bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and molecular epidemiological features of critically ill patients with invasive group A Streptococcus infections: a Belgian multicenter case-series
Authors: Peetermans Marijke , Matheeussen Veerle , Moerman Cedric , De Rydt Fréderic , Thieren Sabine , Pollet Emily , Casaer Michael , De Backer Benjamin , De Paep Rudi , Debaveye Yves , Desmet Lars , Desmet Stefanie , Duval Els I. M. , Fraipont Vincent , Geysels Dieter , Hermans Greet , Lahaye Frederik , Mathy Xavier , Meersseman Philippe , Meex Cécile , Van Herck Jozef , van Kleef-van Koeveringe Stefanie , Layios Nathalie , Wauters Joost , Jorens Philippe G.
Published: January 2024

Background

Recent alerts have highlighted an increase in group A streptococcal (GAS) infections since 2022 in Europe and the United States. Streptococcus pyogenes can cause limited skin or mucosal disease, but can also present as severe invasive disease necessitating critical care. We performed a multicenter retrospective study of patients with GAS infections recently admitted to Belgian intensive care units (ICUs) since January 2022. We describe patient characteristics and investigate the molecular epidemiology of the S. pyogenes strains involved.

Results

Between January 2022 and May 2023, a total of 86 cases (56 adults, 30 children) with GAS disease were admitted to critical care in the university hospitals of Leuven, Antwerp and Liège. We noted a strikingly high incidence of severe community-acquired pneumonia (sCAP) (45% of adults, 77% of children) complicated with empyema in 45% and 83% of adult and pediatric cases, respectively. Two-thirds of patients with S. pyogenes pneumonia had viral co-infection, with influenza (13 adults, 5 children) predominating. Other disease presentations included necrotizing fasciitis (23% of adults), other severe skin/soft tissue infections (16% of adults, 13% of children) and ear/nose/throat infections (13% of adults, 13% of children). Cardiogenic shock was frequent (36% of adults, 20% of children). Fifty-six patients (65%) had toxic shock syndrome. Organ support requirements were high and included invasive mechanical ventilation (77% of adults, 50% of children), renal replacement therapy (29% of adults, 3% of children) and extracorporeal membrane oxygenation (20% of adults, 7% of children). Mortality was 21% in adults and 3% in children. Genomic analysis of S. pyogenes strains from 55 out of 86 patients showed a predominance of emm1 strains (73%), with a replacement of the M1global lineage by the toxigenic M1UK lineage (83% of emm1 strains were M1UK).

Conclusions

The recent rise of severe GAS infections (2022–23) is associated with introduction of the M1UK lineage in Belgium, but other factors may be at play—including intense circulation of respiratory viruses and potentially an immune debt after the COVID pandemic. Importantly, critical care physicians should include S. pyogenes as causative pathogen in the differential diagnosis of sCAP.
Optimal drug regimens for improving ALP biochemical levels in patients with primary biliary cholangitis refractory to UDCA: a systematic review and Bayesian network meta-analysis
Authors: Lin Wei , Wang Jun-xi , Liu Yi-juan
Published: January 2024

Background

Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and fibroblast growth factor 19 analogs were developed as adjunctive therapy. The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with primary biliary cholangitis (PBC) refractory to UDCA in improving ALP levels.

Methods

We searched PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies until 1 December 2023. Randomized controlled trials, cohort studies, and case–control studies comparing the efficacy of different combination treatments and UDCA monotherapy in UDCA-refractory PBC patients were included in the analysis. Cumulative probability was used to rank the included treatments.

Results

A total of 23 articles were eligible for our network meta-analysis. In terms of improving ALP levels, In terms of improving ALP biochemical levels, bezafibrate combined with UDCA (MD 104.49, 95% CI 60.41, 161.92), fenofibrate combined with UDCA (MD 87.81, 95% CI (52.34, 129.79), OCA combined with UDCA (MD 65.21, 95% CI 8.99, 121.80), seladelpar combined with UDCA (MD 117.39, 95% CI 19.97, 213.95), elafibranor combined with UDCA (MD 140.73, 95% CI 74.34, 209.98), saroglitazar combined with UDCA (MD 132.09, 95% CI 13.99, 247.04) was more effective than UDCA monotherapy. Elafibranor in combination with UDCA was the most likely (32%) to be the optimal drug regimen.

Conclusion

As second-line therapy for UDCA-refractory PBC, PPAR agonists were more effective than any other drugs with other mechanisms in improving ALP biochemical levels, with elafibranor being the best.
Abomasal infusion of branched-chain amino acids or branched-chain keto-acids alter lactation performance and liver triglycerides in fresh cows
Authors: Gallagher Kristen , Bernstein Isabelle , Collings Cynthia , Main David , Ahmad Ghayyoor , Naughton Sarah , Daddam Jayasimha , Mavangira Vengai , Vandehaar Mike , Zhou Zheng
Published: January 2024

Background

Dairy cows are at high risk of fatty liver disease in early lactation, but current preventative measures are not always effective. Cows with fatty liver have lower circulating branched-chain amino acid (BCAA) concentrations whereas cows with high circulating BCAA levels have low liver triglyceride (TG). Our objective was to determine the impact of BCAA and their corresponding ketoacids (branched-chain ketoacids, BCKA) on production performance and liver TG accumulation in Holstein cows in the first 3 weeks postpartum.

Methods

Thirty-six multiparous Holstein cows were used in a randomized block design experiment. Cows were abomasally infused for the first 21 d postpartum with solutions of 1) saline (CON, n = 12); 2) BCA (67 g valine, 50 g leucine, and 34 g isoleucine, n = 12); and 3) BCK (77 g 2-ketovaline calcium salt, 57 g 2-ketoleucine calcium salt, and 39 g 2-ketoisoleucine calcium salt, n = 12). All cows received the same diet. Treatment effects were determined using PROC GLIMMIX in SAS.

Results

No differences were detected for body weight, body condition score, or dry matter intake averaged over the first 21 d postpartum. Cows receiving BCK had significantly lower liver TG concentrations compared to CON (6.60% vs. 4.77%, standard error of the mean (SEM) 0.49) during the first 3 weeks of lactation. Infusion of BCA increased milk yield (39.5 vs. 35.3 kg/d, SEM 1.8), milk fat yield (2.10 vs. 1.69 kg/d, SEM 0.08), and lactose yield (2.11 vs. 1.67 kg/d, SEM 0.07) compared with CON. Compared to CON, cows receiving BCA had lower plasma glucose (55.0 vs. 59.2 mg/dL, SEM 0.86) but higher β-hydroxybutyrate (9.17 vs. 6.00 mg/dL, SEM 0.80).

Conclusions

Overall, BCAA supplementation in this study improved milk production, whereas BCKA supplementation reduced TG accumulation in the liver of fresh cows.

Graphical Abstract
Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes
Authors: Lei Huijun , Li Jiaheng , Zhao Bojin , Kou Si Hoi , Xiao Fengxia , Chen Tianhui , Wang San Ming
Published: January 2024

Background

Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs.

Methods

We retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis.

Results

Using the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns.

Conclusion

Our study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.
New psychometric evidence from the Revised Mental Health Inventory (R-MHI-5) in Peruvian adolescents from a network psychometrics approach
Authors: Rojas-Mendoza Estefany , Alania-Marin Vaneryn , Travezaño-Cabrera Aaron
Published: January 2024

Background

Mental health is an aspect that has been relegated in recent years, prioritizing physical health care. However, there are more and more mental problems and disorders worldwide. In this context, adolescents are considered at risk for developing psychological difficulties due to the important transition stage they are going through. Given this, an adequate measurement of mental health in the adolescent population is necessary. This research aims to evaluate the internal structure and estimate the reliability of the R-MHI-5.

Method

The sample covered 662 adolescents (55.2% men and 44.7% women) aged 12 to 17 years (M = 14.5; SD = 1.6).

Results

Exploratory graph analysis revealed a two-dimensional structure encompassing well-being and psychological distress. Furthermore, confirmatory factor analysis results indicated that a model with two related factors demonstrated superior fit indices (CFI = 0.99; TLI = 0.99; SRMR = 0.04; RMSEA = 0.101) in comparison to a one-dimensional model (CFI = 0.85; TLI = 0.71; SRMR = 0.23; RMSEA = 0.451). Additionally, adequate values were found in the reliability of the dimensions.

Conclusion

It is concluded that the R-MHI-5 is an instrument with robust psychometric evidence from the perspective of the EGA and CFA, providing adequate evidence of reliability and validity so that it can be used effectively in future research and prevention and intervention processes. Furthermore, our study is the first to provide psychometric evidence of the scale from a media approach in Peruvian adolescents.
A description of a pre-emptive typhoid Vi capsular polysaccharide vaccination campaign after the 2015 earthquake in Nepal and vaccine effectiveness evaluation
Authors: Dhoubhadel Bhim Gopal , Sawada Ikumi , Shrestha Dhruba , Fukuya Yoshifumi , Raya Ganendra Bhakta , Nébié Eric Ipyn , Hayashi Yumiko , Pasakhala Rasila , Suzuki Motoi , Morimoto Konosuke , Parry Christopher M. , Ariyoshi Koya
Published: January 2024

Background

A 7.8 R scale earthquake hit Nepal in April 2015 and caused about 9000 deaths along with damage to infrastructure, including the water and sewage system. Bhaktapur was one of the highly affected districts. A typhoid vaccination campaign (pre-emptive) was carried out among children who were living in the temporary shelters in this district. The assessment of vaccine effectiveness after a pre-emptive typhoid vaccine campaign following an earthquake has previously not been attempted in Nepal.

Objective

To describe the pre-emptive typhoid Vi capsular polysaccharide vaccination campaign and an evaluation of the vaccine effectiveness.

Methods

We conducted a pre-emptive typhoid Vi capsular polysaccharide vaccination campaign among children between 2 and 15 years of age dwelling in 23 temporary shelters in Bhaktapur district after the earthquake. Surveillance of clinical typhoid was carried out from 2014 to 2017 in Siddhi Memorial Hospital, the only hospital for children in the district. We calculated vaccine effectiveness using a case–control study design (clinical typhoid as cases and chest x-ray confirmed pneumonia as controls).

Results

Three thousand nine hundred sixteen children of age 2–15 years residing in the 23 temporary shelters in Bhaktapur received the typhoid Vi capsular polysaccharide vaccine between July and December 2015. 2193 children of age 2–15 years were admitted to the hospital during the study period and 260 (11.9%) were diagnosed with clinical typhoid. The numbers of children admitted with clinical typhoid decreased over the study period (105 in 2014 and 47 in 2017; P = 0.001). Overall vaccine effectiveness was calculated at 52% (95% CI −46 to 85%), and it was 87% (95% CI −25 to 99) among children less than 5 years of age.

Conclusions

We successfully conducted a pre-emptive vaccination campaign against typhoid after the 2015 Nepal earthquake. The pre-emptive vaccination campaign appeared to be more effective among children less than 5 years of age. Further studies are needed to assess the effectiveness of pre-emptive use of typhoid vaccines in the emergency situations. We highlight the challenges of calculating vaccine effectiveness of a typhoid vaccine in an emergency setting.
Potential applicability of blockchain technology in the maintenance of chain of custody in forensic casework
Authors: Patil Harsh , Kohli Ravshish Kaur , Puri Sorabh , Puri Pooja
Published: January 2024

Background

Proper investigation of digital evidence is of prime significance in cyber investigations. From the collection of evidence, its preservation, and its analysis, it is important to maintain its integrity in the legal system due to the involvement of different stakeholders like law enforcement agencies, digital analysts, and the judiciary. This review paper focuses on how blockchain technology can be used to collect evidence efficiently.

Main text

In the present scenario, the manual logs of the chain of custody are used to ensure that the evidence remains confidential and transparent. It is accompanied by filling out the application forms and maintaining logs within the organization handling the evidence. Hence, it is important to ensure the validity, integrity, and verifiability of evidence as it moves through different hierarchical levels. There are certain issues associated with the current chain of custody, such as evidence loss, theft, tampering, and, even worse, evidence manipulation inside the system. To avoid this situation and to make the process coherent, this review paper aims to highlight the potential use of blockchain technology to preserve chain of custody.

Conclusion

Although this scientific technology is mainly used to run cryptocurrencies, with careful consideration and application, this could play a key role in supporting and managing the chain of custody. It is a distributed database that keeps track of blocks. These blocks are collection of entries that keep growing continually and are secured from editing and manipulation by retaining the hash of the previous block in the chain. This is a decentralized technology that is not easily compromised in terms of security and therefore has the potential to solve our problem area. A future research agenda needs to be established, which lays the solid foundation for further studies on this evident emerging area.
Guiding principles for transdisciplinary and transformative fire research
Authors: Copes-Gerbitz Kelsey , Sutherland Ira J. , Dickson-Hoyle Sarah , Baron Jennifer N. , Gonzalez-Moctezuma Pablo , Crowley Morgan A. , Kitchens Katherine A. , Devisscher Tahia , Burr Judith
Published: January 2024

Background

Managing landscape fire is a complex challenge because it is simultaneously necessary for, and increasingly poses a risk to, societies and ecosystems worldwide. This challenge underscores the need for transformative change in the way societies live with and manage fire. While researchers have the potential to act as agents of transformative change, in practice, the ability to affect change is often constrained by siloed and biased expertise, rigid decision-making institutions, and increasingly vulnerable social-ecological systems where urgent rather than long-term solutions are prioritized. Addressing these challenges requires more holistic and equitable approaches to fire research that promote new models of transdisciplinary thinking, collaboration, and practice.

Results

To advance transformative solutions to this complex fire challenge, we propose four principles for conducting transdisciplinary fire research: (1) embrace complexity, (2) promote diverse ways of knowing fire, (3) foster transformative learning, and (4) practice problem-centered research. These principles emerged from our experience as a group of early-career researchers who are embedded within and motivated by today’s complex fire challenge within British Columbia (BC), Canada. In this forum piece, we first describe the four principles and then apply the principles to two case studies: (1) BC, a settler-colonial context experiencing increased size, severity, and impacts of wildfires, and (2) our ECR discussion group, a space of collective learning and transformation. In doing so, we present a unique contribution that builds on existing efforts to develop more holistic fire research frameworks and demonstrates how application of these principles can promote transdisciplinary research and transformation towards coexistence with fire, from local to global scales.

Conclusions

In this forum piece, we identify and apply four guiding principles for transdisciplinary fire research. Collectively, these principles can foster more inclusive applied fire research that matches the scope and scale of today’s fire challenge and promotes transformative change towards coexisting with fire.
Patient reported outcomes (PROs) among patients with metastatic castration-resistant prostate cancer (mCRPC) by homologous recombination repair mutations (HRRm) gene clusters: Findings from the phase 3 TALAPRO-2 study cohort 2.
Authors: Fizazi Karim , Shore Neal D. , Fong Peter C.C. , Azad Arun , Matsubara Nobuaki , Saad Fred , De Giorgi Ugo , Joung Jae Young , Jones Robert J. , Zschaebitz Stefanie , Oldenburg Jan , Dunshee Curtis , Carles Joan , Fay Andre P. , Cislo Paul , Kirker Melissa , Healy Cynthia G. , Niyazov Alexander , Agarwal Neeraj
Published: January 2024

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Background: Cohort 2 of the TALAPRO-2 (NCT03395197) study demonstrated benefit in radiographic progression-free survival (rPFS) with talazoparib (TALA) plus enzalutamide (ENZA) (n=200) vs placebo (PBO) + ENZA (n=199) across gene subgroups in men with HRRm receiving first-line treatment for mCRPC. Post-hoc analyses aimed to understand PROs by HRR gene clusters. Methods: PROs were assessed at day 1 and scheduled visits (every 4 weeks until week 53, then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and PR25 and BPI-SF. Prespecified PRO endpoints included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive deterioration (TTDD) with a clinically meaningful change of ≥10-points for the EORTC QLQ-C30. Stratified log-rank test and Cox proportional hazards model were used to make TTDD between-arm comparisons. Mutually exclusive gene clustering alteration dominance hierarchy was applied in the following order: any BRCA1/2 alteration (BRCAm cluster), PALB2 (PALB2 cluster), CDK12 (CDK12 cluster), ATM (ATM cluster), then any of all other HRR7genes (MLH1, CHEK2, NBN, FANCA, ATR, RAD51C, MRE11A). Results: A significantly longer TTDD in GHS/QoL was observed for TALA + ENZA vs PBO + ENZA in the BRCAm (HR=0.54, 95% CI (0.29, 0.99); p=0.043; median NE vs 19.0) and CDK12 clusters (HR=0.43 (0.19, 0.98); p=0.019, median 30.7 vs 16.6). Overall changes from baseline in GHS/QoL and worst pain are reported in the Table. Conclusions: PRO findings by HRR gene clusters are consistent with rPFS benefit analyses by gene clusters. This was an exploratory post-hoc analysis limited by missing PRO assessments and sample sizes especially in the PALB2 cluster. Clinical trial information: NCT03395197 . [Table: see text]
Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.
Authors: De Giorgi Ugo , Azad Arun , Fizazi Karim , Matsubara Nobuaki , Saad Fred , Joung Jae Young , Fong Peter C.C. , Jones Robert J. , Zschaebitz Stefanie , Oldenburg Jan , Shore Neal D. , Dunshee Curtis , Carles Joan , Fay Andre P. , Cislo Paul , Kirker Melissa , Healy Cynthia G. , Niyazov Alexander , Agarwal Neeraj
Published: January 2024

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Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .
Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager, in patients (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN).
Authors: Beltran Himisha , Dowlati Afshin , Jain Prantesh , Johnson Melissa Lynne , Sanborn Rachel E. , Thompson Jonathan Robert , Mamdani Hirva , Schenk Erin L. , Aggarwal Rahul Raj , Sankar Kamya , Gramza Ann W. , Anand Banmeet S , Choudhury Noura J.
Published: January 2024

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Background: HPN328 is a delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for T1/2 extension, and anti-CD3 for T cell engagement and activation. HPN328 treatment resulted in robust and specific anti-tumor activity in preclinical in vitro and in vivo DLL3-expressing NEPC models. Methods: Patients (pts) with relapsed/refractory, metastatic NEPC, small cell lung cancer (SCLC) and other NEN associated with DLL3 expression are eligible. Verification of DLL3 expression is required for NEN other than SCLC or NEPC for eligibility. Primary objectives are safety, maximum tolerated dose (MTD), recommended dose(s) for expansion (RDE) determination, and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. HPN328 is administered IV weekly or biweekly with a priming dose preceding the target dose in higher dose cohorts. Adverse events (AEs) are graded (G) by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of 21Aug23, 66 pts received HPN328 as a single agent at target doses of 0.015-24 mg across 14 dose escalation cohorts. Ten (10) pts had NEPC and 2 had small cell bladder cancer (SCBC). The remainder were SCLC or other NEN. Median number of prior regimens for all patients was 2 (1-6). Treatment is ongoing in 29 pts, with 3 from early escalation cohorts on study for more than a year. Treatment-related AEs in >10% of pts included CRS (52%), fatigue (35%), dysgeusia (33%), nausea (17%), vomiting and diarrhea (14% each), decreased appetite (12%), and pyrexia (11%). Nearly all CRS occurred after the initial priming dose and not with subsequent infusions. The most common ≥ G3 events were neutropenia (9%) and pneumonia and anemia (5% each). G3 CRS was a dose-limiting toxicity (DLT) in 2 pts at a priming dose of 2 mg; subsequent target dose escalation continued to 24 mg with a priming dose of 1 mg and no further DLTs of CRS; MTD at the target dose has not been reached. The 2 SCBC patients had confirmed partial responses (PR). Of the 10 NEPC patients, 3 of 6 with at least one imaging study had unconfirmed PRs. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented. Clinical trial information: NCT04471727 .
Differential treatment effect on overall survival (OS) based on early prostate-specific antigen (PSA) response in metastatic hormone-sensitive prostate cancer (mHSPC): A secondary analysis of TITAN trial.
Authors: Roy Soumyajit , Malone Shawn , Sun Yilun , Wallis Christopher J.D. , Kishan Amar Upadhyaya , Morgan Scott C. , Gebrael Georges , Swami Umang , Jia Angela , Brown Jason R , Saad Fred , Agarwal Neeraj , Spratt Daniel Eidelberg
Published: January 2024

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Background: Early PSA response has been found to be associated with improved outcome in mHSPC patients treated with androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPI). However, it is unknown if the treatment effect on OS varies based on early PSA response in these patients. Methods: We performed a secondary analysis of TITAN study in which men with mHSPC were randomly assigned to ADT plus placebo vs. ADT plus apalutamide (ADT+APA). To compare the association of OS with early PSA response, defined as achieving a PSA nadir of ≤0.2 ng/mL at ≤6 months of randomization, between two arms, we applied multivariable Cox regression model on a landmark population with an interaction term between the treatment arm and PSA response. Adjusted OS were calculated. Confounders were chosen based on their association with PSA response and OS. Results: Overall, 1049 patients were eligible with 526 in the ADT arm and 523 in the ADT+APA arm. Approximately 24% (125/526) patients in the ADT arm and 62% (323/523) patients in the ADT+APA arm achieved early PSA nadir. On landmark analysis, ADT+APA was associated with improved OS among those with an early PSA nadir (HR: 0.66; 95% CI: 0.44-1.00) but no improvement in OS among those without an early PSA nadir (HR: 1.15 [0.87-1.46]) with differential treatment effect between groups stratified by early PSA nadir by 6 months (p=0.03). Adjusted 4-year OS for patients who reached PSA nadir was 66% (95% CI: 56-75) in the ADT alone arm and 78% [74-83] in the ADT+APA arm while for patients who did not reach PSA nadir, adjusted 4-year OS was 46% [41-52] and 47% [40-54] in the ADT alone and ADT+APA arm, respectively. Numbers needed to treat (NNT) was 7.8 (95% CI: 6 to 15) for the overall landmark population, 7.7 [5 to 36] for patients with PSA nadir by 6 months, and 55 [10 to -4] for those without PSA nadir, respectively. Conclusions: In this exploratory analysis of TITAN study, early PSA nadir at or before 6 months was associated with superior OS in both treatment arms. However, there was evidence of differential treatment effect on OS based on early PSA nadir with no beneficial effect from ADT+APA in those who did not reach early PSA nadir. Patients with lack of early PSA nadir had inferior and similar OS in both treatment groups. Further investigation is needed to determine how to best manage patients treated with doublet therapy without an early PSA response.
(ARTO trial-NCT03449719): Role of local treatment after progression in patients with castrate-resistant prostate cancer undergoing first-line abiraterone treatment.
Authors: Francolini Giulio , Di Cataldo Vanessa , Detti Beatrice , Garlatti Pietro , Caini Saverio , Bruni Alessio , Ingrosso Gianluca , D'Angelillo Rolando Maria , Alitto Anna Rita , Augugliaro Matteo , Triggiani Luca , Parisi Silvana , Facchini Gaetano , Banini Marco , Simontacchi Gabriele , Desideri Isacco , Meattini Icro , Valicenti Richard K. , Livi Lorenzo
Published: January 2024

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Background: ARTO (NCT03449719) is a multicentre, randomized phase II trial testing the benefit of concomitant stereotactic body radiation therapy (SBRT) and abiraterone acetate (AA)+ prednisone administration in oligometastatic Castrate Resistant Prostate Cancer (CRPC) patients. Results already showed significant benefit in terms of biochemical response and Progression Free Survival (PFS) in the experimental arm. To explore role of local treatment throughout the whole clinical history of these patients, here is reported a subgroup analysis focusing on impact of treatment (SBRT vs second line systemic therapy) after progression. Methods: Patients affected by oligometastatic CRPC (</= 3 non-visceral metastatic lesions) were enrolled in the trial and randomized 1:1 to receive either AA+ prednisone alone (control arm) or associated with concomitant SBRT on all sites of disease (treatment arm). PFS2 was defined as time between first progression event and second progression, death or last follow up. Cox regression analysis was performed to compare PFS2 in patients treated with SBRT on oligo-progressive metastatic sites vs patients undergoing second line systemic therapy (primarily taxane chemotherapy). Results: One hundred fifty-seven patients were enrolled in ARTO trial. At last follow up (August 2023), 77 patients progressed after abiraterone+ prednisone treatment (23 vs 54 in the experimental vs control arm, respectively). Of these, 14 received best supportive care and were excluded from the analysis, 23 underwent SBRT on oligo-progressive metastatic sites (17 and 6 originally randomized to the experimental vs control arm, respectively), 40 were treated with second line systemic treatment. A second progression event was detected in 14 patients. Median PFS 2 was 10 months (95% CI 10-17) and 10 months (95% CI 7-12) for patients undergoing SBRT vs second line treatment, respectively (HR 1.26, 95% CI 0.33-4.75, p 0.73). Conclusions: When oligoprogressive status is detected, SBRT may achieve similar benefit if compared to second line systemic treatment. These data, in the context of a randomized trial with positive results for primary endpoints, suggest that repeated SBRT may be a viable treatment option in selected patients. Clinical trial information: NCT03449719 .
Intensification of ADT with enzalutamide in high-risk patients with biochemical relapse following radical prostatectomy undergoing salvage radiation: Initial results from RTOG 3506 (STEEL).
Authors: Posadas Edwin Melencio , Gay Hiram Alberto , Rodgers Joseph P , Morgan Todd Matthew , Xiao Ying , Yu James B. , Michalski Jeff M. , Bouchard Myriam , Desai Neil B , Funk Ryan , Boike Thomas , Jurgens Donald James , Wong Anthony C. , Shen Xinglei , Miyawaki Lloyd T , Bland Christopher S , Hairston John C , Sandler Howard M. , Pugh Stephanie L , Feng Felix Y
Published: January 2024

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Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that intensification of androgen receptor (AR) blockade with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post prostatectomy prostate cancer patients who have had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of ADT with an LHRH analog (LHRHa) or intensified ADT comprised of LHRHa + enzalutamide. The primary endpoint was progression free survival (PFS) with progression defined as PSA ≥ 0.05 ng/mL or initiation of new therapy following SRT. The target accrual of 170 patients provided 80% power to detect a HR=0.65 using a one-sided logrank test with a type I error of 0.10. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had > 1 aggressive feature. Median follow-up time at the time of this report was 15.8 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. PFS favored the enzalutamide-intensified arm (HR=0.72, 80% confidence interval [CI]:0.56-0.94, one-sided p=0.14). Grade 3 adverse events (AEs) related to treatment in the standard versus enzalutamide arms were 11 vs. 23%, while Grade 4 AEs were 4% vs. 1%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. The largest differences (>7%) in AEs included insomnia, decreased lymphocytes. Diarrhea was less frequent with enzalutamide (40% vs 54%). Conclusions: The addition of enzalutamide to standard ADT did not meaningfully increase toxicity. While there was a trend toward PFS benefit from intensification, it has not yet met statistical significance. Updates on PFS and other clinical endpoints including quality of life will be reported with longer follow-up. Clinical trial information: NCT03809000 .
Oral cyclophosphamide (Cyc) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort from a tertiary public cancer center in Brazil.
Authors: Ricucci Shinkado Yumi , Pineda Labanda Diana Del Cisne , Polho Gabriel Berlingieri , Alves Contado Gustavo , Crusoé Nathália de Souza Del Rey , Horita Vivian , Resende Martins João Carlos , Fialho de Freitas Guilherme , Muniz David Queiroz Borges , Mota Jose Mauricio
Published: January 2024

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Background: Oral Cyc is an active treatment for mCRPC, although largely unused in current clinical practice due to the rise of more effective options and no evidence of survival benefit. Real-world data on its use in developing countries is still scarce. Methods: We reviewed our institutional database to identify mCRPC pts who received oral Cyc. Medical charts were analyzed to extract clinical data. PSA50 response was determined as the proportion of patients achieving a prostate specific antigen (PSA) declines ≥50%. Radiographic responses and progression were evaluated by Prostate Cancer Working Group 3. Survival estimates used the Kaplan-Meier method and correlations were made with the Chi-square test for categorical variables. Results: From January 2011 to January 2023, 287 pts received oral Cyc. Most patients (>96%) received 100 mg once daily 3 weeks on/1 week off. Median age was 64.3 years (interquartile range [IQR] 35.8-85.3). 63.1% had metastatic de novo disease, 57.1% had Gleason ≥8, and 5.9% had visceral metastasis. 78.1% received two or more previous lines of treatment, and most pts (73.5%) had docetaxel previously. Any PSA decline was observed in 36.0%, and 15.0% had a PSA50 response. Median time for a PSA50 response was 2.7 months (IQR 1.3-3.8). Radiographic overall response rate was 24.2%. Median time on treatment was 2.53 months (IQR 0.40-51.9). Median time to PSA, clinical, or radiological progression among responders was 6.9 months (IQR 0.7-51.9), but 16.6% (n=7) had responses lasting for ≥12 months. Permanent treatment discontinuation due to toxicity occurred in 14.1%, and 8.0% were hospitalized due to adverse events. Table shows the association between baseline factors with PSA50 response. Correlative biomarker studies are ongoing and will be presented. Conclusions: Metronomic oral Cyc can benefit a small proportion of patients with mCRPC in a scenario of limited healthcare resources. [Table: see text]
Radiographic progression without PSA progression in metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective analysis from the ENZAMET trial (ANZUP 1304).
Authors: Davis Ian D. , Martin Andrew James , Zielinski Robert Richard , Thomson Alastair , Tan Thean Hsiang , Sandhu Shahneen , Reaume M. Neil , Pook David William , Parnis Francis , North Scott A. , Marx Gavin M. , McCaffrey John , McDermott Raymond S. , Inderjeeth Andrisha Jade , Horvath Lisa , Frydenberg Mark , Chowdhury Simon , Chi Kim N. , Stockler Martin R. , Sweeney Christopher ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: January 2024

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Background: ENZAMET randomized 1125 participants with mHSPC to compare enzalutamide (ENZA) versus a standard non-steroidal anti-androgen (NSAA) and demonstrated superior progression-free survival and overall survival (PFS and OS) with ENZA. Radiographic progression in the absence of prior/concurrent PSA progression (rProg1st) is an emerging biomarker of poor clinical outcomes. We sought to determine the frequency of rProg1st, and correlate the impact of enzalutamide on transitions between disease states for the ENZAMET cohort. Methods: The ENZAMET dataset was analyzed using a multi-state Cox proportional hazards regression model that partitioned the clinical experience of participants (pts) into 4 states: (1) Evt-Free (event-free), (2) rProg1st (radiologic progression recorded without prior/concurrent evidence of confirmed PSA progression), (3) OtherProg (All Other type of clinical progression events (PSA and treatment switch, excluding death), (4) Death. Results: Radiographic progression was recorded in 388/1125 (34%) pts. Radiographic progression without confirmed prior/concurrent PSA progression per protocol was recorded in 114/1125 (10%) with similar proportions in those assigned ENZA 55/114 (48%) vs NSAA 59/114 (52%). Baseline characteristics of the 114 pts with rProg1st were similar to the other pts in ENZAMET, and were similar in the ENZA and NSAA groups (Table 1). Compared with NSAA, ENZA delayed both rProg1st (HR 0.66, 95%CI: 0.46 to 0.96, p=0.03) and OtherProg (HR 0.37, 95%CI: 0.31 to 0.44, p<0.001). 5-year OS rates were 24% (95%CI: 18-34) in the rProg1st group versus 42% (95%CI: 38-47) in the OtherProg group. Of those who had not progressed (495/1125) with a median follow-up of 68 months, 8% had died of causes other than prostate cancer. As previously reported ENZA prolonged overall survival in the whole trial cohort (N=1125, HR 0·70, 95%CI 0·58 to 0·84, p<0·0001). Conclusions: Participants who had radiographic progression without prior/concurrent PSA progression had worse overall survival whether assigned NSAA or enzalutamide. Enzalutamide reduced the hazards for, and delayed the times to, rProg1st and OtherProg. There were no baseline characteristics that helped identify these pts upfront; we plan molecular biological analyses to help identify this unique group earlier. Clinical trial information: NCT02446405 . [Table: see text]
Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki-67.
Authors: Zhao Fengnian , Zhao Jinge , Shi Yifu , Wei Xinyuan , Chen Ni , Shen Pengfei , Zeng Hao
Published: January 2024

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Background: The marker of proliferation Ki-67 (KI67) is a well-known biomarker reflecting cell proliferation activity and was reported to be associated with the treatment efficacy of chemotherapy in different tumors. However, it is unknown whether KI67 also has a role in predicting the efficacy of the next-generation hormone therapies, e.g., abiraterone, for patients with prostate cancer (PCa). Methods: Clinicopathological data of 144 men with metastatic PCa who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry (IHC) using the prostate biopsy specimen. The predictive value of KI67 and other factors on the therapeutic efficacy of abiraterone treatment was explored. Kaplan-Meier curve and COX regression analysis were used for survival analysis. The endpoints were PSA progression-free survival (PSA-PFS) and radiographic progression-free survival (rPFS) according to the PCWG3 criteria. Results: Among the 144 included patients, 82 (56.9%) and 62 (43.1%), respectively, received abiraterone therapy at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% for the total cohort (interquartile range: 10%-30%). When taken as a continuous variable, KI67 positivity was adversely related to both PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.02-1.03, P=0.001) of the abiraterone therapy, while was not associated with PSA response. The results of multivariate COX regression analysis implied that, after adjusting by mHSPC/mCRPC stage, ISUP grading, pain score, visceral metastasis, and metastatic burden, KI67 was still an independent predictor of PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.008) of the abiraterone therapy. Moreover, when patients were divided into two groups with high and low KI67, using cutoffs of 10%, 20%, and 30%, KI67 remained a significant predictor of both PSA-PFS (HR: 1.67, 1.91, 2.29; P value: 0.052, 0.004, <0.001) and rPFS (HR: 1.54, 1.83, 1.88; P value: 0.119, 0.008, 0.008) of the abiraterone treatment. Subgroup analysis based on whether patients received abiraterone at mHSPC or mCRPC stage suggested that KI67 30% (median PSA-PFS: 11.4- vs. 27.6-Mo, P<0.001; median rPFS: 16.6- vs. 33.6-Mo, P=0.001) was the optimal cutoff to maximize patient prognostic differentiation for the mHSPC cohort, while KI67 20% (median PSA-PFS: 6.9- vs. 14.9-Mo, P=0.033; median rPFS: 10.1- vs. 16.5-Mo, P=0.030) was the optimal cutoff for the mCRPC cohort. Conclusions: Our study revealed that KI67 positivity in prostate biopsy specimens was a robust predictor of abiraterone efficacy for patients with advanced PCa. Further validation using datasets from other centers is needed to strengthen the findings of our work.
Effect of combined treatment with sipuleucel-T and IL-15 on tumor control, tumor-infiltrating immune effectors, and key mediators of immunoresistance in a preclinical prostate cancer model.
Authors: Pachynski Russell Kent , Saeed Muhammad Azeem , Peng Bo , Van Tine Brian Andrew , Sheikh Nadeem Anwar , Fehniger Todd A.
Published: January 2024

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Background: Sipuleucel-T (sip-T) is an autologous therapeutic vaccine produced using a tumor antigen-cytokine fusion protein, and the only FDA approved cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC) patients. Sip-T significantly improves overall survival (OS), but has limited impact on PSA and radiographic responses. Here, we present the first high dimensional analysis of the sip-T product; we used a preclinical model of human prostate cancer to show the effects of IL-15 on anti-tumor efficacy, tumor infiltration of effector cells, and reversal of immunosuppressive mediators. Methods: We performed a comprehensive assessment of the sip-T product collected from prostate cancer patients using mass cytometry (CyTOF). Control and IL-15 stimulated sip-T were evaluated, and changes in leukocyte subsets as well as markers of activation and exhaustion were identified. Using a preclinical mouse model of human prostate cancer, we examined the effects of IL-15 treatment on sip-T. CyTOF, flow cytometry, RNAseq, and qPCR were used to evaluate the effects of IL-15 on sip-T phenotype, function, and in vitro and in vivo efficacy. Results: CyTOF analysis revealed that CD3+ T cells constituted the highest proportion of sip-T, followed by B-cells, natural killer (NK) cells, NKT, and monocytes, with only a small percentage of dendritic cells. Following sip-T stimulation with IL-15, a significant expansion and activation of CD8+ T-cell and NK cell populations was seen. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner, with significantly increased tumor cytotoxicity and evidence of antigen spread. IL-15 treatment combined with sip-T in a preclinical mouse model showed significant suppression of tumor growth compared to sip-T alone, with increased tumor-infiltrating lymphocytes (TIL). A significant increase in interferon (IFN)-γ producing CD8+ T and NKT cells within the tumor microenvironment was seen in the IL-15 group. Tumor transcriptomic analyses revealed IL-15 treatment was able to reverse immunoresistance, with significant decreases in PD-L1, CTLA, TIGIT, B7-H3, and others compared to sip-T alone. Conclusions: This is the first study to evaluate the sip-T product using CyTOF, and the first pre-clinical in vivo prostate tumor modeling of sip-T. IL-15 treatment significantly enhances anti-tumor efficacy, effector immune cell activation and tumor infiltration, and reverses key mediators of immune suppression. Studies with modified IL-15 cytokines are ongoing and will be presented.
Prevalence of HRR mutations in Indian patients with mCRPC.
Authors: Batra Atul , Menon Nandini Sharrel , Vaswani Bharat , Talwar Vineet , Bajaj Rajat , Chandrakanth MV , Hingmire Sachin Sharadchandra , Prabhash Kumar , Choudhary Priyanshu , Pathania Bhavana
Published: January 2024

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Background: Prostate cancer is the 12th most common cancer in India. Almost all patients with metastatic prostate cancer progress to castration-resistant prostate cancer. Ph3 studies demonstrated benefit of PARPi for patients with mutations in HRR pathway. However, the prevalence of HRR gene mutations in Indian patients with mCRPC is not known. This non-interventional multicenter study aimed to determine the prevalence of HRR gene mutations in the Indian patients with mCRPC. Methods: The study included mCRPC patients from 8 centres across India. A total of 213 patients were screened, of which 192 patients completed the study. Comprehensive molecular profiling on tumour tissue was performed using next-generation sequencing (NGS) to identify 15 HRR gene mutations. The QC-passed libraries were sequenced to a minimum depth of >250X on a validated Illumina sequencing platform. Results: NGS analysis revealed HRR gene mutations (Pathogenic, likely pathogenic and VUS) in 41/192 (21.4%, 95% CI: 15.78, 27.83)) of the patients (Table). Among the HRR gene mutations identified, BRCA2 mutations were the most prevalent.68/192 (35%) patients failed tumor testing and underwent reflex germline testing. Among patients having no known family history, 24 patients (12.5%) harboured a HRR gene mutation. Most patients (n=23, 12.0%) had Gleason score of 9 to 10. Conclusions: Pathogenic and likely pathogenic HRR gene mutations were prevalent in approximately one-fifth of the mCRPC patients in India. 64.5% patients had a successful test result on the tumor tissue sample. [Table: see text][Table: see text]