tbuckley/cabot-search huggingface dataset:
Anlotinib plus everolimus as first-line treatment for advanced non–clear cell renal cell carcinoma: A single-center, single-arm, phase II trial.
Authors: Hailiang Zhang, Dingwei Ye
Journal: Journal of Clinical Oncology (2024)

e16533 Background: For patients (pts) with recurrent or stage IV non-clear cell renal cancer (nccRCC),the medical treatment guidelines recommend the first choice to participate in clinical trials, or use TKI drugs such as sunitinib, and mTOR inhibitors such as everolimus. Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI). It’s antitumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. ALTER-UC-001 is a single-center, single-arm, phase II trial which evaluated the efficacy and tolerability of anlotinib plus everolimus as first-line therapy in pts with nccRCC (NCT05124431). Methods: Patients with advanced nccRCC and no prior systemic drug therapy for advanced disease were eligible for this trial; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. The patients received 12mg anlotinib once daily on days 1-14 every 3 weeks by oral, and 5mg everolimus orally once daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall disease control rate (DCR), progression free survival (PFS), and over survival (OS). Adverse events will be monitored throughout the study and graded according to CTCAE V5.0. Results: Between Jan 2022 and Dec 2023, 24 pts were enrolled and received study treatment. The median age was 56 years old (range: 20 to 79 years). Nineteen pts (79.2%; 19/24) had a ECOG PS score of 1, and five pts (20.8%; 5/24) had a ECOG PS score of 0. All pts had not received prior treatment. In addition, 17 (70.8%) had received surgical treatment and 1 (4.2%) had received radiotherapy. The data cutoff was Dec 2023, with a median follow-up of 6.04 (range, 1.34-18.1) months.14 pts had the best overall response (unconfirmed) assessments which inferred the ORR of 57.1%(PR in 8 pts 95% CI, 29.6-81.2)and the DCR of 100% (PR in 8 pts and SD in 6 pts; 95% CI, 73.2-100). The median PFS has not reached. Any grades of adverse events (AEs) were observed in 91.7% (22/24) of pts, the most common of which were mucositis (29.1%), hypertension (25.0%) , creatinine increased(16.7%), proteinuria (16.7%) and glutamic-pyruvic transaminase increased (12.5%).Seven (29.1%) pts experienced grade 3 TRAEs, including hypertension (8.3%), proteinuria (8.3%), mucositis (4.2%), platelet count decreased (4.2%), creatinine increased (4.2%), chronic gastritis (4.2%) and bleeding (4.2%). No treatment-related deaths occurred. Three (12.5%) and two (8.3%) pts had suspension of treatment because of TRAEs caused by everolimus and anlotinib respectively. Conclusions: Anlotinib plus everolimus as first-line therapy is efficacious and safe for pts with advanced nccRCC. We will report more data in the future. Clinical trial information: NCT05124431 .
Metabolic profiles of children aged 2–5 years born after frozen and fresh embryo transfer: A Chinese cohort study
Authors: Wei Zhou, Wanbing Feng, Jinli Chang, Jingmei Hu, Fuxia Li, Kuona Hu, Jiejing Jiao, Xinyi Xue, Ting Lan, Wenjing Wan, Zi-Jiang Chen, Linlin Cui
Journal: PLoS Medicine (2024)

Background Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. Methods and findings This was a prospective cohort study. Using data from the “Assisted Reproductive Technology borned KIDs (ARTKID),” a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET ( n = 2,181) and fresh embryo transfer ( n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. Conclusions In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.
Biological Age, Chronological Age and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis
Authors: Janelle Vu Pugashetti, John S. Kim, Swaraj Bose, Ayodeji Adegunsoye, Angela L Linderholm, Ching-Hsien Chen, Mary E. Strek, Kevin R. Flaherty, Susan Murray, Chad A. Newton, Shehabaldin Alqalyoobi, Shwu-Fan Ma, Josyf C. Mychaleckyj, Russell P. Bowler, MeiLan K. Han, Jeffrey L. Curtis, Fernando J. Martinez, Jennifer A Smith, Imre Noth, Justin M. Oldham
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood.
Association of machine learning (ML)–derived histological features with transcriptomic molecular subtypes in advanced renal cell carcinoma (RCC).
Authors: Niha Beig, Shima Nofallah, David F. McDermott, Robert J. Motzer, Thomas Powles, Brian I. Rini, Hartmut Koeppen, Romain Banchereau, Miles Markey, Isaac Finberg, Geetika Singh, Limin Yu, Robert Egger, Chintan Parmar, Jake Conway, Stephanie Hennek, Daniel Ruderman, Samuel Vilchez, Mahrukh A Huseni, Jennifer Margaret Giltnane
Journal: Journal of Clinical Oncology (2024)

4519 Background: Metastatic RCC (mRCC) is a molecularly heterogeneous disease. Transcriptomic analysis in the Phase 3 IMmotion 151 (Im151) trial identified 7 molecular subtypes that showed differential outcomes to Atezolizumab+Bevacizumab (A+B) vs Sunitinib (S) treatment (Motzer, Cancer Cell 2020). Here, we present histological correlates of these subtypes as identified in whole slide images (WSI) of hematoxylin and eosin (H&amp;E) stained tumors. Methods: ML models identified 922 H&amp;E derived, human interpretable histological features (ML HIFs) in RCC associated with tumor and stromal (including vessels, immune cells, fibroblasts) cell and tissue morphologies, and nucleus shape. These ML HIFs were then extracted from WSI in 2 mRCC trials – Im151 (n=797) and IMmotion150 (Im150, n=203). Previously described 7 molecular subtypes were combined into 4 subgroups (Angiogenic [comprised of Angiogenic/Stromal and Angiogenic], Complement/OmegaOxidation, T-effector, and Proliferative [comprised of Proliferative and Stromal Proliferative]) for computational power. Due to low prevalence, snoRNA subset was excluded. Univariate analysis with FDR correction was applied to identify positively associated ML HIFs in each of the 4 subgroups in the Im151 WSI and then validated in Im150 subgroups. Representative ML HIFs that showed uniquely higher abundance in each molecular subgroup in both studies were dichotomized by tertiles as ‘high’ or ‘low/intermediate’ and associated with progression free survival (PFS) to fit Cox proportional hazard models in Im151 study. Results: 169 ML HIFs were differentially enriched across 3 molecular subgroups in both Im151 and Im150 data sets. Angiogenic subgroup had higher prevalence of 40 ML HIFs associated with density of endothelial cells in cancer epithelium. T-effector subtype showed higher abundance of 64 ML HIFs associated with immune cell presence in stroma. Proliferative subgroup showed higher prevalence of 40 ML HIFs associated with nuclear morphologies. No ML HIFs were uniquely associated with the Complement/OmegaOxidation subgroup. Consistent with transcriptional findings in Im151, ML HIFs that were enriched in T-effector and Proliferative subgroups showed improved PFS benefit to A+B vs S (Table). Conclusions: We identified unique histological features of RCC tumors that correlate with previously defined molecular subtypes. Our results suggest that clinically relevant RCC subtypes may be extracted directly from H&amp;E-stained WSI and may complement gene expression based patient stratification and selection strategies. [Table: see text]
Phase 2 study of neoadjuvant enzalutamide and paclitaxel for luminal androgen receptor-enriched TNBC: Trial results and insights into “ARness”
Authors: Bora Lim, Sahil Seth, Clinton Yam, Lei Huo, Takeo Fujii, Jangsoon Lee, Roland Bassett, Sara Nasser, Lisa Ravenberg, Jason White, Alyson Clayborn, Gil Guerra, Jennifer K. Litton, Senthil Damodaran, Rachel Layman, Vicente Valero, Debasish Tripathy, Michael Lewis, Lacey E. Dobrolecki, Jonathan Lei, Rosalind Candelaria, Banu Arun, Gaiane Rauch, Li Zhao, Jianhua Zhang, Qingqing Ding, W. Fraser Symmans, Jeffrey T. Chang, Alastair M. Thompson, Stacy L. Moulder, Naoto T. Ueno
Journal: Cell Reports Medicine (2024)

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC.
Costs associated with novel first-line (1L) treatments in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) from a United States (US) Medicare and commercial payer perspective.
Authors: Chiemeka Ike, Thitima Kongnakorn, Eszter Tichy, Javier Sanchez Alvarez, Mairead Kearney
Journal: Journal of Clinical Oncology (2024)

e16552 Background: Recent drug approvals in the 1L treatment (tx) setting have expanded options for pts with la/mUC. It is important to understand the economic burden of these novel therapies within the current tx landscape. This study estimated first-year cost of care in the US from a Medicare and commercial payer perspective for pts with la/mUC treated with the following 1L tx: enfortumab vedotin (EV) + pembrolizumab (PEM) in platinum-eligible pts, nivolumab (NIV) + platinum-based chemotherapy (PBC) in cisplatin-eligible pts, and 1L PBC with or without avelumab (AVE) 1L maintenance (1LM). Methods: A cost of care model was developed to estimate direct medical care costs in the first year of tx with EV + PEM, NIV + PBC, and PBC with and without AVE 1LM in pts with la/mUC who are eligible for 1L PBC; pts treated with NIV + PBC were eligible for cisplatin. The latest available costs (2023 USD)—including drug acquisition and administration, disease management, adverse event (AE) management, and subsequent therapy (second-line or later line) costs—were calculated based on tx duration, progression-free survival, overall survival, and AE incidence with various therapies. Efficacy and safety data were sourced from key published trials (EV-302, CheckMate-901, JAVELIN Bladder 100) and product prescribing information. Results: Estimated first-year costs per treated pt are shown in the Table. Cost per treated pt was estimated to range between $56,952 to $438,660 and $90,918 to $457,390 for Medicare and commercial payers, respectively, with the highest cost for EV+PEM and the lowest for PBC only. Drug acquisition costs in the 1L represented the majority of the costs except PBC, for which subsequent tx and administration costs represented the largest cost component. Conclusions: Costs per treated pt were lower for PBC with AVE 1LM than for EV+PEM and NIV+PBC. As value-based oncology care is becoming increasingly important in the US, comprehensive understanding of costs across different tx options and sequences can facilitate informed tx choice. [Table: see text]
Real-world clinical and toxicity outcomes in older Veterans with metastatic renal cell carcinoma (mRCC) treated with front-line systemic therapy.
Authors: Ragia Aly, Ziyi Yang, Jordan Marie Schmitt, Jennifer King
Journal: Journal of Clinical Oncology (2024)

e16525 Background: The United States veteran population represents a unique group of patients with distinct health care challenges, particularly for older veterans. Here, we describe a real-world cohort of veterans with mRCC treated with systemic therapy and assess if outcomes and toxicities with front-line systemic therapy differ for older adult veterans. Methods: Veterans diagnosed with mRCC between 2010- 2023 at the Richard L. Roudebush VA in Indianapolis and treated with front-line systemic therapy were identified. Patients were classified as £65yo and &gt;65yo. Comparisons between groups were done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS), with Cox model used to adjust for confounders. Results: A total of 73 patients with mRCC were identified. Median age was 67.4. 31 patients (42%) were £65yo and 42 (58%) were &gt;65. 99% of patients were male. 69% of patients had clear cell histology, 11% papillary, 11% poorly differentiated, 5% unclassified, 2% chromophobe, 2% sarcomatoid, and 2% other. 52% of patients ≤65yo had IMDC int/poor risk disease vs. 85% of patients &gt;65 (p=0.016). There was no statistically significant difference in disease grade, stage, or presence of sarcomatoid/rhabdoid features between groups. The table lists and compares therapies received and toxicity outcomes. The median PFS was 18.7 months in pts ≤65yo vs. 7.1 months in pts &gt;65 (p=0.24). The median OS was 58.1 months in pts ≤65 vs. 12.6 months in pts &gt;65. (p=0.048). When using the Cox model to adjust for IMDC risk, the OS difference was not maintained, with a hazard ratio of 1.16 (CI 0.59, 2.27; p=0.664). Conclusions: In this cohort of veteran patients with mRCC, older veterans had higher rates of IMDC int/poor risk disease, likely leading to decreased survival outcomes. Front-line systemic therapies used were similar to younger veterans without an apparent difference in toxicity. This material is the result of work supported with resources and the use of facilities at the Richard L. Roudebush VA in Indianapolis. [Table: see text]
Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC).
Authors: Brian I. Rini, Elizabeth R. Plimack, Viktor Stus, Rustem Gafanov, Tom Waddell, Dmitry Nosov, Frederic Pouliot, Boris Alekseev, Denis Soulieres, Sergio Jobim Azevedo, Delphine Borchiellini, Raymond S. McDermott, Rodolfo F. Perini, Julia Markensohn, L. Rhoda Molife, Yiwei Zhang, Michael Nebozhyn, Andrey Loboda, Amir Vajdi, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

4505 Background: P + A improved OS, PFS, and ORR over S in 1L advanced RCC in KEYNOTE-426 (NCT02853331).Here, we present exploratory biomarker results including RNAseq, WES, and PD-L1. Methods: Patients (pts) with treatment-naive advanced RCC were randomly assigned 1:1 to P + A or S. Association between T-cell–inflamed gene signature (Tcell inf GEP), angiogenesis gene signature (RNAseq), and PD-L1 CPS (22C3 IHC) with clinical outcomes were tested at prespecified α=0.05. Other RNA signatures (Cristescu et al. Clin Cancer Res. 2022. 2022;28:1680) and molecular subtypes, based on clustering identified from IMmotion151 (Motzer et al. Cancer Cell. 2020;38:803), were tested at prespecified α = 0.10 after multiplicity adjustment. DNA mutations ( VHL, PBRM1, SETD2, and BAP1) by WES were tested at prespecified α = 0.10 after multiplicity adjustment. Results: Of 861 pts, 369 (P + A) and 361 (S) had archival samples for RNAseq; 347 (P + A) and 351 (S) had WES samples. PD-L1 CPS was negatively associated with OS ( P=0.013) for S. There was a strong positive association of Tcell inf GEP with OS ( P=0.003), PFS ( P&lt;0.0001), and ORR ( P&lt;0.0001) for P + A. Angiogenesis was positively associated with OS ( P=0.013) for P + A; there was a strong positive association with OS ( P&lt;0.0001), PFS ( P&lt;0.001), and ORR ( P=0.002) for S. For other RNA signatures, positive association with mMDSC was found for PFS ( P=0.018) and ORR ( P=0.093) with P + A. For S, positive association was found with hypoxia (OS, P=0.034; ORR, P=0.071) and negative associations with MYC (OS, P&lt;0.001; PFS, P=0.012) and proliferation (OS, P=0.002). Across all molecular clusters, ORR favored P + A over S, with the highest P + A ORR in the immune/proliferative cluster (Table). By WES, PBRM1 mutation had positive association with ORR ( P=0.004) and PFS ( P=0.079) for P + A. For S, positive associations were observed with OS for VHL ( P=0.073) and PBRM1 ( P=0.001) mutations and a negative one observed for BAP1 mutation ( P=0.046). P + A improved ORR over S regardless of mutational status. Conclusions: There was a strong relationship of Tcell inf GEP with clinical outcomes with P + A. Angiogenesis was positively associated with outcomes with S and only with OS with P + A. Further understanding the role of the immune microenvironment in combination therapy will be critical to advance treatment strategies. Clinical trial information: NCT02853331 . [Table: see text]
Preliminary results of bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04).
Authors: Feng Wen, Ping Tan, Tianhai Lin, Hao Zeng, Qiang Wei, Peng Zhang, Yali Shen
Journal: Journal of Clinical Oncology (2024)

e16557 Background: To evaluate the treatment safety and efficacy of short-course radiotherapy combined with PD-1 antibody (Toripalimab) as a potential bladder-preserving therapy for high-risk / extremely high risk non-muscle invasive bladder cancer (NMIBC). Methods: HOPE-04 is a single-arm open-label, phase II trial, which designs to evaluate the safety and efficacy of short-course radiotherapy (5 × 5 Gy) and Toripalimab as a novel bladder sparing treatment in patients with high-risk / extremely high risk NMIBC. Fifty-five pathological and imaging diagnosed NMIBC patients with or without BCG treatment will be recruited. Radiotherapy of 5× 5 Gy/fractions will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of Toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about one year). The primary endpoints are disease free survival (DFS) and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life. Results: Until now, 11 patients were included successfully, with 2 female patients and 9 male patients. And the median age was 62.36 years old. Of them, 5 patients were low grade differentiation, and 6 patients were high grade. The median follow-up time was 12.56 months. Two patients with history of multiple recurrence sites repeatedly suffered from local recurrence after radiotherapy and received radical cystectomy. The pathologic stagings were pT1N0 for both patients after surgery. Therefore, the one year- bladder intact DFS rate was 62.5% and the median RFS was not achieved. No patient died so far. For safety analysis, 4 patients suffered from immune-related adverse event, namely, grade 2 arthritis, grade 1 rash and grade 1 hyperthyroidism which led to treatment interruption of Toripalimab. And 2 patients experienced radiotherapy related toxicities, including grade 1 frequent urination and urgency, grade 1 erythra and grade 1 anal sagging sensation. No treatment related dose reduction happened. Conclusions: HOPE-04 is the first encouragement of short-course radiotherapy and Toripalimab combination in the treatment of high-risk / extremely high risk NMIBC, which extends the therapeutic options of bladder preservation treatment for this population. Our preliminary results show a promising effect both in prevention of local recurrence as well as distant metastasis, and toxicities were manageable, which would be verified by the final analysis. Clinical trial information: ChiCTR2200059970 .