bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors affecting the duration of initial medical care seeking among older rural patients diagnosed with rheumatoid arthritis: a retrospective cohort study
Authors: Ohta Ryuichi , Sano Chiaki 
Published: June 2024

Abstract
Background
Early diagnosis and treatment of rheumatoid arthritis (RA) are essential to prevent progressive joint destruction and improve the quality of life (QOL) of patients. This study aimed to identify the factors associated with the duration from symptom onset to seeking initial medical care among older rural patients diagnosed with RA.

Methods
This retrospective cohort study was conducted in Unnan City, Japan, using electronic patient records. Data from patients aged > 65 years, who were admitted to the Unnan City Hospital between April 2016 and March 2021, were analyzed. The primary outcome was the duration from symptom onset to the initial visit to the medical institution. Demographic factors, laboratory data, and data on symptoms were collected and analyzed using statistical tests and regression models.

Results
In total, 221 participants were included in this study. The longer duration from symptom onset to medical care usage was significantly associated with age (adjusted odds ratio [OR]: 1.09, 95% confidence interval [CI]: 1.03–1.15), isolated conditions (adjusted OR: 4.45, 95% CI: 1.85–10.70), and wrist symptoms (adjusted OR: 3.22, 95% CI: 1.44–7.17). Higher education level and alcohol consumption were also associated with the duration from symptom onset to medical care usage.

Conclusions
Older age, isolated conditions, and specific joint symptoms were significant factors influencing delays in seeking medical care among older rural patients with RA. Interventions to improve health literacy, increase social support, and raise awareness of RA symptoms are essential for expediting diagnosis and improving patient QOL. Further research is needed to explore additional psychosocial factors and beliefs that affect health-seeking behaviors in patients with RA.
Myosteatosis on computed tomography as a predictor of therapeutic response to CDK4/6 inhibitors plus aromatase inhibitors in patients with advanced breast cancer.
Authors: Kim Min Hwan , Kim Hyunwook , Baek Seungjin , Han Sookyeong , Kim Gun Min , Sohn Joohyuk , Rhee Yumie , Hong Namki 
Published: June 2024

1030 Background: Recent evidence indicates that a dysregulated host metabolism influences treatment outcomes in patients with breast cancer. We investigated the association of computed tomography (CT)-derived body composition indices as imaging biomarkers of host metabolic status with therapeutic responses in patients with hormone receptor-positive, HER2-negative advanced breast cancer (ABC) on endocrine plus CDK4/6 inhibitor (CDK4/6i) treatment. Methods: The study involved a prospective cohort of patients with ABC at the Yonsei Cancer Center who received CDK4/6i and aromatase inhibitors as first-line therapy. Body composition parameters were estimated from the pretreatment non-enhanced CT images of the third lumbar spine. Myosteatosis was defined as skeletal muscle radiodensity (SMD) of low tertile (≤28.7 Hounsfield Units). The primary outcome was progression-free survival (PFS). Results: Among the 247 participants (mean age, 54.8 years; body mass index [BMI], 23.7 kg/m2), 45.7% had events during a median follow-up of 36.4 months. Low SMD was an independent predictor of worse PFS after adjusting for age and visceral metastases (adjusted hazard ratio [HR]=1.20 per standard deviation decrement, p=0.041), whereas BMI, muscle area, and fat area did not. Participants with myosteatosis had a higher risk of progression than those without (PFS, 27.2 vs. 51.1 months; p=0.009; adjusted HR 1.84, p=0.003). Strong associations between myosteatosis and poor PFS were observed in groups with pre-menopause status (HR, 3.04 vs. 1.19 in post-menopause; p for interaction <0.05) and without visceral metastases (HR, 2.95 vs. 1.19 in with visceral metastases; p for interaction <0.05). Conclusions: CT-derived myosteatosis predicts poor treatment outcomes in patients with ABC undergoing first-line treatment with aromatase inhibitors and CDK4/6i.
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: Rini Brian I. , Plimack Elizabeth R. , Stus Viktor , Gafanov Rustem , Waddell Tom , Nosov Dmitry , Pouliot Frederic , Alekseev Boris , Soulieres Denis , Azevedo Sergio Jobim , Borchiellini Delphine , McDermott Raymond S. , Perini Rodolfo F. , Markensohn Julia , Molife L. Rhoda , Zhang Yiwei , Nebozhyn Michael , Loboda Andrey , Vajdi Amir , Powles Thomas 
Published: June 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 (TcellinfGEP), 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 TcellinfGEP with OS ( P=0.003), PFS ( P<0.0001), and ORR ( P<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<0.0001), PFS ( P<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<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 TcellinfGEP 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 safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma.
Authors: Pal Sumanta Kumar , Tannir Nizar M. , Grell Peter , Gao Xin , Kotecha Ritesh R , Picus Joel , De Braud Filippo G. , Takahashi Shunji , Wong Alvin , Suárez Cristina , Otero Javier A , Kundamal Nicole , Yang Xin , Sharaby Sherif , Roy Mike , Barzaghi-Rinaudo Patrizia , Albiges Laurence 
Published: June 2024

4513 Background: Targeting HIF2α inhibition has been proven to be an effective therapeutic option in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC). DFF332, a small molecule inhibitor that selectively targets HIF2α transcriptional activity, has shown dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This is the first in human, Phase I/Ib, open-label, multicenter, study (CDFF332A12101, NCT04895748) of DFF332 in adult pts with advanced ccRCC. The study evaluated the safety, tolerability, antitumor activity, pharmacokinetics (PK) and pharmacodynamics of DFF332. Here we report the preliminary data of the dose escalation of DFF332 monotherapy, administered orally at 50 mg or 100 mg weekly (QW) or at 25 mg, 50 mg, 100 mg or 150 mg once daily (QD) in 28-day treatment cycles. Results: Between Nov 30, 2021 to Nov 15, 2023, 40 pts (male, 78%) with a median age of 62.5 (38-79) years received treatment with DFF332. All pts received ≥1 prior line of therapy. At data cutoff, 18 pts were continuing treatment, while the treatment was discontinued in 19 pts (48%) due to progressive disease, and in 3 pts (8%) based on the physician's decision. The median (range) duration of exposure was 12.1 (1.0-75.6) weeks. Overall, 37 pts (93%) reported ≥1 adverse event (AE) regardless of relationship to study drug. Most common AEs were fatigue (33%), anemia (30%), increased blood cholesterol, and constipation (each 15%). Treatment-related AEs (TRAEs) were reported in 24 pts (60%): anemia, increased blood cholesterol, fatigue (each 13%), and hypertriglyceridemia (10%) being the most common TRAEs. Grade 3 TRAEs were increased weight and hypertension (1 pt [2.5%] each). Hypertension was the only treatment-related serious AE reported in 1 pt. No grade 4 TRAEs and dose-limiting toxicities have been observed so far. None of the patients reported hypoxia. At cut-off, 18 pts (45%) had stable disease (SD) and two pts (5%) achieved partial response [PR] accounting to a disease control rate (complete response + PR + SD) of 50%. Preliminary PK results demonstrated fast oral absorption, slow elimination, and dose-proportional exposure. Conclusions: During this phase I study, the monotherapy of DFF332 has shown a promising safety profile across all doses and schedules. Additionally, there have been indications of clinical activity and a dose-proportional modulation of erythropoietin. Currently, we are conducting an ongoing analysis of the PK and biomarker data, which will be included in the presentation. Clinical trial information: NCT04895748 .
A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial.
Authors: Maluf Fernando Cotait , Trindade Karine , Preto Daniel D Almeida , Monteiro Fernando Sabino Marques , Luz Murilo , Beato Patricia Milhomem , Bastos Diogo Assed , Soares Joao Paulo Holanda , Lopes dos Santos Victor Marcondes , Werneck De Carvalho Luis Eduardo , Muniz David Queiroz Borges , Racy Douglas , Halabi Susan , Rebelatto Taiane Francieli , Werutsky Gustavo , de Jesus Rafaela Gomes , Fay Andre P. 
Published: June 2024

5009 Background: Over the last six decades, platinum-based chemotherapy has been the standard of care first-line treatment for advanced penile squamous cell carcinoma (PSCC). Advanced PSCC has poor prognosis with limited treatment options. Immune checkpoint inhibitors (ICI) have been associated with improved efficacy in different types of malignancies, however the benefit in PSCC is uncertain. Methods: LACOG 0218 ( NCT04224740 ) is a phase II single arm trial evaluating pembrolizumab plus platinum-based chemotherapy as first-line treatment in advanced PSCC. Patients (pts) with metastatic or locally advanced disease (recurrent or TanyN3M0 or T4NanyM0) not amenable to curative-intent therapy received: 5-FU 1000mg/m²/day IV D1-D4; cisplatin 70mg/m² (or carboplatin AUC 5) IV D1; and pembrolizumab 200mg IV D1 every 3 weeks (Q3W) for 6 cycles, followed by pembrolizumab 200mg IV Q3W up to 34 cycles. The primary endpoint is confirmed overall response rate (cORR) assessed by investigator (INV) according to RECIST 1.1. Considering a drop-out rate of 10%, 33 patients were required to reject the null hypothesis that ORR is 20% or less, if the true ORR is 40% (two-sided alpha level of 0.10, power 78.5%). Results: From Aug2020 to Dec2022, 37 pts were enrolled in 11 Brazilian centers and 33 pts were eligible for efficacy analysis. Median age was 56y (range, 30-76), 64.9% of pts had metastatic disease, 21.6% had recurrent disease, and 13.5% had locally advanced disease. Efficacy results are presented in the table. cORR by INV was 39.4% (95% CI 22.9-57.9); with 1 complete response and 12 partial responses. cORR INV according to PD-L1 status (66.7% in CPS 0% vs. 33.3% in CPS≥1%); TMB status (75% in high vs. 36.4% in low); and HPV16 status (HPV16 positive 55.6% vs. 35.0%). The most frequent genomic alterations detected by NGS were: TP53(57.1%), CDKN2A (51.4%), and TERT (31.4%). Treatment-related adverse events (AE) rate of any grade was 91.9% and grade 3-4 was 51.4%. Ten pts experienced Grade 5 AE, none of them related to study treatment. Immune-related AEs of any grade was 21.6% and grade 3-4 was 5.4%. 10.8% discontinued treatment due to AE. Conclusions: HERCULES is the first trial to demonstrate the efficacy of ICI in advanced PSCC with manageable safety profile. HPV16 and TMB are potential predictive biomarkers for efficacy. ICI combined with platinum-based chemotherapy is a promising treatment for advanced PSCC warranting further investigation. Clinical trial information: NCT04224740 . [Table: see text]
Post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for metastatic pure seminoma.
Authors: Heidenreich Axel , Daneshmand Siamak , Che Yu , Pfister David A. , Paffenholz Pia , Ghoreifi Alireza , Zschaebitz Stefanie , Hentrich Marcus , Thy Sophia , Albers Peter , Cary Clint , Gerdtsson Axel , Kjellman Anders , Negaard Helene F. S. 
Published: June 2024

5037 Background: Surgical resection of post-chemotherapy residual masses for metastatic seminoma is discussed controversially with regard to oncological and functional outcome. Furthermore, the role of FDG-PET/CT to detect vital seminoma is still unclear. It is the aim of this study is to report the outcomes of patients with pure seminoma who underwent PC-RPLND. Methods: In this retrospective multi-institutional study, pure seminoma patients whounderwent PC-RPLND for marker negative, FDG-PET/CT positive residual masses > 3cm or marker negative retroperitoneal relapse following first line chemotherapy between 2000 and 2023 were included. Patients with residual masses and negative FDG-PET/CT, inadequate systemic chemotherapy, insufficient clinical data, positive markers, or with residual or relapsing masses following salvage chemotherapy were excluded. Perioperative and long-term outcomes were reviewed. Results: 109 patients were included. All patients received first-line cisplatin-based chemotherapy. Clinical features of the patients are presented in the table. 92.6% of PC-RPLNDs were performed via an open transperitoneal approach. 61 (55.9%) and 48 (44.1%) pts underwent unilateral and a full bilateral resection, resp. Adjunctive surgery was performed in 46 (42%) pts, the most common of which were ureteral resection/repair in 16 (15%) pts, and vascular resection/repair in 14 (13%) pts. Median (IQR) blood loss and length of hospital stay were 550 (300 – 5800) mL and 4 (2 – 18) days, resp. Clavien - Dindo complications ≥ 3a developed in 11 (10.1%) pts. Final pathology revealed necrosis/fibrosis in 75 (69%) and seminoma in 34 (31%). FDG-PET/CT for residual masses > 3cm showed a positive predictive value of only 20%. Except for marker negative progression (p<0.001), no reliable clinicopathologic parameters were identified to predict presence of viable seminoma. With a median (IQR) follow-up of 56 (2 – 164) months, 15 (14%) patients relapsed (12 with lymph node, 3 with visceral/skeletal metastases). 3 (3%) patients died of disease. Conclusions: One third of patients with progressive or > 3cm FDG-PET-CT positive residual retroperitoneal masses following first-line chemotherapy for metastatic seminoma may have viable tumor. FDG-PET/CT has a poor positive predictive value and might be omitted as staging procedure. In selected cases, PC-RPLND may be a valuable option if performed in high-volume centers with expertise in testicular cancer management.[Table: see text]
Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Secondary analysis of the SPARTAN trial.
Authors: Roy Soumyajit , Saad Fred , Malone Shawn , Sun Yilun , Spratt Daniel Eidelberg , Kishan Amar Upadhyaya , Wallis Christopher J.D. , Jia Angela , Mohamad Osama , Swami Umang , Ong Michael , Agarwal Neeraj , Chowdhury Simon , Morgan Scott C. 
Published: June 2024

5046 Background: While exposure to concomitant medications (conmeds) have been found to influence survival and treatment response in patients with metastatic prostate cancer, it is unclear if exposure to these medications affect treatment response and survival in men with non-metastatic castrate resistant prostate cancer (nmCRPC) treated with androgen receptor signaling inhibitors (ARSI). We performed an exploratory analysis of the SPARTAN trial to determine whether receipt of conmeds influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with nmCRPC. Methods: SPARTAN is a phase III randomized controlled trial in which nmCRPC patients were randomly assigned 2:1 to receive apalutamide or placebo in addition to androgen deprivation therapy (ADT). We focused on 5 groups of commonly prescribed classes of conmeds: biguanides (metformin), HMG-CoA reductase inhibitors (statins), angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid derivatives (ASA), and proton pump inhibitors (PPI) given their plausible biologic and clinical rationale. To determine the potential effect-modification, we applied Cox regression models with interaction term between the conmed class, the randomized treatment in addition to a minimally sufficient set of confounders. To determine the independent association of each class of conmeds with outcome, we applied IPTW-based survival analysis and log-rank test. Results: Overall, 1152 patients (772 and 380 in the apalutamide and placebo arm, respectively) were eligible for this secondary analysis. For OS, we did not find any statistically significant heterogeneity of treatment effect from ADT plus apalutamide across subgroups stratified by concomitant exposure to the conmeds listed above. We noted a significant difference (p=0.01) in treatment effect from apalutamide on MFS between patients with concomitant receipt of statins (adjusted hazard ratio [aHR]: 0.20; 95% CI: 0.15-0.28) vs without statins (aHR: 0.31 [0.24-0.39]). On IPTW-based analysis, patients with concomitant metformin (median: NR vs 31 months (mos); p=0.002) and concomitant ACEI (median: 37 vs 29 mos; p=0.006) had significantly superior MFS. Patients with exposure to all of metformin, ACEI, and statin had significantly improved MFS (median: NR vs 31 mos; p<0.001). Conclusions: In this post-hoc exploratory analysis, treatment effects from apalutamide on MFS and OS were consistent across subgroups stratified by exposure to conmeds. Exposure to concomitant metformin or ACEI was associated with a significant improvement in MFS.
Biomarker assessment and pharmacology of HP518, an AR PROTAC degrader from the phase 1 dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Azad Arun , UNDERHILL CRAIG R , Gurney Howard , Horvath Lisa , Voskoboynik Mark , Ellerington Scott , Dai Yiyun , King Ivan , Perabo Frank , Guo George 
Published: June 2024

5058 Background: HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that degrades both wild-type AR and clinically relevant AR ligand-binding domain (LBD) mutants including L702H. To evaluate the safety, PK, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), we conducted a first-in-human, Phase 1, open-label, multicenter, non-randomized, dose escalation study in pts with mCRPC. We report biomarker, pharmacology and efficacy data from this Phase 1 study. Methods: Pts with mCRPC with disease progression on at least 1 novel hormonal agent (NHA) and ≤ 1 line of chemotherapy received HP518 QD orally in sequential cohorts (25, 50, 100, 200, and 300, 400, 500 mg per day, Bayesian N-CRM design). Primary objectives were to assess HP518 safety and select the RP2D. Secondary objectives included evaluating the PK of HP518, PSA50 response and radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives were to evaluate AR expression in circulating tumor cells (CTCs) at the highest dose cohort before and after 12 weeks of treatment and genomic profile using cell-free DNA (cfDNA). Results: As of 29Jan2024, a total of 22 pts were enrolled. Overall, HP518 was well tolerated, with a favorable safety profile. No DLT, and a cumulative of ten SAE (1 related/9 unrelated) were observed. There were twelve Grade ≥3 treatment-emergent adverse events (TEAEs) in 6 pts treated up to 500 mg; no grade ≥4 TEAEs. The most common TEAE in all cohorts was grade 1 or 2 vomiting and nausea. PSA50 response was seen in 3 pts. 2 pts had confirmed partial responses (PR) per RECIST criteria. 2 pts received HP518 for ≥24 weeks including 1 pt with a durable PSA50 and PR response for 52 weeks. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12h post-dose. Over the 5-fold dose range (100 to 500 mg), the increase in Cmax and AUC0-last was approximately dose proportional on day 1. A steady state was reached after day 56. ctDNA data were available from 19 pts, of which four patients were diagnosed with AR LBD mutations. Three LBD mut non-responder pts had low drug exposures. In addition, one AR LBD mut patient had high mutational burden suggestive of AR-independent resistance. cDNA and CTC analysis showed diverse molecular changes in the AR including four pts with AR-V7 splice variant as well as non-AR resistance patterns in most patients. Conclusions: HP518, a novel AR PROTAC degrader, demonstrated encouraging efficacy in mCRPC pts, with responses seen in patients with full-length AR, AR LBD mutations, and AR amplification. These data support further investigation of HP518 in mCRPC pts. Clinical trial information: NCT05252364 .