bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening blood donors for malaria, can we increase the number of eligible donors? An observational retrospective study
Authors: Corbacho-Loarte María Dolores , Martín Oihane , Chamorro-Tojeiro Sandra , Crespillo-Andújar Clara , Norman Francesca F. , Pérez-Molina José A. , Sanz Marta González , Cancio-Suárez Marta Rosas , Ruiz-Calvo Gabriel , López Alberto Richart , Rubio José Miguel , López-Vélez Rogelio , Monge-Maillo Begoña
Published: June 2024

Background

In non-endemic countries, malaria can be transmitted through blood donations from imported cases. To ensure standards of quality and safety of human blood, the European Union and Spanish national law, requires a deferral period, or a screening by immunological or genomic test among those donors with potential risk of malaria. Scientific societies, European Committee on Blood Transfusion, and Spanish Society of Haematology and Haemotherapy, refer only to the result of the immunological test.

Methods

An observational retrospective study was performed in potential donors with a positive immunological test for malaria done in the Regional Transfusion Center in Madrid and referred to the National Reference Unit for Tropical Diseases in Madrid between 2015–2020. At consultation a Polymerase Chain Reaction (PCR) for malaria was performed.

Results

During the study period, 121 possible donors attended for consultation at NRU-Trop. Median age: 38.5 (IQR:33–48); median time to consultation was 32 months (IQR:12.5–110). Eighty-two (67.8%) donors were migrants and thirty-nine were travellers (32.2%). ELISA values were available for 109 subjects (90.1%), 56 individual left malaria endemic area > 3 years before. All donors tested negative for Plasmodium spp PCR test (n = 121, 100%).

Conclusions

None of the subjects with a positive immunologic test deferred as blood donors had a positive genomic test. The presence of Plasmodium spp in collected blood was not detected by molecular techniques. To avoid the loss of potential blood donors, especially those with low incidence red blood cell antigens, as more precise microbiology techniques become available, updating the existing legislation becomes necessary to increase the availability of donated blood.
Risk of recurrent venous thromboembolism and major bleeding according to risk factor profiles in Asian patients: a subgroup analysis EINSTEIN-Extension and EINSTEIN-CHOICE
Authors: Yamada Norikazu , Fu Weiguo , Shi Zhenyu , Park Ki-Hyuk , Kim Hyo-Soo , Dai Xiangchen , Lensing Anthonie WA , Pap Akos F , Kohno Tomoko , Tajima Tsubasa , Watakabe Tadashi , Mitsumori Tomoyuki
Published: June 2024

Background

Risks of recurrence and major bleeding with extended anticoagulation in Asian patients with venous thromboembolism (VTE) are similar to those in non-Asian patients but risks according to baseline risk factor profiles is not well documented.

Methods

Subgroup analysis of two randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with placebo or aspirin (100 mg) for extended treatment in Asian patients with VTE who had completed 6–12 months of anticoagulation. Index events were classified as unprovoked, provoked by major persistent risk factors, minor persistent risk factors, minor transient risk factors, or major transient risk factors. One-year cumulative risks of recurrent VTE were calculated for these risk factor profiles.

Results

367 patients received rivaroxaban, 159 aspirin, and 48 placebo. For patients with unprovoked VTE, one-year cumulative incidences of recurrence in the 202 patients given rivaroxaban, the 89 given aspirin and the 28 given placebo were 1.6%, 5.8%, and 14.8%, respectively. For patients with VTE provoked by minor persistent risk factors, these incidences were 0% in the 74 patients given rivaroxaban, 9.3% in the 36 given aspirin, and 0% in the 12 given placebo. No recurrent VTE occurred in patients with VTE provoked by major persistent or transient risk factors or minor transient risk factors. Rivaroxaban was not associated with a significant increase in major bleeding.

Conclusions

Rivaroxaban seems to be an effective and safe option for extended treatment in Asian patients, especially those presenting with unprovoked VTE. Subgroups of patients with provoked risk factors were too small to draw meaningful conclusions.

Trial registration

NCT00439725 and NCT02064439.
The COVID-19 pandemic and the use of benzodiazepines and benzodiazepine-related drugs in Estonia: an interrupted time-series analysis
Authors: Kurvits Katrin , Toompere Karolin , Jaanson Peeter , Uusküla Anneli
Published: June 2024

Background

The COVID-19 pandemic has posed challenges that worsened people’s mental health. We explored the impact of the COVID-19 pandemic on the mental well-being of the population, as indicated by the prevalence rates of benzodiazepine and benzodiazepine-related drug (BDZ) use.

Methods

This population‐based, time‐series analysis included all prescriptions of BDZs dispensed in Estonia between 2012 and 2021. The monthly prevalence rates of BDZ use were calculated. Autoregressive integrated moving average models with pulse and slope intervention functions tested for temporary and long-term changes in monthly prevalence rates after the onset of the COVID-19 pandemic.

Results

Throughout the 10-year study period, a total of 5,528,911 BDZ prescriptions were dispensed to 397,436 individuals. A significant temporary increase in the overall prevalence rate of BDZ use in March 2020 (2.698 users per 1000, 95% CI 1.408–3.988) was observed, but there was no statistically significant long-term change. This temporary increase affected all the examined subgroups, except for new users, individuals aged 15–29 years, and prescribing specialists other than general practitioners and psychiatrists. The long-term increase in BDZ use was confined to females aged 15–29 years (0.056 users per 1000 per month, 95% CI 0.033–0.079), while no significant change was observed among males of the same age (0.009 users per 1000 per month, 95% CI – 0.017 to 0.035). Among females aged 15–29 years, a significant long-term increase in BDZ use was observed for anxiety disorders (0.017 users per 1000 per month, 95% CI 0.010–0.023), depressive disorders (0.021 users per 1000 per month, 95% CI 0.012–0.030), and other mental and behavioral disorders (0.020 users per 1000 per month, 95% CI 0.010–0.030), but not for sleep disorders (– 0.008 users per 1000 per month, 95% CI – 0.018–0.002).

Conclusion

The COVID-19 pandemic led to a short-term increase in BDZ use immediately after the pandemic was declared. In the long term, young females experienced a sustained increase in BDZ use. The prolonged effect on girls and young women suggests their greater vulnerability. These results underscore the need to effectively address the long-term effects of the pandemic among youth.
DNA methylation profiles of ovarian cysts resemble ovarian tissues but not endometrial tissues
Authors: Zhang Xiaohui , Zhao Xiaojing , Wang Jiapo , Zhang Yifang , Chen Jinhong
Published: June 2024

Introduction

Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remain unknown.Despite the high prevalence of ovarian chocolate cyst, its origin is still under debate.

Methods

Prevailing retrograde menstruation model predicts that ectopic endometrial cells migrate and develop into ovarian chocolate cyst. However, other models were also proposed. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases.

Results

A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and microRNA expression.Because DNA methylation states exhibit a tissue specific pattern, we profiled the DNA methylation for ovarian cysts and paired eutopic endometrial and ovarian tissues from four patients. Surprisingly, DNA methylation profiles showed the ovarian cysts were closely grouped with normal ovarian but not endometrial tissues.

Conclusions

These results suggested alterative origin of ovarian cysts or strong epigenetic reprogramming of infiltrating endometrial cells after seeding the ovarian tissue. The data provide contributing to the pathogenesis and pathophysiology of endometriosis.
First identification of Cytauxzoon manul in Eurasian lynx (Lynx lynx) in northwestern China
Authors: Cui Nannan , Su Lixin , Wang Ziqi , Hornok Sándor , Tang Lijuan , Yang Meihua , Zhang Yujiang , Zhao Guoyu , Wang Yuanzhi
Published: June 2024

Background

Multiple species of the genera Cytauxzoon and Hepatozoon can infect wild felines, but the diversity of these and other apicomplexan parasites in Eurasian lynx is scarcely known. The aim of this study was to detect Cytauxzoon and Hepatozoon species with molecular methods in Eurasian lynxes and their ticks in northwestern China.

Methods

DNA was extracted from the heart, liver, spleen, lung, and kidney samples of three Eurasian lynxes as well as from their five ixodid ticks. These DNA samples were screened with polymerase chain reactions (PCRs) for Cytauxzoon with the partial cytochrome b gene (CytB), cytochrome c oxidase subunit I gene (COI), and small subunit ribosomal RNA gene (18S rRNA), and Hepatozoon with three different fragments of small subunit ribosomal RNA gene (18S rRNA). PCR products were sequenced, aligned, and phylogenetically analyzed.

Results

One adult female of Eurasian lynx (#1, adult female) was co-infected with Cytauxzoon manul and Hepatozoon felis genotype I, while an adult male lynx (#2) was infected with C. manul. Interestingly, H. felis genotype I was both detected in a male cub (#3) and two out of five infesting Hyalomma asiaticum ticks.

Conclusions

For the first time, Cytauxzoon manul is reported here from Eurasian lynx. In addition, H. felis has not been known to occur in this host species in China and Central Asia. Thus, the findings of this study extend our knowledge on the geographical distribution and host range of these haemoprotozoan parasites. Moreover, this is also the first evidence of C. manul and H. felis co-infection in Eurasian lynx.

Graphical Abstract
Epidemiology of sarcoptic mange in a geographically constrained insular red fox population
Authors: Wails Christy N. , Helmke Claire C. , Black Kathleen M. , Ramirez-Barrios Roger , Karpanty Sarah M. , Catlin Daniel H. , Fraser James D.
Published: June 2024

Background

Sarcoptic mange is a skin disease caused by the contagious ectoparasite Sarcoptes scabiei, capable of suppressing and extirpating wild canid populations. Starting in 2015, we observed a multi-year epizootic of sarcoptic mange affecting a red fox (Vulpes vulpes) population on Fire Island, NY, USA. We explored the ecological factors that contributed to the spread of sarcoptic mange and characterized the epizootic in a landscape where red foxes are geographically constrained.

Methods

We tested for the presence of S. scabiei DNA in skin samples collected from deceased red foxes with lesions visibly consistent with sarcoptic mange disease. We deployed 96–100 remote trail camera stations each year to capture red fox occurrences and used generalized linear mixed-effects models to assess the affects of red fox ecology, human and other wildlife activity, and island geography on the frequency of detecting diseased red foxes. We rated the extent of visual lesions in diseased individuals and mapped the severity and variability of the sarcoptic mange disease.

Results

Skin samples that we analyzed demonstrated 99.8% similarity to S. scabiei sequences in GenBank. Our top-ranked model (weight = 0.94) showed that diseased red foxes were detected more frequently close to roadways, close to territories of other diseased red foxes, away from human shelters, and in areas with more mammal activity. There was no evidence that detection rates in humans and their dogs or distance to the nearest red fox den explained the detection rates of diseased red foxes. Although detected infrequently, we observed the most severe signs of sarcoptic mange at the periphery of residential villages. The spread of visual signs of the disease was approximately 7.3 ha/week in 2015 and 12.1 ha/week in 2017.

Conclusions

We quantified two separate outbreaks of sarcoptic mange disease that occurred > 40 km apart and were separated by a year. Sarcoptic mange revealed an unfettered spread across the red fox population. The transmission of S. scabiei mites in this system was likely driven by red fox behaviors and contact between individuals, in line with previous studies. Sarcoptic mange is likely an important contributor to red fox population dynamics within barrier island systems.

Graphical Abstract
DNA methylation and stroke prognosis: an epigenome-wide association study
Authors: Jiménez-Balado Joan , Fernández-Pérez Isabel , Gallego-Fábrega Cristina , Lazcano Uxue , Soriano-Tárraga Carolina , Vallverdú-Prats Marta , Mola-Caminal Marina , Rey-Álvarez Lucía , Macias-Gómez Adrià , Suárez-Pérez Antoni , Giralt-Steinhauer Eva , Rodríguez-Campello Ana , Cuadrado-Godia Elisa , Ois Ángel , Esteller Manel , Roquer Jaume , Fernández-Cadenas Israel , Jiménez-Conde Jordi
Published: June 2024

Background and aims

Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis.

Methods and results

To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor outcome defined as mRS > 2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the first 24 h. We searched for differentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value < 10–5 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify differentially methylated regions (DMRs).

After doing the epigenome-wide association study, we found 29 DMPs at p-value < 10–5 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-valuediscovery = 1.54·10–6; p-valuereplication = 9.17·10–4; p-valuemeta-analysis = 6.39·10–9). Besides, four DMRs were identified in patients with poor outcome annotated to zinc finger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value < 1·10–9 in all cases).

Discussion

Patients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms.
Cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy for relapsed or refractory classic Hodgkin lymphoma in China
Authors: Xie Shitong , Sheng Yanan , Chuang Ling-Hsiang , Wu Jing
Published: June 2024

Background

Relapsed or refractory classic Hodgkin lymphoma (RRcHL) associates with poor prognosis and heavy disease burden to patients. This study evaluated the cost-effectiveness of brentuximab vedotin (BV) in comparison to conventional chemotherapy in patients with RRcHL, from a Chinese healthcare perspective.

Methods

The lifetime cost and quality adjusted life years (QALYs) were estimated through a partitioned survival model with three health states (progression free, post progression, and death). Two cohorts for each BV arm and chemotherapy arm were built, representing patients with and without transplant after BV or chemotherapy, respectively. Clinical parameters were retrieved from BV trials and the literature. Resource utilization data were mainly collected from local expert surveys and cost parameters were reflecting local unit prices. Utility values were sourced from the literature. A discount rate of 5% was employed according to the Chinese guideline. A series of deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness and uncertainty associated with the model.

Results

Results of the base case analysis showed that the incremental cost-effectiveness ratio (ICER) for BV versus chemotherapy was $2,867 (¥19,774). The main model driver was the superior progression-free and overall survival benefits of BV. The ICERs were relatively robust in a series of sensitivity analyses, all under a conventional decision threshold (1 time of Chinese per capita GDP). With this conventional threshold, the probability of BV being cost-effective was 100%.

Conclusions

Brentuximab vedotin can be considered a cost-effective treatment versus conventional chemotherapy in treating relapsed or refractory classic Hodgkin lymphoma in China.
Emotional intelligence, spiritual intelligence, depression and anxiety, and satisfaction with life among emerging adults in Israel and India: the impact of gender and individualism/collectivism
Authors: Walter Ofra , Kasler Jonathan , Routray Surekha
Published: June 2024

Much research has focused on how emotional and spiritual intelligences promote well-being and help combat mental health issues. This comparative study, which was conducted in Israel and India with emerging adults enrolled in higher education, explored the relationship of emotional intelligence, spiritual intelligence, anxiety and depression, and satisfaction with life. The results in Israel showed a positive correlation of emotional intelligence with satisfaction with life, but in India, only spiritual intelligence correlated positively with satisfaction with life. In both groups, female participants scored higher on all variables than male participants. We offer initial explanations for these results.
Trans-cyclooctene—a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs
Authors: Adhikari Karuna , Vanermen Maarten , Da Silva Gustavo , Van den Wyngaert Tim , Augustyns Koen , Elvas Filipe
Published: June 2024

Background

Trans-cyclooctenes (TCOs) are highly strained alkenes with remarkable reactivity towards tetrazines (Tzs) in inverse electron-demand Diels–Alder reactions. Since their discovery as bioorthogonal reaction partners, novel TCO derivatives have been developed to improve their reactivity, stability, and hydrophilicity, thus expanding their utility in diverse applications.

Main body

TCOs have garnered significant interest for their applications in biomedical settings. In chemical biology, TCOs serve as tools for bioconjugation, enabling the precise labeling and manipulation of biomolecules. Moreover, their role in nuclear medicine is substantial, with TCOs employed in the radiolabeling of peptides and other biomolecules. This has led to their utilization in pretargeted nuclear imaging and therapy, where they function as both bioorthogonal tags and radiotracers, facilitating targeted disease diagnosis and treatment. Beyond these applications, TCOs have been used in targeted cancer therapy through a "click-to-release" approach, in which they act as key components to selectively deliver therapeutic agents to cancer cells, thereby enhancing treatment efficacy while minimizing off-target effects. However, the search for a suitable TCO scaffold with an appropriate balance between stability and reactivity remains a challenge.

Conclusions

This review paper provides a comprehensive overview of the current state of knowledge regarding the synthesis of TCOs, and its challenges, and their development throughout the years. We describe their wide ranging applications as radiolabeled prosthetic groups for radiolabeling, as bioorthogonal tags for pretargeted imaging and therapy, and targeted drug delivery, with the aim of showcasing the versatility and potential of TCOs as valuable tools in advancing biomedical research and applications.
Assessing the effects of plant density and nitrogen on millet yield in Southern Niger using the CERES-millet model
Authors: Garba Maman , Kamara Alpha Y. , Mohamed Ali M. L. , Tofa Abdullahi I. , Mahamane Soulé A. , Salissou Hanarou , Kapran Balkissa I. , Abdoulaye Tahirou , Garba Ismail I.
Published: June 2024

Background

The dryland production environments in Niger Republic (Niger) generate variable crop production risks that reduce crop yields and increase regional food insecurity. Optimal combinations of crop varieties and management are needed to maximize crop water-limited yields in these environments.

Methods

In this study, we calibrated and validated the CERES-Millet model using data from field experiments. Seasonal analysis (1984–2020) was carried out in 18 selected sites across the three agroecological zones (AEZs) to test the effects of plant density and N fertilization on grain yield. The treatment included five different plant densities (1.5, 3, 6, 9, and 12 plants m
−2
) and four N rates (0, 20, 40, and 60 kg N ha
−1
). Three millet varieties (CHAKTI, HKP, and SOSAT-C88) were compared. Millet production risk was assessed at each AEZ using cumulative probability distribution graphs. The acceptable grain yield required to compensate for the minimum production cost of millet in Niger was set to 975 kg ha
−1
(75th percentile of the simulated data).

Results

The CERES-Millet model reasonably reproduced number of days to flowering (
d
-index > 0.50; RMSE < 2 days), number of days to maturity (
d-
index > 0.50; RMSE < 2 days), and grain yield
d-
index > 0.78; RMSE < 100 kg ha
−1
) for all the three varieties. The results showed that there was significant response to N (40 – 110% yield increase following N application) and plant density (30–80% yield increase by increasing density above 1.5 plants m
−2
) in all the AEZs depending on variety. The SOSAT was the most responsive variety to N application and plant density in all AEZs. Under low N application (0–20 kg ha
−1
) and low (1.5—3 plants m
−2
) to moderate plant density (6 plants m
−2
), CHAKTI and HKP had the highest production risks. Increasing N application above 20 kg ha
−1
mitigate these risks where grain yield was above the 975 kg ha
−1
threshold representing the minimum production cost for millet in more than 50% of the years under all plant densities except in Sahel where this threshold was only achieved in < 20% of the years. In all AEZs, increasing plant density above 6 plants m
−2
increases this risk under low to moderate N application, but the downside risk was mitigated when N was applied at high rates.

Conclusion

This study demonstrated N application rate and plant density recommendations must be tailored to specific variety and AEZs to maximize grain yield and reduce volatility in Niger.
Concurrent self-administered transcranial direct current stimulation and attention bias modification training in binge eating disorder: feasibility randomised sham-controlled trial
Authors: Flynn Michaela , Campbell Iain C. , Schmidt Ulrike
Published: June 2024

Background

Binge eating disorder (BED) is a common and disabling condition, typically presenting with multiple psychiatric and obesity-related comorbidities. Evidence-based treatments are either resource-intensive (psychotherapies) or have side-effects (medications): these achieve remission in around 50% of cases. Novel treatments are needed.

Aims

This randomised sham-controlled trial aimed to assess feasibility, acceptability and preliminary efficacy of at-home, self-administered transcranial direct current stimulation (tDCS) and attention bias modification training (ABMT) in adults with binge eating disorder.

Method

Eighty-two participants with binge eating disorder were randomly allocated to real tDCS with ABMT, sham tDCS with ABMT, ABMT only or waitlist control. Intervention groups received ten sessions of their allocated treatment over 2–3 weeks. tDCS (2 mA, 20 min) was self-administered using a bilateral (anode right/cathode left) montage targeting the dorsolateral prefrontal cortex. Outcomes were assessed at baseline, post-treatment and 6-week follow-up.

Results

Prespecified feasibility criteria (recruitment ≥80 participants and retention rate ≥75%) were exceeded, and treatment completion rates were high (98.7%). All interventions reduced binge eating episodes, eating disorder symptoms and related psychopathology between baseline and follow-up, relative to waitlist control (medium-to-large between-group effect sizes for change scores). Small-to-medium effect sizes for change scores favoured real tDCS with ABMT versus comparators, suggesting the verum intervention produces superior outcomes.

Conclusions

At-home, self-administered tDCS with ABMT is feasible and acceptable, and preliminary data on efficacy are promising. This approach could be a useful and scalable alternative or adjunct to established treatments for binge eating disorder. Confirmatory trials can, and should, be pursued.
Utility of ctDNA burden as a prognostic biomarker for efficacy in TALAPRO-2: A phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Azad Arun , Fizazi Karim , Laird Douglas , Matsubara Nobuaki , De Giorgi Ugo , ButtIgliero Consuelo , Karsh Lawrence Ivan , Joung Jae Young , Yip Steven , Zschaebitz Stefanie , Albacker Lee A. , Healy Cynthia G. , Lin Xun , Chelliserry Jijumon , Agarwal Neeraj
Published: June 2024

5020

Background: TALAPRO-2 (NCT03395197) demonstrated that 1L TALA + ENZA significantly improved radiographic progression-free survival (rPFS) vs PBO + ENZA for pts with mCRPC. ctDNA burden is a candidate prognostic biomarker with potentially broad utility across treatments and tumor types. We assessed the potential prognostic utility of baseline (BL) ctDNA burden and changes in ctDNA burden at Week 9 (WK 9) in TALAPRO-2 pts. Methods: Retrospectively analyzed serial ctDNA samples from BL and WK 9 were assessed using FoundationOneLiquid CDx. Plasma tumor fraction was calculated based on aneuploidy (Husain et al. JCO Precis Oncol. 2022. PMID: 36265119). We categorized ctDNA burden as high (ctDNA burden quantifiable) vs low (unknown ctDNA burden). Data cutoff date was August 16, 2022. Results: In the all-comers intent-to-treat population, 678 pts were evaluable for ctDNA burden at BL: 26% (89/337) of TALA + ENZA pts were ctDNA-high and 74% (248/337) were ctDNA-low; 29% (98/341) of PBO + ENZA pts were ctDNA-high and 71% (243/341) were ctDNA-low. High ctDNA burden at BL was prognostic of inferior rPFS in the TALA + ENZA and PBO + ENZA arms (Table). A relatively favorable median rPFS was observed for pts with low ctDNA at BL and WK 9 for TALA + ENZA (n=206) and PBO + ENZA (n=207), as reported in the Table. At WK 9, 72 pts in the TALA + ENZA and 77 pts in the PBO + ENZA arms were evaluable for ctDNA conversion from high to low. In both treatment arms, conversion from high to low ctDNA was prognostic of improved rPFS vs pts who remained ctDNA-high (Table). Pts who remained ctDNA-low had a more favorable rPFS vs conversion from high to low ctDNA: TALA + ENZA, hazard ratio (HR) 95% confidence interval (CI), 0.45 (0.29–0.71), P=0.0003; PBO + ENZA, 0.34 (0.23–0.52), P<0.0001). Conclusions: High ctDNA burden at BL was negatively prognostic, and ctDNA conversion from high to low at WK 9 was prognostic of improved rPFS in TALAPRO-2. Limitations included not all clinical trial sites were able to perform ctDNA collection and most samples were below the limit of quantification. These results support the broad prognostic utility of ctDNA burden in mCRPC. Clinical trial information: NCT03395197 . [Table: see text]
Clinical and genomic landscape of neuroendocrine prostate cancer (NEC) vs. prostate adenocarcinoma (AdenoK).
Authors: Gebrael Georges , Ostrowski Micah , Williams Jessica , Hage Chehade Chadi , Narang Arshit , Ozay Zeynep Irem , Chawla Neal Shiv , Mathew Thomas Vinay , Chehrazi-Raffle Alex , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: June 2024

5026

Background: NEC represents an aggressive form of prostate cancer, characterized by a high incidence of visceral metastases and a poor prognosis [PMID: 23169519]. A previous study has shown that, in a cohort of 30 patients (pts) with NEC, there was a significant enrichment for the loss of RB1 and the mutation or deletion of TP53 in these pts compared to those with AdenoK [PMID: 26855148]. Herein, we sought to compare the genomic landscape of pts with NEC to those with AdenoK using a large real-world genomic dataset. Methods: In this IRB-approved retrospective study, the de-identified Tempus Lens dataset was used to identify patients diagnosed with NEC and AdenoK across all stages and having comprehensive genomic profiling (CGP). Baseline demographic information was collected. Pathological variables were summarized using descriptive statistics to compare the NEC and AdenoK groups, using the Chi-square test with a significance threshold of P < 0.05. Genomic alterations with an incidence of ≥ 5% were included in the analysis. Homologous recombination repair (HRR) alterations in 14 pre-specified genes per the olaparib FDA label were also compared between both groups. Results: A total of 13,683 pts (AdenoK: 13472; NEC: 211) were included in the analysis. The median age of the NEC cohort was 65 [24 – 90+], with 55.9% of pts identified as White. Of pts with NEC, 37.9% were never smokers, while 32.7% were ex-smokers. In the AdenoK cohort, the median age was 66 [21- 90+], with 45.4% of patients identified as White. 36.62% of pts never smoked and 29.33% were ex-smokers. In the NEC cohort, the three most common alterations were TP53(63.98%), RB1(53.08%), and PTEN(28.91%). Compared to AdenoK, the NEC cohort had a significantly higher prevalence of TP53 (63.98 vs 34.97%; P<0.001), RB1 (53.08 vs 6.09%; P<0.001), PTEN (28.91 vs 18.1%; P<0.001), BRCA2(15.17 vs. 10.05%; P=0.01), TMPRSS2-ERG(25.12 vs. 19.29%; P=0.03), MYC(7.11 vs. 2.78%; P < 0.001), CDKN1B(6.16 vs. 2.11%; P < 0.001), and a lower frequency of SPOP (2.84 vs 9.22%; P=0.01), and ATM (6.64 vs 12.33%; P=0.01). HRR alterations frequency was similar between the NEC and AdenoK, respectively (38.83 vs. 38.66%, P=0.73). Conclusions: This is the largest real-world study characterizing the genomic features of prostate NEC compared to AdenoK. Our findings are consistent with prior studies suggesting a distinct genomic profile of NEC. These data can help in an improved understanding of the genetic drivers of this aggressive form of prostate cancer.
High dose chemotherapy in male patients with germ cell cancer: A population-based study by the SWENOTECA group.
Authors: Jansson Anna , Cohn-Cedermark Gabriella Elisabeth , Negaard Helene F. S. , Tandstad Torgrim , Stahl Olof , Hedlund Annika , Karlsdottir Asa , Hellström Martin , Langberg Carl Wilhelm , Sköld Camilla , Haugnes Hege Sagstuen , Glimelius Ingrid
Published: June 2024

5040

Background: Selected patients with advanced germ cell tumors have a poor prognosis. These include patients with brain, bone or liver metastases, very elevated tumor markers or primary mediastinal tumor. High-dose chemotherapy (HDCT) with autologous stem cell support is recommended in the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) guidelines in selected poor risk patients with poor response to/relapse after intense primary treatment. From the year 2011, the HDCT-regimen consisted of two cycles of carboplatin and etoposide. Our aim of this study was to evaluate survival and toxicity in patients treated with HDCT within the population-based SWENOTECA cancer care program in 2011-2021. Methods: All patients treated with HDCT according to guidelines in Sweden and Norway between 2011-2021 were included, in total 80 patients (76 non-seminoma and 4 seminoma). This reflected approximately 3% of all non-seminoma patients. HDCT was administered in three different clinical situations: delayed tumor marker decline during primary or intensified primary treatment (n=26), progressive disease during primary treatment (n=29) (defined as progressive disease within <3 months from last cycle of chemotherapy), or relapse with poor prognosis (n=25). The overall survival (OS) and failure-free survival (FFS) were calculated, and the toxicity was described. Results: The 5-year overall survival (OS) and failure free survival (FFS) after HDCT was 55% and 43% respectively. HDCT due to delayed tumor marker decline had a more favorable outcome, 5-year OS of 75% and 5-year FFS of 53%. HDCT due to relapse resulted in a 5-year OS of 61% and 5-year FFS of 58%. Patients treated with HDCT due to progressive disease during primary treatment had a markedly less favorable 5-year OS of 29% and 5-year FFS of 18%. Four patients (5%) died due to treatment. The most common treatment-related grade 3-4 toxicities were infections (n=69, 86%). Conclusions: In this population-based study, we have shown that HDCT for patients with advanced germ cell cancer according to the SWENOTECA cancer care program is achievable and leads to favorable OS and FFS rates. Furthermore, even though patients that receive HDCT due to progressive disease have a relatively poor outcome, 20-30% of patients do achieve long-term survival. [Table: see text]
Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [177Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).
Authors: Kwan Edmond Michael , Hofman Michael S , Ng Sarah WS , Emmett Louise , Sandhu Shahneen , Buteau James Patrick , Iravani Amir , Joshua Anthony M. , Francis Roslyn J. , Subhash Vinod , Lee Sze Ting , Scott Andrew Mark , Martin Andrew James , Stockler Martin R. , Donnellan Gráinne , Annala Matti , Tolmeijer Sofie H. , Azad Arun , Davis Ian D. , Wyatt Alexander William ,   TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2024

5055

Background: The TheraP trial showed that for patients with PSMA-positive, non-FDG-discordant mCRPC progressing after docetaxel, LuPSMA significantly improved biochemical and objective response rates, progression-free survival (PFS), and quality of life compared to cabazitaxel. While subsequent studies nominated high PSMA SUVmean to inform patient prioritization for LuPSMA, limited genomic data exists to guide optimal selection of these two life-prolonging therapies. We present an exploratory analysis of ctDNA fraction (ctDNA%) in baseline samples from the TheraP trial. Methods: We analyzed 180 baseline blood samples from participants who received ≥1 cycle of protocol-assigned treatment. Plasma cell-free DNA and matched white blood cell DNA underwent targeted sequencing to estimate ctDNA%. Prespecified ctDNA% categories (<2%, 2-30%, and >30%) were associated with previously validated imaging thresholds (PSMA SUVmean ≥10 and FDG metabolic tumor volume [MTV] ≥200mL), rate of PSA reduction ≥50% (PSA50-RR), and PFS, using chi-square test, logistic regression and Cox regression, respectively. Results: ctDNA% was evaluable in 178 (99%) participants, with ctDNA ≥2% in 85%. Median ctDNA% was 28% in ctDNA≥2% samples, and balanced across treatment arms. The odds of a PSA50 response to LuPSMA vs cabazitaxel were significantly higher for men with ctDNA <2% (OR infinite, p=0.0067; PSA50-RR 100% vs 58%), with no difference at ctDNA >30% (OR 1.1, p=1.0; PSA50-RR 46% vs 44%). Higher ctDNA% was associated with shorter PFS in LuPSMA- but not cabazitaxel-treated patients (LuPSMA: HR 5.0, p<0.001 for ctDNA <2% vs >30%; cabazitaxel: HR 1.4, p=0.35 for ctDNA <2% vs >30%; interaction p=0.035). The predictive potential of ctDNA% was additive to PSMA SUVmean in LuPSMA-treated patients. Higher ctDNA% categories were enriched for patients with high FDG MTV and low PSMA SUVmean disease (Table). Conclusions: ctDNA% is a candidate predictive and prognostic biomarker for differential response to LuPSMA versus taxane chemotherapy in patients with molecular imaging-selected mCRPC progressing after docetaxel. Clinical trial information: NCT03392428 . [Table: see text]
BRCA1/2 reversion mutations (BRCArev) in advanced prostate cancer in the absence of prior PARP inhibitor (PARPi) therapy.
Authors: Lin Douglas I. , L Elizabeth , Danziger Natalie , Ye Huihui , Decker Brennan J. , Graf Ryon P , Ross Jeffrey S. , Elvin Julia A. , McKay Rana R.
Published: June 2024

5056

Background: In prostate cancer (PCA), BRCA1/2 alterations confer sensitivity to PARPi; however, in cases other than PCA with homozygous BRCA deletions, somatic BRCArev may restore BRCAfunction and mediate treatment resistance. In this study, we analyzed liquid biopsies of men with advanced PCA to (1) identify BRCArev, (2) to determine the clinical context in which BRCArev developed, and (3) to ascertain potential effect of prior chemotherapy on duration of PARPi response. Methods: BRCA1/2mutations were examined via liquid biopsies (FoundationOne Liquid CDx) during the course of clinical care for PCA patients during a 12-month period (from 01/2023 to 12/2023). Clinicopathological features and treatment history were extracted from medical records and/or treating oncologists’ notes. Results: Among 416 PCA patients with detected BRCA1/2 alterations, 25 (6.0%) patients harbored BRCArev that were predicted to restore BRCA function. Ten of 25 (40%) patients had detailed clinical and treatment history available. In three of 10 (30%) patients, somatic BRCArev were detected in the absence of prior PARPi therapy. All three PARP-naïve patients had been previously treated with chemotherapy (platinum or docetaxel) and radiation. Two patients had castration-resistant prostatic adenocarcinoma, while the third patient had de novo high-stage prostatic small cell neuroendocrine carcinoma without prior androgen deprivation. In all three PARP-naïve patients, multiple reversion mutations were detected per patient post-chemotherapy/radiation. Two of the three patients were predicted to have an original germline BRCA2alteration. The remaining 7 BRCArev-positive patients (70%) had prior PARPi treatment (all Olaparib). In PARPi-treated patients, duration of PARPi treatment prior to identification of BRCArev ranged from 5 to 24 months. 4 out of 7 PARPi-treated patients had received prior docetaxel, and duration of PARPi response was longer in chemo-naïve patients compared with those who had received prior docetaxel before PARPi (Mean: 18.6 vs 8.3 months, respectively). Conclusions: In men with BRCA-mutated PCA, chemotherapy and/or radiation may induce BRCArev in the absence of PARPi therapy. Testing of post-chemotherapy or radiation patients for BRCArev may be warranted prior to the start of PARPi therapy in patients with PCA. Our results support early PARPi therapy prior to radiation or chemotherapy as post-chemotherapy/radiation BRCArev may potentially dampen the future success of subsequent PARPi strategies.[Table: see text]
Association of genomic alterations with clinical outcomes following lutetium-177-PSMA vipivotide tetraxetan in men with metastatic castrate-resistant prostate cancer.
Authors: Gauntner Timothy , Gheeya Jinesh S. , Khorasanchi Adam , Xu Menglin , Hasanov Elshad , Collier Katharine A. , Meng Lingbin , Zimmerman Danielle Elise , Wang Peng , Folefac Edmund , Monk Paul , Mortazavi Amir , Clinton Steven K. , Yang Yuanquan (Aaron)
Published: June 2024

5057

Background: Lutetium-177-PSMA vipivotide tetraxetan (Lu177) is approved for men with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC) previously treated with androgen receptor signaling inhibitors and taxane chemotherapy. The tumor genomic alterations conferring sensitivity or resistance to Lu177 are unknown. We investigated the association of genomic variants with clinical outcomes in men with mCRPC treated with Lu177. Methods: Somatic & germline DNA sequencing data were examined from men treated with ≥1 cycle Lu177 at The James Cancer Hospital of The Ohio State University from 3/2022 – 10/2023. Pathogenic variants from tissue or blood testing were identified. Sets of genes with similar biological function were annotated, including homologous recombination repair (HRR) genes ( BRCA1, BRCA2, ATM, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), established tumor suppressor genes ( TP53, RB1, PTEN) and cell cycle genes ( CCND1, CCND3, CDK4, CDK6, CDK12, CDKN1B, CDKN2B) associated with prostate cancer. The impact of genomic variants on PSA50 response (Chi-Square & Fisher’s exact test), median overall survival (OS) and median progression-free survival (PFS) (Kaplan-Meier method) and OS or PFS (Cox proportional hazards model) was assessed. Results: Of 153 patients treated with Lu177, 120 underwent genomic sequencing: 109 had somatic testing (76 tissue-based, 33 blood-based), 50 had germline and 39 had both somatic & germline testing. Patients with amplification of cell cycle genes (n=8) had poorer OS of 5.1 months (mos.) vs 13.4 mos. for those without amplification (p=0.001, HR 4.26, 95% CI 1.79-10.11), and shorter PFS of 4.3 vs 7.4 mos. (p=0.027, HR 2.40, 95% CI 1.10-5.22). Patients with loss or mutation of HRR genes (n=32) had OS of 13.7 vs 12.2 mos. for those with no HRR alterations, but this was not significant (p=0.101, HR 0.57, 95% CI 0.29-1.12). No other genomic alterations were significantly associated with OS or PFS and none were associated with PSA50 response. The table lists the most frequently altered genes in PSA50 responders vs non-responders (differences not significant by Fisher’s exact test). Conclusions: Genomic alterations warrant investigation in larger cohorts as prognostic and predictive biomarkers for Lu177 therapeutic response. Our data suggest that amplification of genes impacting cell cycle regulatory pathways may be of particular interest. Our findings support continued efforts to determine the impact of cyclin dependent kinase (CDK) 4/6 inhibitors for high-risk and metastatic prostate cancer, either alone or in combination with agents such as Lu177.[Table: see text]
Rezvilutamide (REZ) plus docetaxel (DOC) in patients (pts) with chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone (ABI).
Authors: Liu Zhenhua , Wei Qiang , Feng Ping , Jiang Shusuan , Luo Hong , Liao Hong , Yu Dexin , Chen Zhiwen , Zhang Dahong , Dai Tao , Li Zeng , Zhang Zhiqiang , Bai Hong , Liu Feng , Wang Wenliang , Lin Jiaqin , Wang Yike
Published: June 2024

5059

Background: Despite DOC is recommended for chemo-naïve mCRPC pts previously treated with novel hormone therapy, prognosis remains unfavorable. Herein we report the safety, PK, and preliminary efficacy of addition of REZ (a novel androgen receptor inhibitor) to DOC in chemo-naïve mCRPC pts who had progressed after ABI. Methods: This was a multicenter, 2-part, phase 2 study. Part 1 included a 3 + 3 dose escalation phase and a dose expansion phase. Eligible pts were enrolled to receive REZ (160/240 mg, PO, QD) plus DOC (75 mg/m2, IV, D1, Q3W, up to 10 cycles [C]), followed by REZ monotherapy (240 mg, PO, QD). REZ was given continuously staring from C1D2. DOC was concurrent with prednisone (5 mg, PO, BID). Both dose levels of REZ were selected to be expanded. Primary endpoint of part 1 was safety. Results: As of Aug 31, 2023, 36 pts were enrolled (18 with REZ 160 mg plus DOC and 18 with REZ 240 mg plus DOC). In the REZ 160 mg plus DOC and REZ 240 mg plus DOC groups, rate of pts with ECOG PS of 1 was 83.3% and 61.1%, rate of pts with Gleason score ≥ 8 was 88.9% and 72.2%, rate of pts with >10 bone metastases was 66.7% and 44.4%, and median baseline prostate-specific antigen (PSA) level was 81.7 ng/mL (range: 2.7-5993.0) and 144.0 ng/mL (2.9-3720.0). No DLTs were reported. Treatment-related adverse events of grade ≥ 3 occurred in 32 (88.9%) pts (14 [77.8%] pts with REZ 160 mg plus DOC, and 18 [100.0%] pts with REZ 240 mg plus DOC), with the most common being decreased neutrophil count, decreased white blood cell count, and anemia. C2/C1 ratio of AUC0-24h and Cmax of DOC was 0.73 and 0.78 when combined with REZ 160 mg, while that was 0.58 and 0.68 when combined with REZ 240 mg, which indicated influence of CYP3A strong inducer REZ on CYP3A4 substrate DOC with stronger impact at REZ 240 mg. Rate of PSA response at week 12 was 75.0%, time to PSA progression was 10.5 mo (95% CI, 5.6-11.3), and radiological PFS was 13.8 mo (95% CI, 5.7-19.6) with REZ 160 mg plus DOC, while that with REZ 240 mg plus DOC was 60.0%, 14.1 mo (95% CI, 4.1-21.4), and 8.5 mo (95% CI, 5.6-not reached) (Table). Conclusions: REZ plus DOC was well tolerated with promising efficacy in chemo-naïve mCRPC pts who had progressed after ABI. Clinical trial information: NCT04603833 . [Table: see text]
Biomarkers associated with outcomes from KEYLYNK-010: Pembrolizumab (pembro) plus olaparib (ola) versus next-generation hormonal agent (NHA) in previously treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Park Se Hoon , Goh Jeffrey C. , Shin Sang Joon , Mehra Niven , McDermott Raymond S. , Fong Peter C.C. , Greil Richard , Sade Juan Pablo , Huang Yi-Hsiu , Kramer Gero , Suzuki Hiroyoshi , Poehlein Christian Heinrich , Qiu Ping , Dettman E.J. , Wang April , Chen Cai , Cristescu Razvan , Marton Matthew J. , Antonarakis Emmanuel S.
Published: June 2024

5064

Background: Pembro + ola did not significantly improve rPFS or OS vs NHA in unselected patients (pts) with previously treated mCRPC in the phase 3 KEYLYNK-010 study (NCT03834519). Here, we present the results of prespecified biomarker analyses with respect to rPFS or OS. Methods: Pts were randomly assigned 2:1 to pembro + ola or NHA. PD-L1 combined positive score (CPS) was measured by IHC (22C3 pharmDx); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, CDK12, TMB, and MSI were analyzed in tissue samples using FoundationOne CDx or ctDNA using FoundationOne Liquid CDx; AR-V7 was analyzed using Epic Sciences’ CTC assay. Associations (continuous scale) with outcomes were evaluated using adjusted Cox proportional hazards regression, and 1- (pembro + ola) and 2-sided (NHA) P values were calculated; significance was prespecified at α < .05. For biomarkers with sufficient sample size for subgroup analysis, rPFS and OS HRs were evaluated for pembro + ola vs NHA. Results: Of 782 treated pts, PD-L1 was evaluable in 730 (pembro + ola, 490; NHA, 240); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, and CDK12 in 718 (pembro + ola, 489; NHA, 229); TMB in 414 (pembro + ola, 275; NHA, 139); MSI in 316 (pembro + ola, 210; NHA, 106); and AR-V7 status in 544 (pembro + ola, 367; NHA, 177). In the biomarker-evaluable population, 28% had HRRm, 10% had BRCAm, 45% had TP53m, 34% had PTENm, 8% had SPOPm, 7% had ATMm, 7% had CDK12m, 4% were TMB-H (≥10 mut/Mb), 2% were MSI-H, and 13% were AR-V7 positive. For pembro + ola, positive associations were only observed between PD-L1 CPS and rPFS ( P = 0.034) and between HRRm and BRCAm and rPFS (adjusted P = 0.003 and < 0.001, respectively). No associations were observed for NHA (all P > 0.05). rPFS and OS HRs for pembro + ola vs NHA by biomarker status are shown (Table), with notable results observed for AR-V7 status. Conclusions: For pembro + ola, PD-L1 CPS had a weak positive association with rPFS, while HRRm and BRCAm had strong positive associations with rPFS; these biomarkers did not correlate with NHA outcomes. We observed a potential benefit with pembro + ola over NHA (for rPFS and OS) in AR-V7–positive mCRPC pts, which requires validation. Clinical trial information: NCT03834519 . [Table: see text]