bluuebunny/crossref_metadata_2025_split huggingface dataset:
Occurrence of NECTIN4 amplification in solid tumors and enfortumab vedotin response in metastatic urothelial cancer.
Authors: Klümper Niklas , Tran Ngoc Khanh , Zschaebitz Stefanie , Hahn Oliver , Zengerling Friedemann , Nagy Dora , Kristiansen Glen , Ivanyi Philipp , Grunewald Camilla Marisa , Darr Christopher , Schlack Katrin , Rausch Steffen , Ritter Manuel , Junker Kerstin , Hartmann Arndt , Grünwald Viktor , Hölzel Michael , Eckstein Markus 
Published: January 2024

673 Background: The anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains are frequent genomic events in mUC leading to NECTIN4 amplifications. Here, we aimed to evaluate the potential of NECTIN4 amplification as a genomic biomarker to predict EV response in patients with mUC. Methods: We established a NECTIN4-specific fluorescence in-situ hybridization (FISH) assay to assess NECTIN4 copy number variations (CNVs) in a multicenter EV-treated mUC patient cohort (UC-EV, N=77), and CNV data were correlated with membranous NECTIN4 protein expression (H-score) assessed via immunohistochemistry, EV treatment responses and outcomes. Next, we conducted a pan-cancer analysis of the The Cancer Genome Atlas (TCGA) datasets, comprising 10,712 patients across 32 cancer types, to investigate the relationship between NECTIN4 CNV, mRNA expression (RNAseq) and protein levels (RPPA) across entities. Results: In TCGA cohorts, NECTIN4 amplification occurs frequently across different solid cancer types, especially in 15-20% of bladder cancers (17% in TCGA-BLCA), as well as 5-10% in breast cancer (TCGA-BRCA) and lung adenocarcinoma (TCGA-LUAD). We confirmed the amplification frequency in our UC-EV cohort (18%). NECTIN4 amplification is significantly associated with both increased NECTIN4 mRNA expression (e.g., TCGA-BLCA, BRCA, LUAD) and membranous NECTIN4 protein expression (UC-EV), and represents a stable genomic alteration during metastatic progression. In the UC-EV cohort, all patients with NECTIN4 amplification (N=14) responded to EV. In multivariable Cox adjusted for age and sex, NECTIN4 amplifications led to a 93% risk reduction for death compared to a NECTIN4non-amplified status (HR=0.07, 95%-CI 0.01–0.53; P<0.001). Conclusions: Our study highlights the value of NECTIN4 amplifications to predict EV responses in patients with mUC. NECTIN4 amplifications occur frequently in different cancer types and therefore have the potential to be a novel tumor-agnostic genomic biomarker that enables tailored NECTIN4-targeted therapies in various entities.
Effect of neutrophil to lymphocyte ratio (NLR) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in real-world setting.
Authors: Lynn David , Dawsey Scott , Patgunarajah Ubenthira , Pramod Nikhil , Wei Wei , Hobeika Charbel , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa 
Published: January 2024

678 Background: Elevated inflammatory biomarkers like the neutrophil to lymphocyte ratio (NLR) has been associated with poor prognosis in several cancers, including UC but there is limited evidence on its role as a prognostic biomarker in patients (pts) with mUC treated with ICIs. We studied the effect of baseline (pre-treatment) NLR on outcomes with ICI in mUC pts in our large cohort of patients with mUC treated with ICIs. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received >/= 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Patient characteristics including age, sex, race, primary site (bladder vs upper tract UC (UTUC)), tumor histology and pre-ICI treatment NLR values were collected and divided into four quartiles: (NLR <2.7, 2.7-4.0, 4.0-7.1, and >7.1). Impact of NLR on overall survival (OS) and progression free survival (PFS) post ICI start date was studied. OS and PFS were estimated using the Kaplan Meier method and compared by log rank test. Results: Of the 335 pts, NLR values were available for 320 pts. Median age was 73 yrs (35-95) and 76% pts were males. 247 pts (74%) received P and 88 (26%) received A. We found that in the 320 patients with available NLR values, the highest quartile values of NLR >/= 7.1 was significantly associated with worse OS (p=0.01). We did not find a statistically significant impact of NLR on PFS (p=0.06). (Table). Conclusions: In our large real-world cohort of pts with mUC receiving ICI, we report the effect of baseline NLR on outcomes with ICI and that NLR >/=7.1 was associated with significantly worse OS. Further validation studies are warranted to risk-stratify pts with mUC planned for ICI treatment. [Table: see text]
Real-world outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and tumors harboring androgen receptor (AR) ligand-binding domain (LBD) mutations.
Authors: Stewart Tyler F. , Chandiwana David , Doyle Ashley , Boame Nana , Saha Jayati , Zhang Nicole , Benjumea Darrin , Rava Andrew , Parameswaran Janaki , Edwards Michelle L. , Lang Joshua Michael 
Published: January 2024

77 Background: In mCRPC, AR T878 and/or H875 and L702H mutations have been associated with disease progression and poor prognosis. This study characterized real-world overall survival (rwOS), testing practices, mutation prevalence, and treatment patterns in patients with mCRPC with and without tumors with missense mutations in the AR LBD (amino acids 671–920). Methods: In this retrospective analysis of the Guardant Inform Database (Mar 11, 2014–Jun 30, 2022), men (aged ≥18 y) with mCRPC who were tested with Guardant360 (G360) next-generation sequencing and diagnosed/treated at a clinical site in the US with a first-line (1L) treatment were included. Matched rwOS was assessed in 2 subpopulations: patients with any missense mutation in AR LBD, excluding those with AR L702H alone ( AR LBD group), and patients with AR T878 and/or H875 without L702H ( AR 878/875 group) and compared with patients without any AR LBD missense mutations (control group). Patients were matched (1:5) on key prognostic variables, including age, Elixhauser Comorbidity Index weighted score, smoking status, prior novel hormonal agent (NHA) use, and 1L treatment year. Mutation prevalence, patient demographics, frequency and timing of G360 tests, and treatment patterns were assessed in patients treated from 2018 to 2022 to reflect more recent trends. Results: In the matched rwOS analysis, patients in the AR LBD group (n=275) had statistically significantly shorter 1L median rwOS compared with the control group (n=1375): 27.3 vs 47.8 months; P<0.0001. Similarly, patients in the AR 878/875 group (n=154) had shortened median rwOS compared with the control group (n=770): 28.9 vs 44.4 months; P=0.0004. Of 4833 patients treated for mCRPC from 2018 to 2022, 20% had AR LBD mutations, 4% had AR 878/875 with L702H, and 6% had AR 878/875 without L702H. Most patients (59%) were first tested at some point after 1L therapy, with only 15% of patients receiving >1 G360 test. Mutation prevalence was higher in patients tested in fourth-line (4L) compared with 1L, particularly for AR L702H mutations (17% vs 10%) and all AR LBD mutations (27% vs 20%). Use of NHAs was lower in 4L compared with 1L (20% vs 33%), whereas use of taxanes was higher (31% vs 22%). Conclusions: Patients with AR LBD–mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.
Real-world experience on tolerability and safety of relugolix combined with androgen signaling inhibitors in patients with advanced prostate cancer.
Authors: Guan Jian , Adroja Shubham , Ajmal Zainub , Gao Yuan , Spetsieris Nicholas , Hu Siqi , Satkunasivam Raj , Brooks Michael A , Farach Andrew M. , Butler E. Brian , Miles Brian , Efstathiou Eleni 
Published: January 2024

85 Background: Relugolix is the first oral GNRH antagonist approved by the FDA in 2021 for the treatment of advanced prostate cancer (PCa). Approval was based on HERO study, which showed a rapid and sustained testosterone suppression superior to that of Leuprolide coupled with a significantly shorter time to eugonad state after discontinuation. Relugolix was associated with a 54% lower risk of major adverse cardiovascular events as compared with Leuprolide. There is very little data available regarding the tolerability safety of Relugolix in combination Enhanced Androgen Signaling Inhibitors (ASI). Here we provide real world experience on the combination of Relugolix and ASIs in patients(pts) with advanced PCa, focusing on safety, tolerability and pharmacodynamic outcome measures. Methods: Houston Methodist Genitourinary Oncology records were reviewed for identification of pts treated with combination Relugolix plus ASI for at least 1 month, from 09/21 to 07/23. Data collected included pts’ baseline and tumor characteristics, cardiovascular and metabolic comorbidities concomitant medication. We recorded Adverse Events, potential Drug Drug Interaction (DDI) and Testosterone (T) and PSA decline. Results: We report 152 advanced hormone-naive PCa pts with median age of 71 (range 48-96). 81% were White or/and Hispanic, 17 % black, 2 % Asian. Majority (90%) had at least 1 cardiovascular risk factor; hypertension (72%), hyperlipidemia (52%), obesity (41 %), diabetes mellitus (26%), coronary artery disease (30%) and atrial fibrillation (13%). ASIs combined with Relugolix included: Darolutamide (78%), Abiraterone (14%), Apalutamide (7%) and Enzalutamide (1%). All but one pt were compliant (99%). Median treatment exposure is 8 months (range 1 -21). All pts had baseline Testosterone >150ng/dL. All pts reached castrate T levels and 90% of patients achieved a T < 20 ng/dL. 55% pts reached PSA <0.1 at median of 4ms, 75% PSA decline > 90% and 91% PSA decline ≥50%. 7% pts discontinued Relugolix due to adverse events. Three pts (2%) had a major adverse cardiovascular event, including one sudden death, one with congestive heart failure, and one with myocardial infarction. Two pts (1%) reported grade 3 fatigue. G3 LFT elevations recorded in 2 pts (1%). No clinical signals of DDI reported. Conclusions: This is the first large original report of the combination of Relugolix with ASIs in real world practice. The combination has a favorable safety and tolerability profile with no new safety concerns. No new DDI concerns were raised. These findings in combination with pharmacodynamic outcome measures of T / PSA support the use of Relugolix in combination with ASIs as standard of care in advanced PCa.
SECuRE: A dose escalation/expansion study to assess the anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate-resistant prostate cancer.
Authors: Johnson Geoffrey , Lengyelova Eva , Nordquist Luke T. , Prasad Vikas , Anderson Monique , Gervasio Othon , Parker Michelle , Miller Robert M. , Sartor A. Oliver , Tagawa Scott T. 
Published: January 2024

TPS246 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604 .
SWOG S2200 (PAPMET2): A phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC).
Authors: Maughan Benjamin L. , Plets Melissa , Pal Sumanta Kumar , Ged Yasser , Tangen Catherine , Vaishampayan Ulka N. , Lerner Seth P. , Thompson Ian M. 
Published: January 2024

TPS493 Background: The role of immune therapy is not established in PRCC. The S1500 (PAPMET) clinical trial established single agent cabozantinib as the standard of care for PRCC (PMID 33592176) with a median progression free survival (PFS) of 9.0 months compared to 5.6 months with sunitinib. Trials have shown activity of PD-(L)1 antagonists as monotherapy (PMID 33529058) or in combination with targeted therapy (PMID 34491815). In a single arm study of cabozantinib/nivolumab the median PFS was 12.5 months (PMID 35298296). There are no prior randomized studies of immune therapy in PRCC. Single arm trials often overestimate the true effect size (PMID 31218346), highlighting the unmet clinical need for a randomized clinical trial in PRCC. We hypothesize that the combination will have higher clinical activity than single agent cabozantinib. Methods: This is a prospective randomized phase II clinical trial conducted through the NCTN and led by SWOG. The primary endpoint is a comparison of PFS between cabozantinib and cabozantinib/atezolizumab. Secondary endpoints include comparison of objective response rate, overall survival and safety. Patients are treated with cabozantinib 60mg/day versus cabozantinib 60mg/day + atezolizumab 1200 mg q3 weeks. 200 patients will be enrolled and randomized 1:1. Key inclusion criteria include a pathologic confirmation of PRCC; presence of metastasis; 0-1 prior systemic lines of therapy for metastatic disease; and measurable disease as defined by RECIST 1.1 criteria. Prior treatment with adjuvant pembrolizumab is allowed if completed greater than 6 months before enrollment. Key exclusion criteria include clinically significant autoimmune disease; ongoing use of strong CYP3A4 inhibitors, strong CYP3A4 inducers. Planned correlatives include stool microbiome testing and genomic/transcriptomic analysis from blood and baseline tissue assays. Clinical trial information: NCT05411081 .
PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.
Authors: Iyer Gopa , Kwiatkowski David J. , Ding Li , Schmid Anita N. , Navarro Willis H. , Rodon Ahnert Jordi 
Published: January 2024

TPS526 Background: According to SEER data, patients in the USA with advanced genitourinary (GU) cancers such as bladder and kidney cancers have low 5-year survival rates of 8.3% and 17.8%, respectively. This underscores the need for more efficacious treatments. Tumor growth and disease progression may be facilitated by aberrant activation of the mTOR pathway in some GU cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of the mTOR pathway, and their inactivation may result in tumor growth. Inactivating TSC1 and TSC2 alterations have been observed in GU cancers with combined frequencies of up to 9.6% in bladder, 5.8% in kidney, and 0.7% in prostate cancers. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. Clinically, in an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. Enrollment is open to patients with bladder, kidney, and prostate cancers with TSC1 or TSC2 inactivating alterations. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and they have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors will expedite the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .
Black Imaginaries and Nahua Rhetoric in Colonial Mexico: Diario de Don Domingo de San Antón Muñón Chimalpahin Quauhtlehuanitzin
Authors: Cuellar Manuel R. 
Published: January 2024

Abstract
In 1612, Chalca historian Don Domingo de San Antón Muñón Chimalpahin Quauhtlehuanitzin, Mexico’s most prolific Indigenous writer, documented the execution of thirty-five Black and mulatto people. The group of twenty-eight men and seven women was accused of scheming against the Spanish colonial government, threatening to riot, and plotting to “blacken” the population of New Spain by killing Spaniards and forcing racial mixing. Attending to the semantic and morpho-syntactic structure of Nahuatl, this article proposes a linguistic analysis to recontextualize Chimalpahin’s retelling of the alleged plot and the fears of a Black uprising in colonial Mexico from an Indigenous perspective. At stake is how the plurivocal structure of the Nahua archive allows for the inscription of Blackness and racialized subjectivities in colonial Mexico while challenging the claims to an absolute truth imposed by the Spanish.
The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging
Authors: Egan Brian M. , Pohl Franziska , Anderson Xavier , Williams Shoshana C. , Gregory Adodo Imienreluefe , Hunt Patrick , Wang Zuoxu , Chiu Chen-Hao , Scharf Andrea , Mosley Matthew , Kumar Sandeep , Schneider Daniel L. , Fujiwara Hideji , Hsu Fong-Fu , Kornfeld Kerry 
Published: January 2024

ABSTRACT
The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.
Polarisation vision in the dark: green-sensitive photoreceptors in the nocturnal ball-rolling dung beetle Escarabaeus satyrus
Authors: Yilmaz Ayse , Belušič Gregor , J. Foster James , Tocco Claudia , Khaldy Lana , Dacke Marie 
Published: January 2024

ABSTRACT
Many insects utilise the polarisation pattern of the sky to adjust their travelling directions. The extraction of directional information from this sky-wide cue is mediated by specialised photoreceptors located in the dorsal rim area (DRA). While this part of the eye is known to be sensitive to the ultraviolet, blue or green component of skylight, the latter has only been observed in insects active in dim light. To address the functional significance of green polarisation sensitivity, we define the spectral and morphological adaptations of the DRA in a nocturnal ball-rolling dung beetle–the only family of insects demonstrated to orient to the dim polarisation pattern in the night sky.
Intracellular recordings revealed polarisation-sensitive green photoreceptors in the DRA of Escarabaeus satyrus. Behavioural experiments verified the navigational relevance of this finding. To quantify the adaptive value of green sensitivity for celestial orientation at night, we also obtained the polarisation properties of the night sky in the natural habitat of the beetle. Calculations of relative photon catch revealed that under a moonlit sky the green-sensitive DRA photoreceptors can be expected to catch an order of magnitude more photons compared with the UV-sensitive photoreceptors in the main retina. The green-sensitive photoreceptors – which also show a range of morphological adaptations for enhanced sensitivity – provide E. satyrus with a highly sensitive system for the extraction of directional information from the night sky.