux after 50 h at 1.4 A (junction temperature ∼410 K) with <1% chromaticity shift. This work turns thermal robustness from extrinsic protection into intrinsic bonding, providing a molecular design framework for high‐flux photonics.

A phase II trial of intravesical gemcitabine/docetaxel plus systemic pembrolizumab in high-risk non–muscle invasive bladder cancer unresponsive to BCG.

TPS888 Background: High-risk non–muscle invasive bladder cancer (NMIBC) unresponsive/exposed to Bacillus Calmette-Guérin (BCG) represents an area of significant unmet clinical need. Radical cystectomy remains the standard of care, yet many patients are ineligible or decline surgery. Intravesical chemotherapy with gemcitabine/docetaxel has shown promising activity, and immune checkpoint inhibition with pembrolizumab is approved in this setting. Preclinical and retrospective data suggest that combining intravesical chemotherapy with systemic PD-1 blockade may enhance antitumor efficacy. Methods: This is a multicenter, investigator initiated, open-label, single-arm Phase II trial evaluating pembrolizumab (400 mg IV every 6 weeks) in combination with sequential intravesical gemcitabine (1 g) and docetaxel (37.5 mg) in patients with high-risk NMIBC unresponsive/ exposed to BCG who are ineligible for or refuse radical cystectomy. Induction consists of six weekly intravesical instillations, followed by monthly maintenance for up to 12 months. Pembrolizumab is administered for up to nine cycles (1 year). The primary endpoint is complete response (CR) at 3 months, defined as absence of high-risk NMIBC or progressive disease. Secondary endpoints include duration of response, disease-free rate, time to and avoidance of cystectomy, and safety/tolerability. Exploratory objectives include biomarker analyses from tumor tissue, blood, and urine, and evaluation of patient-reported outcomes. Status: Enrollment is ongoing, with a planned sample size of up to 37 patients. Interim analyses will assess proof-of-concept, and study continuation will depend on observed safety and early efficacy signals. Correlative studies will explore immune and molecular predictors of response and resistance in the tumor, blood, and urine. Clinical trial information: NCT06972615 .

Artificial intelligence (AI) as a practical decision support tool for oncologists: Genitourinary (GU) cancer cases.

565 Background: Multidisciplinary reviews (MDR) can significantly impact the management of oncologic patients, yet these are often underutilized. We previously presented more than 400 anonymized oncologic cases, including genitourinary (GU) cancer cases, to a MDR panel consisting of specialists belonging to medical oncology, surgical oncology, and radiation oncology. Here, we compare MDR recommendations to those produced by 3 different foundational AI models. Methods: We selected 35 complex GU cancer cases reviewed by MDR panels between 2020 and 2021 from a larger database that included several tumor types. These were then evaluated by OpenAI’s ChatGPT 4.5, Anthropic’s Claude Opus 4, and Google’s Gemini Ultra using PrecisCa’s proprietary prompting method. Recommendations from each system were scored on a 1-5 scale (with 5 being the highest) for completeness, reasoning, clarity, menu of options, recency, and relevance, and compared with those from the MDR panel. A maximum score of 30 points per scenario and 1,050 points overall was possible. Final AI recommendations were also compared with current National Comprehensive Cancer Network (NCCN) guidelines. Comparison in reverse (i.e., additional AI options that the experts had missed) was not conducted due to interval treatment recommendation changes in the preceding 4 years. Results: Patient characteristics, histology, and aggregate competence scores are shown (Table 1). Across all AI models, performance was the best in cases involving testicular cancer and worst in bladder cancer cases. For testicular cancer cases, recency and relevance scores were the highest while scores for reasoning, clarity, and menu of options were the worst. For bladder cancer cases, clarity scores were the highest, and recency the worst. Overall, AI systems excelled in relevance, but less so in completeness and recency. While there was some variation in the concordance and competence ratings from the 3 AI models, there was good concordance with expert opinion for all of them. Discordant cases revealed minor differences that would not have significantly impacted patient management otherwise. Conclusions: This study demonstrates a high degree of concordance between 3 leading AI models and expert panel decisions for common, complex GU cancer clinical scenarios. The findings show that it is not premature to incorporate AI as a decision support tool, in conjunction with human specialists, in daily practice. Patient characteristics, histology, and aggregate competence scores (n=35). Median Age (Range) 52.5 (25-80) Histology  Bladder 7 (20%)  Kidney 11 (31.4%)  Prostate 15 (42.9%)  Testicular 2 (5.7%) Aggregate/Median Competence Scores (Range)  ChatGPT 4.5 880/23.5 (17-30)  Claude Opus 4 931/23.5 (17-30)  Gemini Ultra 889/24 (18-30)

Ag2O-decorated TiO2 for ultrasensitive SERS detection of crystal violet

Use of circulating tumor DNA (ctDNA) in the detection of residual disease and recurrence for patients with testicular cancer.

620 Background: ctDNA has been increasingly investigated as a biomarker of interest for patients with testicular cancer, a highly curable cancer affecting predominantly young men. Traditional serum tumor markers bHCG, LDH and AFP lack sensitivity and specificity, and have significant variance between patients. While miRNA 371 has emerged as a promising biomarker, it is not applicable in teratoma, has limitations in regards to standardization, and has not been brought to mainstream use. In this study, we evaluate the application of ctDNA in the surveillance of testicular cancer. Methods: Under IRB approval, a retrospective chart review was conducted on patients treated between May 2020 and October 2025 at our academic institution, who had any stage or histology of testicular cancer, with at least one resulted ctDNA value by Natera assay. Results: 41 patients (pts) were included in this study, with a total of 153 ctDNA samples collected. 20/41 (48.8%) of patients had seminoma, and 21/41 (51.2%) had non-seminoma. Age ranged from 20-77, with a median age of 31. 16/41 (39.0%) of patients were White, 15/41 (36.6%) Hispanic, 7/41 (17.1%) Other/Mixed, 2/41 (4.9%) Asian and 1/41 (2.4%) Black. 16/41 (39.0%) of patients had stage I disease, 11/41 (26.8%) had stage II disease, and 14/41 (34.1%) had stage III disease. We calculated a sensitivity of 100% (95% CI 79.4% to 100.0%), and a specificity of 100% (95% CI 97.2% to 100.0%) across all three stages for both residual disease and for relapse, based on 148 ctDNA samples (5 were excluded due to incomplete information). Imaging was used as the gold standard, or pathology, when available. 8/153 ctDNA samples showed discordant ctDNA and imaging, in that either ctDNA rise occurred ahead of detection on imaging, or, positive imaging findings with negative ctDNA, which was validated by negative pathology, suggesting that ctDNA was both more sensitive and specific than imaging. Conclusions: ctDNA is a reliable serum tumor marker in patients with testicular cancer of all stages, and warrants further investigation and validation in larger studies. Its sensitivity and specificity are superior to both that of serum tumor markers (bHCG, LDH and AFP) as well as imaging, and its short half-life relative to that of serum tumor markers makes it a diagnostic tool of practical significance.

Tensile‐Strained 2D Bi ₂ Ti ₂ O ₇ for CO ₂ Photoconversion (Adv. Mater. 18/2026)

Perovskite/Silicon Tandem Solar Cells With Stabilized Grain Boundaries

ABSTRACT Halide perovskite absorber with a bandgap near 1.68 eV is pivotal for constructing perovskite/silicon tandem solar cells. However, these wide‐bandgap perovskites are susceptible to light‐induced halide segregation and consequential non‐radiative and transport loss, severely compromising device performance and operational stability. Here, we incorporate a symmetric cross‐link agent, 4,4'‐oxydibenzenesulfonyl hydrazide, to stabilize the iodide‐bromide mixed perovskite lattice. The agents are introduced during film growth to regulate the crystallization process and subsequently assemble at grain boundaries, where they firmly anchor to the perovskite grain surface and stabilize the chemically active boundary regions. Through this approach, photostable wide‐bandgap perovskites are achieved, exhibiting enhanced crystallinity, reduced band‐tail states, and suppressed halide segregation and lattice decomposition. The resultant 1.68 eV single‐junction devices delivered an independently certified power conversion efficiency of 23.48%. When integrated with silicon heterojunction cells, the resulting two‐terminal monolithic perovskite/silicon tandem devices exhibited a power conversion efficiency of 32.19%, and retained 90% of their initial efficiency after 1020 h of continuous operation.

Bladder full or empty for pelvic radiation therapy (BEFORE): A multi-center randomized controlled trial.

TPS408 Background: Pelvic radiation therapy plays a key role in the treatment of most genitourinary (GU), gynecologic (Gyn), and gastrointestinal (GI) malignancies of the pelvis. Commonly, physicians instruct patients undergoing pelvic radiation therapy to present with a reproducibly full bladder for treatment with the hope that increasing the distance between the treatment target and normal tissues will limit toxicity. However, this is challenging for patients and often leads to uncertainties in radiation dose distribution to the adjacent pelvic organs, as the bladder volume varies during a treatment course. Retrospective data suggests that treating with an empty bladder has minimal impact on treatment-related toxicity, but prospective data is very limited. A phase III randomized trial is required to evaluate the relative merits of two bladder fill protocols in terms of safety and patient-reported outcomes. The goal of this trial is to identify the optimal bladder filling approach to minimize toxicity and maximize patient quality of life. Methods: The BEFORE trial (NCT06651697) is an investigator-initiated, multi-center, prospective, open-label, pragmatic, two-arm randomized phase III study enrolling patients undergoing pelvic radiation therapy. Patients of all genders planning to undergo pelvic radiation therapy with curative intent for a primary GU, Gyn, or GI malignancy of the pelvis are eligible. This trial aims to include 300 patients randomized to one of the two arms, empty or full bladder protocol, in a 1:1 ratio stratified by primary tumor site, treatment of lymph nodes, and prior prostatectomy. The primary endpoint is the physician-reported acute any attribution GU and/or GI grade ≥2 toxicity within 3 months post-radiation therapy. Secondary endpoints are radiation attribution acute GU and/or GI toxicity, any attribution and radiation attribution late GU and/or GI toxicity, patient-reported urinary and bowel quality of life, and percentage of treatment fractions requiring delay due to incomplete bladder filling in the full bladder arm. BEFORE has enrolled 89 of 300 planned participants. Clinical trial information: NCT06651697 .

Imaging meets genomics in treatment-naïve prostate cancer: SUVmax on prostate-specific membrane antigen (PSMA) PET as a biomarker of genomic classifier risk.

267 Background: Genomic Classifiers (GC) are increasingly used at the initial staging of prostate cancer to refine prognosis and guide treatment planning. The Decipher genomic classifier is a validated prognostic tool in prostate cancer, that predicts the risk of metastasis and prostate cancer-specific mortality. In parallel, PSMA PET/CT has emerged as a highly sensitive imaging modality for prostate cancer detection and staging, yet its relationship with genomic risk remains unclear. Establishing whether GC risk groups correspond with intraprostatic SUVmax on PSMA PET/CT could provide a non-invasive imaging biomarker and help identify SUV thresholds for discriminating high-risk disease. Methods: We retrospectively analyzed treatment-naïve men with histologically confirmed prostate cancer who had available Decipher genomic classifier testing, multiparametric prostate MRI and PSMA PET/CT obtained prior to or within 35 days following biopsy. Correlation between SUVmax and Decipher score was assessed using Spearman’s rho. Group comparisons were tested with Kruskal-Wallis and Mann-Whitney U tests, including low/intermediate vs high-risk. Diagnostic performance of SUVmax thresholds was evaluated using ROC analysis and Youden’s J statistic. Results: A total of 103 patients met eligibility criteria. Median age was 70 years (range, 46–84), median PSA was 6.7 ng/mL (range, 1.42–88.5), and median intraprostatic SUVmax was 11.45 (range, 2.4–81.8). Decipher risk groups were distributed as low (n=28), intermediate (n=25), and high (n=50). SUVmax was positively correlated with Decipher score (Spearman’s rho = 0.30, p =0.002), exceeding correlations with PSA (rho = 0.23, p =0.018) and Pi-RADS (rho = 0.12, p =0.24). Mann-Whitney analysis showed significant SUVmax differences between High vs Intermediate ( p =0.0055) and low/intermediate vs high ( p =0.042). ROC analysis identified SUVmax ≥15 as the optimal cutoff for predicting high Decipher risk (sensitivity 0.45, specificity 0.76, Youden’s J = 0.206). Conclusions: SUVmax on PSMA PET/CT correlated positively with Decipher genomic risk, with high-risk patients showing greater intraprostatic avidity. While differences across risk groups were modest, an SUVmax ≥15 emerged as the most discriminative threshold for identifying High-risk disease. These findings suggest that PET-derived SUVmax may provide complementary, non-invasive information to genomic classifiers and support integrated risk stratification in prostate cancer.

Mechanisms of seismic improvement in pile-sheet wall supported slopes using ECC and anchor cables

Genomic alterations and pathologic responses to neoadjuvant androgen receptor pathway inhibitor (ARPI) doublets vs docetaxel triplets in the Genomic Umbrella Neoadjuvant study (GUNS).

309 Background: GUNS (NCT04812366) is a multi-centre adaptive phase II trial evaluating 24 weeks of biomarker-selected, neoadjuvant ARPI therapies on depth of pathologic response (<5 mm minimal residual disease [MRD]) in high risk localized prostate cancer (HRLPC). After 8 weeks of an ARPI doublet (LHRHa + apalutamide [APA]), men are assigned to 1 of 4 sub-protocols (SP) combining 16 weeks of an ARPI doublet with drugs defined by specific genomic biomarkers. SP-1 enrolls men with AR-associated genomic alt (ETS fusions, FOXA1, SPOP) treated with an ARPI doublet +/- abiraterone. SP-2 randomises men with aggressive genomic alt ( RB1 , PTEN , TP53, AKT) to an ARPI doublet +/- docetaxel. Biomarkers like PTEN loss are needed to identify men who benefit from ADT-docetaxel, and here we investigate pathologic response to ARPI-docetaxel triplet in a biomarker selected HRLPC setting. Methods: Diagnostic biopsies underwent Tempus’ CLIA-certified 648-gene panel DNA sequencing (seq) and whole-transcriptome RNA-seq. This analysis focuses genomic analyses on the first 151 biopsies, and pathologic response rates in 48 men enrolled to the 1 st stage of SP-2 who completed neoadjuvant therapy and surgery. Results: DNA-seq from 129/151 biopsies reveals a genomic landscape dominated by ETS gene fusions (36%), FOXA1 (23%), TP53 (16%), SPOP (14%), PTEN (13%), and BRCA2 (9%) alterations. Overall tumor mutational burden of HRLPC in GUNS is similar to metastatic PC and enriched for the unfavorable luminal PCS1 transcriptomic subtype. PTEN was IHC negative (≤10% positive PC cells) in 18%, half of whom had no reported genomic PTEN alt . Most PTEN alt cases, especially HOMDELs, were PTEN-IHC neg , but 2 PTEN HOMDEL cases were ≥50% PTEN-IHC pos , illustrating intra-patient or sampling heterogeneity. PTEN-IHC neg or TP53 genomic alt , especially combined with an ETS fusion, was associated with intraductal carcinoma (IDC). SP-2 randomized 48 men with aggressive genomic alt (TP53, PTEN, AKT) to an ARPI doublet (SP-2a) alone or with 6 cycles of docetaxel (SP-2b). MRD rates were significantly higher in SP-2b (26% vs 0%, p-value = 0.0463). Positive margin (17%) and lymph node (37% vs 28%) status were similar. While genomic PTEN alt were excluded from SP-1, men assigned to SP-1 who were later found to be PTEN-IHC neg were more likely to be non-MRD (6/7) than MRD (1/7), suggesting PTEN-IHC neg may reduce response to ARPI. A detailed report on adverse events, clinical correlates, as well as PTEN status by IHC, genomic, and transcriptomic concordance data, will be presented. Conclusions: SP-2 associated genomic alt (TP53, PTEN, AKT) comprise 30% of the alterations in GUNS. Significantly higher rates of MRD in SP-2b patients treated with an ARPI-docetaxel triplet are of interest and support further evaluation with 2 nd stage expansion of SP-2. Clinical trial information: NCT04812366 .

A Soft Microrobot for Single‐Cell Transport, Spheroid Assembly, and Dual‐Mode Drug Screening (Adv. Mater. 18/2026)

High‐Performance, Recyclable Thermosets Enabled by Thiosemicarbazone Dynamic Bonds via Synergistic Dynamic Covalent and Supramolecular Networks

ABSTRACT Recyclable thermosets have emerged as promising candidates to mitigate plastic pollution, yet reconciling high performance with efficient recyclability remains challenging. Here, we report a high‐performance, readily recyclable thermoset engineered through a synergistic dynamic covalent and supramolecular network. This design employs a single thiosemicarbazone (TSC) dynamic linkage to intrinsically unify dynamic covalent and noncovalent bonds within one chemical moiety, thereby overcoming conventional performance‐recyclability trade‐offs. The dual‐network architecture endows the TSC‐derived polymers (PTSCs) with exceptional thermal stability (glass transition temperature: 217°C), mechanical robustness (tensile strength: 127.1 MPa; elongation at break: 16.6%; Young's modulus: 2.1 GPa; toughness: 15.1 MJ m −3 ), dimensional stability, and chemical resistance. Critically, the inherent reversibility of TSC bonds enables closed‐loop recycling through in situ depolymerization and reconstruction over multiple cycles while retaining performance parity with virgin materials. This efficient recycling route confers genuine circularity, avoiding intermediate purification steps, minimizing solvent consumption, and streamlining the recycling workflow. Furthermore, PTSCs enable selective recovery from complex mixed plastic waste streams and carbon fiber composites without sophisticated separation processes. This work establishes a versatile molecular paradigm for designing readily recyclable thermosets with exceptional performance, advancing sustainable high‐performance materials innovation.

Analysis of CA9 and PSMA expression in clear cell renal cell carcinoma (ccRCC) and the effect of prior therapies.

547 Background: In ccRCC, carbonic anhydrase 9 (CA9) and prostate-specific membrane antigen (PSMA) have emerged as potential therapeutic targets. CA9 is overexpressed in ccRCC tumor cells, while PSMA, classically linked to prostate cancer, is expressed in ccRCC tumor-associated vasculature. An ongoing phase 1/2 trial (NCT06245915) is evaluating AB-2100, a programmable circuit T cell therapy using a PSMA-gated CA9 chimeric antigen receptor (CAR), for the treatment of ccRCC. We analyzed CA9 and PSMA expression in primary and metastatic ccRCC, assessing whether expression is retained in metastases and after prior treatment with immunotherapy (IO) and/or tyrosine kinase inhibitors (TKI). Methods: Single-plex immunohistochemistry (IHC) for CA9 and PSMA was performed on serial ccRCC samples. CA9 was scored by the percentage of tumor cells with membranous staining (0–100%), and PSMA by vascular staining positivity (0–3+). A total of 103 ccRCC samples (17 primary, 86 metastatic) from 78 patients (pts) were analyzed. Paired Wilcoxon test compared matched primary-metastatic pairs (n=16; most recent if multiple available). Independent metastatic samples (one per patient, most recent if multiple available, n=77) were analyzed using the Wilcoxon rank-sum test to compare CA9 and PSMA expression in treatment-naive versus treatment-exposed samples. Correlation between the two markers was also evaluated (Spearman’s ρ). Results: Across the 78 pts, 61 received a TKI-based therapy, 46 an IO-containing regimen, and 13 a HIF-2α inhibitor. Of the 103 samples, 54.4% (n=56) were treatment-naive and 45.6% (n=47) were collected after prior exposure to systemic therapy. CA9 expression was uniformly high (median=100%, IQR: 99-100%, range: 10-100%) across 103 evaluable samples. Among matched pairs (n=16), there was no significant loss of CA9 expression in metastatic samples compared to their corresponding primary tumors (paired Wilcoxon test, p = 0.78). PSMA was detected in the tumor vasculature in 102 evaluable cases (median = 2, IQR: 2-3), with comparable expression between 16 matched pairs (paired Wilcoxon test, p = 0.48). No correlation between CA9 and PSMA was found (Spearman's ρ = -0.17). Expression of both markers was not significantly affected by prior TKI- or IO-containing regimens (Table 1). Conclusions: CA9 and PSMA expression is consistently retained in metastatic ccRCC compared to primary tumors, even after systemic treatment. CA9 remains expressed in tumor cells, while PSMA is observed in the tumor vasculature, supporting the rationale for their therapeutic targeting in advanced ccRCC. Treatment-exposed vs naive samples. CA9 PSMA Treatment Group n Median p* n Median p* Naive (ref) 35 100.0 — 35 2.0 — TKI only 11 100.0 0.879 11 2.0 0.231 TKI-containing regimen 35 100.0 0.119 34 2.0 0.434 IO-containing regimen 26 100.0 0.152 26 3.0 0.293 *P-values from Wilcoxon rank-sum test vs naive (reference group).

Analysis of quality-adjusted time without symptoms or toxicity (Q-TWiST) in patients with metastatic hormone-sensitive prostate cancer: From the ARASENS trial.

133 Background: Triplet combination of darolutamide (DARO; an androgen receptor inhibitor) with androgen deprivation therapy (ADT), and docetaxel significantly improved overall survival (OS; HR 0.68; 95% CI 0.57–0.80; P <0.001) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS trial (NCT02799602). DARO also showed benefit of intensified therapy in maximizing efficacy while minimizing toxicity. Q-TWiST is an approach that compares variation in efficacy and toxicity between treatment arms. This study assessed quality of life-adjusted survival of patients with mHSPC using DARO triplet therapy compared with doublet therapy (ADT and docetaxel). Methods: The Q-TWiST method assumes patients progress through a set of three health states. Time Without Symptoms or Toxicity (TWiST), time in RELapse or disease progression (REL), and time with TOXicity (TOX; with grade 3/4 symptoms or toxic effects) were estimated by the 53-month restricted mean using grade 3/4 adverse event (AE), OS, and time to castration-resistant prostate cancer (CRPC) data from ARASENS. Q-TWiST was calculated as the weighted sum of time spent in each health state for each treatment arm (DARO vs placebo [PBO]), adjusted by corresponding utility scores obtained from published sources. Differences in mean Q-TWiST between treatment arms were calculated for utility weights. For each health state, 95% CIs and mean standard errors (SEs) of TWiST, REL, TOX, and Q-TWiST were calculated based on 1000 bootstrap samples. Relative gain in Q-TWiST was calculated by dividing the mean Q-TWiST difference between treatment arms by the restricted mean OS of the PBO arm. Results: The full analysis set included 651 and 654 patients in the DARO and PBO arms, respectively. Patients had similar incidence of grade 3/4 AEs prior to disease progression (47.5% vs 53.2%), lower incidence of CRPC (34.6% vs 59.8%), and improved OS (deaths: 35.2% vs 46.5%) with DARO vs PBO. Significantly, patients had 6.3 months more Q-TWiST with DARO vs PBO driven by an increase in TWiST (mean 17.6 months [SE 0.9] vs 10.9 months [0.7]), and less REL (2.4 months [0.3] vs 8.7 months [0.4]); due to the long treatment duration, there was more TOX (17.2 months [0.9] vs 11.3 months [0.7]) at 53 months (all P <0.001). Partitioned Kaplan–Meier survival curves showed significantly persistent TWiST with DARO vs PBO indicating patients spent more time without grade 3/4 AEs before disease progression ( P <0.001). The DARO Q-TWiST relative gain was 16.0% (clinically important). Conclusions: In ARASENS, DARO triplet therapy provided an additional 6.3 months of OS without symptoms or toxicity and a Q-TWiST relative gain of 16.0% corresponding to higher overall quality-adjusted survival vs doublet therapy at 53 months. This highlights the benefit of the standard of care ARASENS regimen for patients with mHSPC. Clinical trial information: NCT02799602 .

Vibrational contribution to the sub-terahertz dielectric response of kinesin and its hydration shell

Abstract The ability of proteins to change conformation underlies both their biological function and their use in bio-nanoelectromechanical systems as molecular machines and transducers. These conformational transitions are suggested to be facilitated by global physical vibrational modes in the sub-THz frequency range. However, direct experimental detection of these modes is difficult to achieve due to their weak spectroscopic signatures and strong water background. Thus, computational approaches fill knowledge gaps, help steer and interpret experiments. In this study, we used molecular dynamics simulations combined with normal mode analysis to explore the vibrational modes of an all-atom model of the globular motor domain of protein kinesin. We explored the coupling of these modes, via the corresponding modal dipole variation, to the electromagnetic field and predicted the resulting dielectric properties and absorption spectra in absolute units. We found that the inclusion of a water layer in the system leads to a blue-shift and reduced amplitude in the absorption spectra in the low-frequency (0-400 GHz) region. Further decomposition of absorption spectra into protein and water components showed non-additive behavior, arising from partially antiparallel dipole variation vectors of the protein and water fractions, which reduced the overall absorption. Comparison showed that the tubulin heterodimer has stronger absolute sub-THz absorption, consistent with its larger molecular weight and, hence, higher number of atoms and degrees of freedom than kinesin. Together, these results provide a mechanistic understanding of hydration effects on vibrational modes and dielectric properties of proteins. In a greater context, the results have implications for methods in bio-nanoelectromechanical systems for protein dynamics and conformation sensing and in biomedicine and bioelectromagnetics for electromagnetic field-mediated functional modification of proteins.