bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural variant landscapes reveal convergent signatures of evolution in sheep and goats
Authors: Yang Ji , Wang Dong-Feng , Huang Jia-Hui , Zhu Qiang-Hui , Luo Ling-Yun , Lu Ran , Xie Xing-Long , Salehian-Dehkordi Hosein , Esmailizadeh Ali , Liu George E. , Li Meng-Hua
Published: June 2024

Background

Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution.

Results

We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g.,BMPR1B,BMPR2,RALYL,COL21A1, andLRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the geneBMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats.

Conclusions

Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.
Aortic disease and cardiomyopathy in patients with a novel DNMT3A gene variant causing Tatton-Brown–Rahman syndrome
Authors: Zebrauskiene Dovile , Sadauskiene Egle , Dapkunas Justas , Kairys Visvaldas , Balciunas Joris , Konovalovas Aleksandras , Masiuliene Ruta , Petraityte Gunda , Valeviciene Nomeda , Mataciunas Mindaugas , Barysiene Jurate , Mikstiene Violeta , Tomkuviene Migle , Preiksaitiene Egle
Published: June 2024

Tatton-Brown–Rahman syndrome (TBRS) is a rare congenital genetic disorder caused by autosomal dominant pathogenic variants in the DNA methyltransferase DNMT3A gene. Typical TBRS clinical features are overgrowth, intellectual disability, and minor facial anomalies. However, since the syndrome was first described in 2014, a widening spectrum of abnormalities is being described. Cardiovascular abnormalities are less commonly reported but can be a major complication of the syndrome. This article describes a family of three individuals diagnosed with TBRS in adulthood and highlights the variable expression of cardiovascular features. A 34-year-old proband presented with progressive aortic dilatation, mitral valve (MV) regurgitation, left ventricular (LV) dilatation, and ventricular arrhythmias. The affected family members (mother and brother) were diagnosed with MV regurgitation, LV dilatation, and arrhythmias. Exome sequencing and computational protein analysis suggested that the novel familial DNMT3A mutation Ser775Tyr is located in the methyltransferase domain, however, distant from the active site or DNA-binding loops. Nevertheless, this bulky substitution may have a significant effect on DNMT3A protein structure, dynamics, and function. Analysis of peripheral blood cfDNA and transcriptome showed shortened mononucleosome fragments and altered gene expression in a number of genes related to cardiovascular health and of yet undescribed function, including several lncRNAs. This highlights the importance of epigenetic regulation by DNMT3A on cardiovascular system development and function. From the clinical perspective, we suggest that new patients diagnosed with congenital DNMT3A variants and TBRS require close examination and follow-up for aortic dilatation and valvular disease because these conditions can progress rapidly. Moreover, personalized treatments, based on the specific DNMT3A variants and the different pathways of their function loss, can be envisioned in the future.
Optimized continuous homecare provisioning through distributed data-driven semantic services and cross-organizational workflows
Authors: De Brouwer Mathias , Bonte Pieter , Arndt Dörthe , Vander Sande Miel , Dimou Anastasia , Verborgh Ruben , De Turck Filip , Ongenae Femke
Published: June 2024

Background

In healthcare, an increasing collaboration can be noticed between different caregivers, especially considering the shift to homecare. To provide optimal patient care, efficient coordination of data and workflows between these different stakeholders is required. To achieve this, data should be exposed in a machine-interpretable, reusable manner. In addition, there is a need for smart, dynamic, personalized and performant services provided on top of this data. Flexible workflows should be defined that realize their desired functionality, adhere to use case specific quality constraints and improve coordination across stakeholders. User interfaces should allow configuring all of this in an easy, user-friendly way.

Methods

A distributed, generic, cascading reasoning reference architecture can solve the presented challenges. It can be instantiated with existing tools built upon Semantic Web technologies that provide data-driven semantic services and constructing cross-organizational workflows. These tools include RMLStreamer to generate Linked Data, DIVIDE to adaptively manage contextually relevant local queries, Streaming MASSIF to deploy reusable services, AMADEUS to compose semantic workflows, and RMLEditor and Matey to configure rules to generate Linked Data.

Results

A use case demonstrator is built on a scenario that focuses on personalized smart monitoring and cross-organizational treatment planning. The performance and usability of the demonstrator’s implementation is evaluated. The former shows that the monitoring pipeline efficiently processes a stream of 14 observations per second: RMLStreamer maps JSON observations to RDF in 13.5 ms, a C-SPARQL query to generate fever alarms is executed on a window of 5 s in 26.4 ms, and Streaming MASSIF generates a smart notification for fever alarms based on severity and urgency in 1539.5 ms. DIVIDE derives the C-SPARQL queries in 7249.5 ms, while AMADEUS constructs a colon cancer treatment plan and performs conflict detection with it in 190.8 ms and 1335.7 ms, respectively.

Conclusions

Existing tools built upon Semantic Web technologies can be leveraged to optimize continuous care provisioning. The evaluation of the building blocks on a realistic homecare monitoring use case demonstrates their applicability, usability and good performance. Further extending the available user interfaces for some tools is required to increase their adoption.
Longitudinal description and prediction of physical inactivity among patients with borderline personality disorder and personality-disordered comparison subjects
Authors: Glass Isabel V. , Frankenburg Frances R. , Zanarini Mary C.
Published: June 2024

Background

The physical and psychological benefits of physical activity are well-known, and physical activity has been proven to be a helpful adjunct to psychotherapeutic treatment for many symptomatic disorders, including mood and anxiety disorders. The current study explores physical inactivity levels in patients with borderline personality disorder (BPD). The first aim of this study is to describe the 12-year course of physical inactivity in patients with BPD. The second aim is to examine predictors of physical inactivity, including adversity experiences, comorbid symptomatic (formerly axis I) disorders, medical disorders, and demographic factors.

Methods

Two hundred and forty-five patients with BPD were interviewed seven times over 12-years of prospective follow-up as part of the McLean Study of Adult Development (MSAD). Patients were categorized as ever-recovered (i.e., patient had experienced a symptomatic and psychosocial recovery from BPD) or never-recovered. At each follow-up, patients reported physical activity levels (minutes of exercise per week) via a semi-structured interview— the Medical History and Services Utilization Interview (MHSUI). Data was collected from June 1992 to December 2018.

Results

Never-recovered patients with BPD were significantly more inactive than their ever-recovered counterparts (p < 0.001). These rates of inactivity remained stable over time for both groups. Two significant multivariate predictors of inactivity were found: obesity (p = 0.003) and PTSD (p < 0.001).

Conclusions

Non-recovered BPD patients are more likely to be inactive than patients who have recovered. Both clinical and medical factors appear to contribute to inactivity levels in patients with BPD.
Evaluation of the performance of Hydroxypropyl-β-cyclodextrin for the consolidation of vegetable-tanned leather artifacts
Authors: Abdel-Maksoud Gomaa , Nasr Hanaa El-Sayed , Samaha Sayed Hussein , Kassem Mahmoud Saad-ELdeen
Published: June 2024

The fragility and weakness of historical, archaeological, and heritage leather artifacts in museums, and libraries due to unsuitable environmental conditions are significant challenges. This study aims to assess the effectiveness of Hydroxypropyl Beta Cyclodextrin, a novel material, in consolidating leather artifacts by examining their physical, chemical, and mechanical properties. Vegetable-tanned leather samples were treated with different concentrations of Hydroxypropyl Beta Cyclodextrin and subjected to artificial heat aging. Evaluation methods included digital and scanning electron microscopy, contact angle measurements, mechanical testing, color analysis, pH measurement, and Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy. Results showed that Hydroxypropyl Beta Cyclodextrin at 1% and 2% concentrations improved chemical stability, surface morphology, color retention, and mechanical properties of the leather samples. The third concentration yielded less favorable outcomes. This study recommends using Hydroxypropyl Beta Cyclodextrin at 1% and 2% concentrations for consolidating historical leathers.
Why publish? An interview study exploring patient innovators’ reasons for and experiences of scientific publishing
Authors: Dahlberg Marie , Luckhaus Jamie Linnea , Hasson Henna , Jansson Hanna , Lek Madelen , Savage Carl , Riggare Sara , Wannheden Carolina
Published: June 2024

Background

Scientific publications featuring patient-driven innovations (i.e., innovations that are developed and driven by patients or informal caregivers) are increasing. By understanding patient innovators’ experiences of research publication, the scientific community may be better prepared to support or partner with patient innovators. Thus, the aim of this study was to explore patient innovators’ reasons for and experiences of authoring scientific publications about their innovations.

Methods

Qualitative semi-structured interviews were conducted with 15 international patient innovators from three continents who had published in scientific journals. Participants were identified through a scoping review on patient-driven innovations and snowball sampling. Interviews were conducted from June to October 2022 and the data was analyzed using the Framework Method.

Findings

Participants’ reasons for publishing in scientific journals were to strengthen the roles and voices of patients and informal caregivers, and to get recognition for their innovations. Some published as a response to serendipitous opportunities. Several positive experiences were reported: collaborations defined by transparency, mutual respect, and meaningful participation; learning and competence development; and gained confidence regarding the value of lived experiences in research. Participants also reported negative experiences, such as cultural barriers manifested as conservatism in academia and power imbalances between participants and researchers, and structural barriers regarding academic affiliations and research funding.

Conclusions

Despite progress in increasing patient and public involvement in research and publication, our study found that patient innovators still experience barriers. This suggests that continued efforts are needed to facilitate contributions from patient innovators and other public actors to the production of relevant and meaningful research.
Nurturing care assets for food security: a community asset mapping approach
Authors: Buccini Gabriela , Saniatan Kaelia Lynn , Poblacion Ana , Bauman Ana , Hernandez Cristina , Larrison Cali , Simangan Dodds P. , Desai Jyoti , Ferguson Yvonne Owens , Howard Alisa , Thompson-Robinson Melva
Published: June 2024

Background

Zip codes classified by the Food Insecurity Index with moderate and high food insecurity (FI) risk can be a threat to the health and well-being of children during the first 1,000 days (from pregnancy to 2 years). The presence of nurturing care assets (i.e., stable environments that promote health and nutrition, learning opportunities, security and safety, and responsive relationships) can contribute to supporting families and their communities, and ultimately reduce systemic barriers to food security. We aimed to identify and characterize nurturing care assets in under-resourced communities with moderate and high FI risk.

Methods

Four steps were used to conduct a Community Asset Mapping (CAM): (1) review of community documents across five zip codes in Clark County, Nevada (2), engagement of community members in identifying community assets (3), definition of the assets providing nurturing care services, and (4) classification of assets to nurturing care components, i.e., good health, adequate nutrition, safety and security, opportunities for early learning, and responsive caregiving. The Food Insecurity Index was used to determine FI risk in each zip code. Analyses explored whether disparities in nurturing care assets across zip codes with moderate and high FI exist.

Results

We identified 353 nurturing care assets across zip codes. A more significant number of nurturing care assets were present in zip codes with high FI risk. The adequate nutrition component had the most assets overall (n = 218, 61.8%), while the responsive caregiving category had the least (n = 26, 7.4%). Most of the adequate nutrition resources consisted of convenience stores (n = 96), food pantries (n = 33), and grocery stores (n = 33). Disparities in the number and type of good health, early learning, and security and safety assets were identified within zip codes with high FI risk compared to moderate FI risk.

Conclusions

The quantity and type of nurturing care assets can exacerbate existing demographic disparities across zip codes, which are tied to barriers to access to food in under-resourced communities in Clark County, Nevada. Co-creating a nurturing care asset-based zip code strategy to address high FI risk will require strengthening systems across existing nurturing care assets.
Student acceptance towards AsepticTech VR: a teaching and learning tool for cell and tissue culture aseptic techniques
Authors: Lim Cheng Wei , Liew Kong Yen , Lim Sie Hui , Cheema Manraj Singh , Sulaiman Puteri Suhaiza , Harith Hanis Hazeera , Saidi Hasni Idayu , Tham Chau Ling
Published: June 2024

The high cost of establishing a cell and tissue culture facility has denied students an opportunity to practice proper aseptic techniques during their studies. An in-house application named AsepticTech Virtual Reality (VR) was developed to simulate a cell and tissue culture facility for students to train their aseptic techniques virtually. However, the performance gain associated with the application will be limited by the student’s willingness to use the application. Therefore, this study aims to investigate the driving factors behind students’ intention to use AsepticTech VR. A total of 55 biomedical undergraduates were granted access to AsepticTech VR. After using the application, the students completed a Technology Acceptance Model (TAM) questionnaire. It measures seven latent constructs that are believed to influence the students’ behavioral intention to use the application, namely Perceived Usefulness (PU), Perceived Ease of Use (PEU), Attitude Towards Use (ATU), Behavioral Intention (BI), Perceived Enjoyment (PENJ), Perceived Health Risk (PHR) and Self-Efficacy (SE). The questionnaire was preliminarily evaluated on its validity and reliability using Confirmatory Factor Analysis (CFA), Average Variance Extracted (AVE), Composite Reliability (CR), and Cronbach’s alpha. Subsequently, the interactions between the seven latent variables were analyzed via path analysis. Findings of the path analysis suggested that ATU is the most influential factor on BI, followed by PENJ and SE. In turn, ATU was positively and significantly influenced by PENJ, whereas PHR exerted a significant negative influence on ATU. This study revealed that enjoyment and comfort are the principal factors influencing students’ acceptance of AsepticTech VR. This study also identifies other determinants that influence users’ acceptance of AsepticTech VR and paves guidance for the future development of the application.
Response to COVID-19 vaccination imaged by PD-L1 PET scanning
Authors: MacManus Michael P , Akhurst Tim , Lewin Sharon R , Hegi-Johnson Fiona
Published: June 2024

Background

During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging.

Methods

Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection.

Results

Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated.

Conclusion

Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients.

Trial Registration

This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819.
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

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.
Cancer Screening in Low- and Middle-Income Countries
Authors: Martinez Maria Elena , Schmeler Kathleen M. , Lajous Martin , Newman Lisa A.
Published: June 2024

The worldwide cancer burden is growing, and populations residing in low- and middle-income countries (LMICs) are experiencing a disproportionate extent of this growth. Breast, colorectal, and cervical cancers are among the top 10 most frequently diagnosed malignancies, and they also account for a substantial degree of cancer mortality internationally. Effective screening strategies are available for all three of these cancers. Individuals from LMICs face substantial cost and access barriers to early detection programs, and late stage at diagnosis continues to be a major cause for cancer mortality in these communities. This chapter will review the epidemiology of breast, colorectal, and cervical cancers, and will explore prospects for improving global control through novel approaches to screening in cost-constrained environments.
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 .
The effect of ACEi/ARB on survival outcome of patients with mCRPC treated with abiraterone.
Authors: Zhao Junliang , Cai Xinyang , Yang Zhenyu , Long Xingbo , Zhang Tianyou , Zhao Diwei , Li Yuanwei , Zhou Fangjian , Wang Jun , Li Yonghong
Published: June 2024

5071

Background: Androgen deprivation therapy (ADT), such as Abiraterone Acetate (AA), has emerged as a standard treatment for metastatic prostate cancer (mPCa). However, long-term ADT treatment may increase the incidence of cardiovascular adverse events, such as hypertension, which are a common cause of death in patients receiving ADT. Therefore, it is crucial to select appropriate antihypertensive drugs that effectively manage blood pressure and improve overall survival (OS) in these patients. Methods: This study conducted a secondary analysis of the COU-AA-301 and COU-AA-302 trials, which were multicenter double-blind randomized controlled trials (RCTs) to evaluate the efficacy of AA in combination with prednisone and ADT compared to prednisone plus ADT alone in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients were retrospectively assessed and stratified based on the concurrent medication including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) or not. OS and progression-free survival (PFS) were assessed using the Kaplan-Meier method and log-rank test. Multivariable Cox regression analysis was performed to determine the independent correlation of ACEi/ARBs with OS and PFS. Statistical significance was defined as P<0.05. Results: In COU-AA-301, the use of ACEi/ARB medications showed a significant association with improved OS (16.4 vs. 14.2 months, p<0.001) and PFS (3.1 vs. 2.9 months, p=0.002) in AA arm. After adjusting for baseline factors, ACEi/ARB medications were still found to reduce the risk of death (HR 0.72, 95% CI 0.56-0.91) and disease progression (HR 0.81, 95% CI 0.69-0.96). Similarly, in COU-AA-302, ACEi/ARB medications were associated with prolonged OS (37.4 vs. 31.9 months, p=0.003) and PFS (20.3 vs. 14.7 months, p=0.002) in AA arm. By adjusting for baseline factors, ACEi/ARB medications remained significantly associated with lower risk of death (HR 0.70, 95% CI 0.56-0.88) and disease progression (HR 0.70, 95% CI 0.55-0.88). In the placebo group, ACEi/ARB medications demonstrated improved OS only in COU-AA-301 (13.7 vs. 10.6 months, p=0.021). However, this trend did not reach statistical significance after adjusting for baseline factors (HR 0.76, 95% CI 0.55-1.03). Furthermore, the use of ACEi/ARB medications did not confer any PFS benefits in COU-AA-301 and failed to show both PFS and OS benefits in COU-AA-302. Conclusions: The use of ACEi/ARB medications has shown promise in improving OS and PFS in mCRPC patients treated with AAP. However, it is important to acknowledge the inherent limitations of post-hoc analysis, and therefore, further validation through prospective clinical trials is warranted.
PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in patients with metastatic hormone sensitive prostate cancer with HRR gene mutation.
Authors: Zhuang Junlong , Zhang Shun , Zhang Xuyu , Qiu Xuefeng , Guo Hongqian
Published: June 2024

5082

Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged overall survival in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy and safety of this combination therapy in patient with mHSPC. Here, we report the interim analysis results of PROact study, the first phase Ⅱ trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase Ⅱ trial ( NCT05167175 ) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51Dand RAD54L) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Results: Between May 19, 2022 and Dec 8, 2023, a total of 30 patients were enrolled and administered combination therapy. All the patients had de novo mHSPC, and the median age was 68 (range 49-85), with a median PSA of 166 ng/mL at baseline. A total of 7 HRR mutations were identified, included BRCA2 (n=11), CDK12 (n=8), ATM(n=6), PALB2 (n=2), CHEK2 (n=2), RAD51B (n=2) and RAD51D (n=1). As of Jan 29, 2024, the median follow-up was 7.1 months. In the 30 patients who had PSA response evaluated, PSA50 response rate achieved 100% (30/30), and the PSA90 response rate was 96.7%(29/30). In the 12 patients who had RECIST assessment, the objective response rate was 91.7% (11/12). Two achieved complete response, nine obtained partial response, and one had stable disease. The treatment was well tolerated, with 7(23.3%) patients experienced ≥grade 3 treatment-related adverse events (TRAEs). Common TRAE was anemia. Conclusions: This was the first trial to show efficacy and an acceptable safety profile of olaparib plus abiraterone and prednisone in mHSPC patients with HRR mutation. Data of primary endpoint of 1-year rPFS will be reported in the due time. Clinical trial information: NCT05167175 .