bluuebunny/crossref_metadata_2025 huggingface dataset:
CCL5/CCR5-mediated peripheral inflammation exacerbates blood‒brain barrier disruption after intracerebral hemorrhage in mice
Authors: Lin Jie , Xu Ya , Guo Peiwen , Chen Yù-Jié , Zhou Jiru , Xia Min , Tan Binbin , Liu Xin , Feng Hua , Chen Yujie
Published: March 2023

Background

Owing to metabolic disequilibrium and immune suppression, intracerebral hemorrhage (ICH) patients are prone to infections; according to a recent global analysis of stroke cases, approximately 10 million new-onset ICH patients had experienced concurrent infection. However, the intrinsic mechanisms underlying the effects of infection related peripheral inflammation after ICH remain unclear.

Methods

Lipopolysaccharide (LPS) was intraperitoneally injected into ICH model mice to induce peripheral inflammation. Neurobehavioral deficits, blood‒brain barrier (BBB) disruption, and the expression of CCR5, JAK2, STAT3, and MMP9 were evaluated after treatment with recombinant CCL5 (rCCL5) (a CCR5 ligand), maraviroc (MVC) (an FDA-approved selective CCR5 antagonist), or JAK2 CRISPR plasmids.

Results

Our study revealed that severe peripheral inflammation increased CCL5/CCR5 axis activation in multiple inflammatory cell types, including microglia, astrocytes, and monocytes, and aggravated BBB disruption and neurobehavioral dysfunction after ICH, possibly in part through the JAK2/STAT3 signaling pathway.

Conclusions

CCR5 might be a potential target for the clinical treatment of infection-induced exacerbation of BBB disruption following ICH.
Network pharmacology-based mechanism prediction and pharmacological validation of Bushenhuoxue formula attenuating postmenopausal osteoporosis in ovariectomized mice
Authors: Xia Chenjie , Zhu Haowei , Li Jin , Jin Hongting , Fu Danqing
Published: March 2023

Background

Bushenhuoxue (BSHX) formula, a ten-compound herbal decoction, is widely used to treat postmenopausal osteoporosis (PMOP) in China. However, the mechanism is not clear yet.

Methods

The underlying biological processes and signaling pathways were predicted by network pharmacology. In vivo experimental study, 24 female C57BL/6 J mice were randomly divided into sham, ovariectomized (OVX) and BSHX formula groups. Mice in the latter two groups were subjected to bilateral ovariectomy, and mice in the BSHX formula group were extra treated by BSHX formula at an oral dosage of 0.2 mL/10 g for 8 weeks. The femur samples were harvested for tissue analyses including μCT assay, histology and immunohistochemical (IHC) staining of VEGF signaling.

Results

A total of 218 active ingredients and 274 related targets were identified in BSHX formula. After matching with 292 targets of PMOP, 64 overlapping genes were obtained. GO and KEGG enrichment analyses on these 64 genes revealed that angiogenesis and VEGF signaling were considered as the potential therapeutic mechanism of BSHX formula against PMOP. Animal experiments showed that mice in the BSHX formula-treated group presented increased bone mass, microstructural parameters, blood vessel numbers and an activation of VEGF signaling (VEGF, COX2, eNOS and CD31) compared to the OVX mice.

Conclusion

This study revealed that BSHX formula exerts anti-PMOP effects possibly through activating VEGF signaling-mediated angiogenesis.
Combinatorial batching of DNA for ultralow-cost detection of pathogenic variants
Authors: Stoltze Ulrik Kristoffer , Hagen Christian Munch , van Overeem Hansen Thomas , Byrjalsen Anna , Gerdes Anne-Marie , Yakimov Victor , Rasmussen Simon , Bækvad-Hansen Marie , Hougaard David Michael , Schmiegelow Kjeld , Hjalgrim Henrik , Wadt Karin , Bybjerg-Grauholm Jonas
Published: March 2023

Background

Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed.

Methods

We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data.

Results

We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing.

Conclusions

Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.
Changes in CSF sPDGFRβ level and their association with blood–brain barrier breakdown in Alzheimer’s disease with or without small cerebrovascular lesions
Authors: Lv Xinyi , Zhang Mengguo , Cheng Zhaozhao , Wang Qiong , Wang Peng , Xie Qiang , Ni Ming , Shen Yong , Tang Qiqiang , Gao Feng ,   China Aging Neurodegenerative Disorder Initiative (CANDI) Consortium
Published: March 2023

Background

CSF-soluble platelet-derived growth factor receptor beta (sPDGFRβ) is closely associated with pericyte damage. However, the changes in CSF sPDGFRβ levels and their role in blood–brain barrier (BBB) leakage at different stages of Alzheimer’s disease (AD), with or without cerebral small vessel disease (CSVD) burden, remain unclear.

Methods

A total of 158 individuals from the China Aging and Neurodegenerative Disorder Initiative cohort were selected, including 27, 48, and 83 individuals with a clinical dementia rating (CDR) score of 0, 0.5, and 1–2, respectively. CSF total tau, phosphorylated tau181 (p-tau181), Aβ40, and Aβ42 were measured using the Simoa assay. Albumin and CSF sPDGFRβ were measured by commercial assay kits. CSVD burden was assessed by magnetic resonance imaging.

Results

CSF sPDGFRβ was the highest level in the CDR 0.5 group. CSF sPDGFRβ was significantly correlated with the CSF/serum albumin ratio (Q-alb) in the CDR 0–0.5 group (β = 0.314, p = 0.008) but not in the CDR 1–2 group (β = − 0.117, p = 0.317). In the CDR 0–0.5 group, CSF sPDGFRβ exhibited a significant mediating effect between Aβ42/Aβ40 levels and Q-alb (p = 0.038). Q-alb, rather than CSF sPDGFRβ, showed a significant difference between individuals with or without CSVD burden. Furthermore, in the CDR 0.5 group, CSF sPDGFRβ was higher in subjects with progressive mild cognitive impairment than in those with stable mild cognitive impairment subjects (p < 0.001). Meanwhile, CSF sPDGFRβ was significantly associated with yearly changes in MMSE scores in the CDR 0.5 group (β = − 0.400, p = 0.020) and CDR 0.5 (A+) subgroup (β = − 0.542, p = 0.019).

Conclusions

We provide evidence that increased CSF sPDGFRβ is associated with BBB leakage in the early cognitive impairment stage of AD, which may contribute to cognitive impairment in AD progression.
Cluster analysis of COVID-19 recovery center patients at a clinic in Boston, MA 2021–2022: impact on strategies for access and personalized care
Authors: Tukpah Ann-Marcia C. , Patel Jhillika , Amundson Beret , Linares Miguel , Sury Meera , Sullivan Julie , Jocelyn Tajmah , Kissane Brenda , Weinhouse Gerald , Lange-Vaidya Nancy , Lamas Daniela , Ismail Khalid , Pavuluri Chandan , Cho Michael H. , Gay Elizabeth B. , Moll Matthew
Published: March 2023

Background

There are known disparities in COVID-19 resource utilization that may persist during the recovery period for some patients. We sought to define subpopulations of patients seeking COVID-19 recovery care in terms of symptom reporting and care utilization to better personalize their care and to identify ways to improve access to subspecialty care.

Methods

Prospective study of adult patients with prior COVID-19 infection seen in an ambulatory COVID-19 recovery center (CRC) in Boston, Massachusetts from April 2021 to April 2022. Hierarchical clustering with complete linkage to differentiate subpopulations was done with four sociodemographic variables: sex, race, language, and insurance status. Outcomes included ICU admission, utilization of supplementary care, self-report of symptoms.

Results

We included 1285 COVID-19 patients referred to the CRC with a mean age of 47 years, of whom 71% were female and 78% White. We identified 3 unique clusters of patients. Cluster 1 and 3 patients were more likely to have had intensive care unit (ICU) admissions; Cluster 2 were more likely to be White with commercial insurance and a low percentage of ICU admission; Cluster 3 were more likely to be Black/African American or Latino/a and have commercial insurance. Compared to Cluster 2, Cluster 1 patients were more likely to report symptoms (ORs ranging 2.4–3.75) but less likely to use support groups, psychoeducation, or care coordination (all p < 0.05). Cluster 3 patients reported greater symptoms with similar levels of community resource utilization.

Conclusions

Within a COVID-19 recovery center, there are distinct groups of patients with different clinical and socio-demographic profiles, which translates to differential resource utilization. These insights from different subpopulations of patients can inform targeted strategies which are tailored to specific patient needs.
China’s innovation and research contribution to combating neglected diseases: a secondary analysis of China’s public research data
Authors: Ma Jiyan , Zhang Lanchao , Li Xianzhe , Shen Jiashu , Sun Yinuo , Huang Yangmu
Published: March 2023

Background

Many emerging and developing economies, such as China, have played the important roles in combating global neglected diseases (NDs). This study aims to explore China’s public landscape of research projects and funding of NDs and to provide empirical evidence on promoting China’s participation in addressing global health priorities that disproportionately affect developing countries.

Methods

We systematically sourced China’s public funding information from the National Natural Science Foundation of China and provincial science and technology agency websites up to August 16, 2019. Following the G-FINDER R&D scope, we screened projects of NDs for analysis. National-funded projects were reviewed on an annual basis for exploring the trends and distribution of funding flows. Information on provincial-funded projects was compared with national projects by disease, research type, and geographical distribution.

Results

A total of 1266 projects were included for analysis and categorized by year, funding source, recipient, disease, research type, region, and province. China’s national public funding for ND research reached a historical peak of USD 16.22 million in 2018. But the proportion of ND research to all public-funded projects was less than 0.5%, and over half of the ND projects were allocated to “the big three,” i.e., tuberculosis, HIV/AIDS, and malaria. About 58% of national and provincial ND projects focus on basic research. Economically developed regions and municipalities play dominant roles in leading national ND research, such as Beijing, Shanghai, and Guangdong. Provincial ND projects are primarily driven by endemic regions.

Conclusions

As a new emerging high-tech innovator, China has gradually increased public input to ND-related innovation and research. But there is still a large funding gap among NDs that requires China’s increased support and participation. National development plans and cooperative health needs should be taken into account for China’s participation in promoting global research and development (R&D) for combating NDs.
Using EV charging control to provide building load flexibility
Authors: Bhundar Harsimrat Singh , Golab Lukasz , Keshav Srinivasan
Published: March 2023

Buildings are responsible for a significant fraction of the overall electrical load. Given the increasing penetration of renewables into the generation mix, it is important to make building loads flexible, to better match the variability in generation. Of course, building loads can be made arbitrarily flexible using sufficient stationary storage, but this comes at considerable cost. In this paper, we investigate how to reduce this cost by exploiting electric vehicle (EV) charging control for unidirectional and bidirectional charging. Specifically, we design a model-predictive control algorithm to reshape building load to match a specified load shape. In realistic settings and for two use cases, we investigate the degree to which the amount of stationary storage is reduced using EV charging control. In both cases, we find that our controller reduces the need for stationary storage compared to existing solutions. Moreover, bidirectional EV charging control substantially reduces the required amount of stationary storage.
Experimental study on transition of dynamic airfoil in pitching oscillation
Authors: Wei Binbin , Gao Yongwei , Hu Shuling
Published: March 2023

The transition characteristics of dynamic airfoil have significant effects on the aerodynamic performance of wind turbines, helicopter rotor blades, jet engine compressor blades, etc. The time domain and time-frequency domain characteristics of transition on a NACA0012 airfoil during its pitching oscillation were experimentally studied using wall pressure measurement technology with high time accuracy in this paper. The variable slip window technology was used to detect the transition position, and the proper orthogonal decomposition (POD) method and wavelet analysis were combined to perform the time-frequency analysis. In the gradual forward movement of the transition, the low-frequency instability is gradually enhanced by the main flow and the inverse pressure gradient, and significantly submerges the high-frequency fluctuated feature. The higher order moments of the wall pressure during dynamic airfoil transition deviate significantly from the Gaussian characteristics, which is caused by the low-frequency instability and high-frequency burst. The POD method is able to distinguish low-frequency instability from the high-frequency feature. The reduced frequency had significant effects on the transition. With the increase of the reduced frequency, the hysteresis effect of the transition became more and more significant, and the frequency component of transition was more concentrated and the energy was stronger.
Prevalence of TP53 gene Pro72Arg (rs1042522) single nucleotide polymorphism among Egyptian breast cancer patients
Authors: Ahmed Shaza , Safwat Gehan , Moneer Mohamed M. , El Ghareeb AbdelWahab , El Sherif Ahmed A. , Loutfy Samah A.
Published: March 2023

Background

The P53 protein has an essential role in several cellular processes, including DNA repair, apoptosis, and cell cycle arrest. The pathophysiology of many cancer types has frequently been linked to polymorphisms in theTP53locus. Over 200 single nucleotide polymorphisms (SNPs) have been identified in TP53. However, Pro72Arg (rs1042522) at codon 72, shows contradictory results in terms of cancer risk. In this study, we aimed to determine if the Pro72Arg (rs1042522) SNP in theTP53gene would be linked to breast cancer (BC) risk among Egyptian patients.

Materials and Methods

Genomic DNA was extracted from blood samples of 100 healthy volunteers and 100 breast cancer patients (50 familial and 50 non-familial).TP53Genotyping was performed using tetra-primer amplification refractory mutation (Tetra-ARMS) PCR. Data were analyzed using SNPstat software.

Results

The prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele [Pro/Arg (CG) and Arg/Arg (GG)] were significantly higher in BC patients compared to healthy volunteers and were associated with BC susceptibility (OR 0.2; [95% CI 0.11–0.38];P = 0.0001). However, there was no statistical significant difference in the prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele between familial and non-familial BC patients. In addition, there was no association between the prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele and BC patients’ clinical and pathological characteristics including tumor size, tumor grade, lymph node status, presence of lymphovascular invasion, expression of ER, PR and Her-2 in both of familial and non-familial BC patients.

Conclusions

TP53(Pro72Arg) rs1042522 is more prevalent among BC patients but not associated with disease progression.
Underutilization of best systemic therapy in patients with metastatic prostate cancer.
Authors: Roadman Daniel , Cao David , Vourganti Srinivas
Published: March 2023

111

Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age <18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.
Leukocyte subtypes and myeloid derived suppressor cells as prognostic markers in metastatic castration resistant prostate cancer treated with cabazitaxel: A satellite study of the CABASTY phase III trial.
Authors: Heisbourg Jean-David , Oudard Stephane , Beuzeboc Philippe , Bennamoun Mostefa , Saldana Carolina , Voog Eric , Barthelemy Philippe , Thiery-Vuillemin Antoine , Hasbini Ali , Houede Nadine , Belhouari Houda , Helissey Carole , Parfait Beatrice , Thibaudin Marion , Phan Letuan , Kotti Salma , Yaovi Eric
Published: March 2023

126

Background: CABASTY trial investigated the benefit of an adapted schedule of cabazitaxel (16 mg/m2 bi-weekly versus 25 mg/m2 tri-weekly) in mCRPC patients previously treated with docetaxel and alternative androgen-targeted therapy. The study met its endpoints with a significantly decreased incidence of grade ≥ 3 neutropenia without a decrease in overall survival. This preplanned analysis evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelets ratio (NPR) myeloid derived suppressor cells (MDSC) and leukocyte subtypes counts in this setting. Methods: 44 patients treated with cabazitaxel were included. Peripheral blood mononuclear cells were isolated and myeloid compartment analysis were performed at baseline, week 6 (S6) and week 12 (S12) of treatment using a multi-parametric flow cytometry panel. We investigated at each timepoints the association of NPR, NLR, MDSC and leukocytes subtypes with PSA response rate (PSArr), Progression Free Survival, and Overall Survival with a preplanned uni- and multivariate analysis. Results: The NLR, NPR, MDSC subtypes and lymphocytes count at baseline were prognostic in the CABASTY trial regardless of the cabazitaxel regimen. Patients with a high lymphocyte count and/or a low NLR, NPR, and MDSC counts at baseline had a significantly improved PSAr, PFS and OS. In the multivariate analysis, a NPR > 1,84 and lymphocytes count < 1,2 G/L at baseline were significantly associated with OS [HR 2.007 (1.3 - 3.1)] and [HR 0.38 (0.20 - 0.73)]. Conclusions: High NLR, NPR, neutrophil and MDSC counts as well as a low lymphocyte count at baseline and during treatment predict poor outcomes in mCRPC patients treated with cabazitaxel. NPR and lymphocyte count are readily available biomarkers that may be useful for risk stratification in future clinical trials and could be incorporated into prognostic nomograms. Clinical trial information: NCT02961257 .
Lutetium-177 PSMA radioligand therapy for metastatic castration resistant prostate cancer in Germany: Population-based data with multicenter validation from 2016 to 2020.
Authors: Flegar Luka , Thoduka Smita George , Librizzi Damiano , Luster Markus , Zacharis Aristeidis , Heers Hendrik , Eisenmenger Nicole , Ahmadzadehfar Hojjat , Eiber Matthias , Weber Wolfgang A , Groeben Christer , Huber Johannes
Published: March 2023

146

Background: Our purpose was to investigate the adoption and current trends of Lutetium-177 PSMA radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC) in Germany. Methods: We analyzed the nationwide German hospital billing database (Destatis) and the hospitals’ quality reports for 177Lutetium PSMA RLT from 2016 to 2020 using the reimbursement.INFO tool. For detection of trends over time we applied linear regression models. For validation of these billing data, we included a total of 1239 177Lu-PSMA RLT cycles from 392 patients within the WARMTH multicenter study from 2016 to 2018. Additionally, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020 for further validation. Results: We identified 12553 cases which were treated with 177Lu-PSMA RLT. The number of 177Lu-PSMA RLTs steadily increased from 1077 to 3640 therapies during the study period (+641 RLT/year; p<0.005). In 2016, 25 departments of nuclear medicine offered this treatment, which increased to 44 nuclear medicine departments in 2020. In 2016, 16% of nuclear medicine departments (4/25) performed more than 100 177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p<0.005). In 2016, 88% (22/25) of 177Lu-PSMA RLTs were performed at a university hospital, which decreased to 70% (31/44) in 2020. The proportion of patients older than 65 years receiving 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. Conclusions: Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. Most of the therapies are performed at academic hospitals.
Carboplatin in metastatic castrate resistant prostate cancer: A retrospective study of heavily pretreated patients (COMPACT).
Authors: Pemberton Lara , Allen Connor , Handel Eleanor , Weickhardt Andrew James , Tran Ben , Crumbaker Megan , Shapiro Jeremy David , Risbridger Gail P. , Pook David William
Published: March 2023

158

Background: Despite a lack of up-to-date clinical trial data, many clinicians advocate the use of Carboplatin monotherapy to treat patients with advanced Castrate Resistant Prostate Cancer (CRPC) who have exhausted multiple other treatment options. The aim of this study was to determine the overall survival (OS) and response rate in patients with advanced CRPC treated with Carboplatin monotherapy after progressing on other chemotherapy agents. Methods: Retrospective multicentre study of the use of Carboplatin in advanced CRPC patients in Australia. Demographic data, PSA response rates, survival data and Carboplatin treatment protocols, such as dose and duration, were collected. Exploratory analyses on potential prognostic parameters were performed. Results: 51 patients received Carboplatin: median age 68 (range 55–86 years). Most patients (78.3%) received Carboplatin AUC 5 at 3-weekly intervals. The median number of cycles of Carboplatin was 3 (range 1-17). Median time on treatment was 63 days (range 1-441). Median overall survival was 29.4 weeks (IQR 11.7 weeks). 6 (11.8%) patients had a PSA response ≥50%. The median time to PSA progression on Carboplatin was 67 days (range 15-418). 16 patients (31%) required a dose delay or reduction and 8 patients (15.6%) ceased Carboplatin secondary to side effects/ toxicity. Conclusions: Our findings demonstrate that in heavily pre-treated CRPC, Carboplatin has a modest benefit in a minority of patients with a low rate of toxicity in the advanced prostate cancer population.
Updated results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.
Authors: Chin Arnold I. , Ly Ann , Rodriguez Sara , Sachdeva Ankush , Zomorodian Nazy , Zhang Hanwei , Kim Jiyoon , Li Gang , Rettig Matthew , Liu Sandy , Drakaki Alexandra
Published: March 2023

165

Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. Primary endpoint was to estimate ORR, PFS, and OS compared to historical controls as well as safety and tolerability. Targeted gene mutation sequencing as well as sequential single cell sequencing of peripheral blood mononuclear cells (PBMCs) for immune profiling as well T cell receptor (TCR) repertoire was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR was 43% (95% CI: 0.06, 0.80) overall and within each cohort. PFS rate at 12 months was 64% (95% CI: 0.44,0.95) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 43% (95% CI: 0.18,1.00) within cohort 2. OS rate at 12 months was 79% (95% CI: 0.60,1.00) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 71% (95% CI: 0.45,1.00) within cohort 2. 4 patients in cohort 1 with locally advanced disease underwent radical cystectomy, with no PD at a mean follow up of 29 months. Grade 3 or higher AEs occurred in 87% of patients, while 40% of patients experienced grade 3 or higher AEs related to pembrolizumab. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Single cell sequencing showed progressive enrichment of CD8+ T cells with clonal expansion of specific TCRs in responding patients. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475 .
A phase I trial of androgen deprivation, darolutamide, and ipatasertib in a safety cohort with castration-resistant prostate cancer (ADDITION).
Authors: Fenton Sarah Elizabeth , Springsdorf Rachel , Kenny Siobhan , Bere Lauren , Ross Ashley , Kocherginsky Masha , Hussain Maha H. A. , VanderWeele David James
Published: March 2023

174

Background: Alterations activating the PI3K-AKT pathway are found in 40-50% of patients with aggressive prostate cancer. This leads to an abrogated response to therapy with androgen-receptor (AR) pathway inhibitors (ARPIs) and is associated with poor outcomes. Preclinical in vivo models suggest there is synergy between ARPIs and AKT inhibitors. Methods: This is a single-arm study of the AR inhibitor darolutamide, the AKT inhibitor ipatasertib, and androgen deprivation therapy (ADT). The phase I safety cohort included patients with castration-resistant prostate cancer (CRPC). ADT was administered per institutional standards. Patients started with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The starting dose of ipatasertib was 400 mg daily with plans to de-escalate if ≥ 2 dose-limiting toxicities (DLTs) were identified in the first six patients. The DLT period was the first 4 weeks of combination therapy. The primary endpoint was to identify the recommended phase II dose (RP2D) of ipatasertib. A phase II biomarker-selected cohort was planned to receive the combination neoadjuvantly. That portion of the study was terminated prior to patient enrollment due to the withdrawal of industry support. Results: Six patients with metastatic CRPC were enrolled in the phase I cohort. They had received a median of 3 prior systemic therapies in addition to ADT (range 1-6). All patients completed the DLT period, and no DLTs were observed. The RP2D of ipatasertib, when given with darolutamide, is 400mg daily. Two patients (33%) had serious adverse events (SAEs) (diarrhea; grade 3) related to ipatasertib outside the DLT period. Two patients (33%) had SAEs unrelated to study drugs; pyelonephritis (one patient; grade 3) secondary to obstruction, and respiratory failure (one patient; grade 5) attributed to disease progression. Two (33%) patients had at least a 50% decline in PSA as the best PSA response, including 2 of 3 patients with known PI3K pathway alterations. Median PSA progression free survival (PFS) was 3.35 months (95% CI 3.06-NA). Median radiographic PFS was 2.91 months (95% CI 2.79-NA). Conclusions: Combination therapy with darolutamide and ipatasertib in CRPC is safe and a RP2D of ipatasertib was established. Toxicity was similar to the therapies given alone, and the most common treatment-related SAE was diarrhea. Partial response to combination therapy was seen in men with CRPC and known PI3K alterations. Clinical trial information: NCT04737109 .
Comparative effectiveness of abiraterone and enzalutamide in the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort study in a large database of deeply curated EHR real-world data (RWD) from community oncology practices in the US.
Authors: An Huijun , Schoen Martin W. , Rider Jennifer , Schorer Anna E. , Ken Jessica , Chen Li , Alabaster Amy , Natanzon Yanina
Published: March 2023

175

Background: Abiraterone(A) and enzalutamide(E), both oral androgen receptor targeted agents, are available as first-line treatment options for mCRPC patients. Direct comparisons of efficacy have not been performed for mCRPC patients primarily receiving their cancer care outside of academic centers or integrated health care systems. The study aims to evaluate the real-world effectiveness between first-line A and E-containing regimens in mCRPC patients primarily receiving care in the US community oncology setting. Methods: Patients were selected from ConcertAI Patient 360 Prostate data product, a large de-identified database of deeply curated EHR RWD, sourced from data sharing agreements with community oncology practices. mCRPC patients treated with a first-line A or E-cont. regimen between 1/2011 and 6/2022 were included. OS, TTNT, TTD outcomes were described using KM estimates and evaluated with Cox proportional hazard (HR) model. Confounding was addressed with inverse probability treatment weighting (IPTW) propensity scores based on age, BMI, ECOG, prior anti-androgen exposure, smoking status, comorbidities, and nadir PSA. Sensitivity analysis evaluated KM and HR for each covariate strata. Hazard ratios were also evaluated with multiple imputation by chained equations for missing covariates. Results: From 3,578 mCRPC patients, 1,210 (33.8%) received E-cont. regimen and 1,357 (37.9%) received A-cont. regimen(ref) with a median of 8 months duration for both drugs. Adjusted HR (aHR) for all three outcomes showed a slight increase in effectiveness for E albeit not significant (OS (aHR 0.99, CI 0.87-1.12), TTNT (aHR 0.98, CI 0.89-1.08). Adjusted model including imputation (iHR) supported unimputed results (OS (iHR 0.97, CI 0.88-1.07), TTNT (aHR 0.94, CI 0.9-1.10). The HRs for OS, TTNT and TTD in sicker patients were consistent (2+ ECOG TTNT (aHR 0.95, 0.81-1.12)), (BMI >30, TTNT (aHR 0.84, 0.61-1.18)), and reached significance for some models (2+ ECOG TTD (aHR 0.66, 0.48-0.91)). Conclusions: First-line E-cont. regimens consistently showed increased effectiveness in outcomes compared to A-cont. regimens in mCRPC patients treated in community oncology setting. The effects sizes are modest and did not reach significance, however analysis of the sickest patients showed a trend of consistently larger effect sizes which reached significance for some outcomes. More work needs to be done to evaluate if these results support findings from other RWD sources.
Activity of lutetium-177 PSMA (Lu-PSMA) and determinants of outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with cabazitaxel: The PACAP study.
Authors: Flippot Ronan , Telli Tugce , Velev Maud , Flechon Aude , Turpin Lea , Bergman Andre M. , Turco Fabio , Fendler Wolfgang Peter , Giraudet Anne Laure , Montravers Françoise , Vogel Wouter V. , Gillessen Silke , Berardi Simona , Herrmann Ken , Kryza David , Paone Gaetano , Garcia Camilo , Foulon Stéphanie , Pages Arnaud , Fizazi Karim
Published: March 2023

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Background: Cabazitaxel and Lu-PSMA both improved survival in patients with mCRPC after docetaxel and an androgen receptor pathway inhibitor (ARPI), but there is limited data regarding Lu-PSMA activity after cabazitaxel. We aimed at assessing activity of Lu-PSMA and determinants of outcomes in this setting. Methods: Consecutive mCRPC patients from 6 European centers treated with Lu-PSMA after cabazitaxel were included in this retrospective study. Endpoints included radiographic progression-free survival (rPFS), time to PSA progression (PSA-TTP), PSA decline, objective response, overall survival, and safety. Results: Of 101 patients included (median age 67y), 64% had ISUP grade 4-5 disease; 71% had bone +/- nodal (LN) metastases, 22% visceral metastases, 7% LN only. All patients and 92% had received previous docetaxel and a prior ARPI (≥ 2 in 47%) before cabazitaxel respectively. Patients had received a median number of 6 cabazitaxel cycles (range 1-26). DNA damage repair alterations (DDR) were found in 11/48 (23%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (range 1-14). With a median follow-up of 5.7 months, the median rPFS from Lu-PSMA initiation was 4.3 months (m, 95%CI 3.2-5.7) and median PSA-TTP was 3.5 m (95%CI 3.0-4.5). Overall, 44 patients (44%) experienced a PSA decline ≥ 50% (PSA50), 54 (53%) ≥ 30% (PSA30), and 67 (66%) any PSA decline. Objective response rate was 34%. Baseline characteristics associated with shorter rPFS on Lu-PSMA included ISUP grade 4-5 disease (median rPFS of 3.5 vs. 7.2m, p=0.02) and a time to castration resistance < 12 months (3.1m vs. 4.5m, p=0.04). Patients with LN only had longer rPFS compared to those with bone and visceral metastases (median NR vs. 3.6 and 3.7m, respectively, p=0.02). There was no association between activity of Lu-PSMA and DNA damage repair alterations, duration of previous cabazitaxel therapy, and number of previous ARPI. During Lu-PSMA, a profound PSA decline was associated with longer rPFS: patients achieving PSA50, PSA30 or any PSA decline had respective median rPFS rates of 9.0, 8.3 and 6.2 months, while those who did not experience any PSA decline had a median rPFS of only 2.6 months. Conclusions: Lu-PSMA demonstrated substantial PSA decline but limited duration of response after cabazitaxel in a real-life setting. Adverse baseline characteristics and absence of PSA decline may help early identification of poor responders.
TRIUMPH: Phase II trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer harboring germline DNA repair gene mutations.
Authors: Markowski Mark Christopher , Sternberg Cora N. , Wang Hao , Sullivan Rana , King Serina , Lotan Tamara L. , Antonarakis Emmanuel S.
Published: March 2023

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Background: Androgen deprivation therapy (ADT) is the backbone of treatment for patients (pts) with metastatic prostate cancer (PCa), but many pts find this difficult to tolerate. Treatment with non-castrating regimens may avoid or delay the toxicities of hormonal therapy. The activity of PARP inhibitors (PARPi) in pts with homologous recombination DNA-repair (HRD) mutations (muts) and metastatic castration-resistant PCa has been established. We hypothesized here that the benefit of ARPi can be maintained in the absence of ADT in a biomarker-selected (HRD mutated) population with PCa. We designed a Phase 2 study in men with hormone-naïve, metastatic PCa who harbored a germline HRD mut treated with rucaparib monotherapy (without ADT). Methods: This was a multi-center, single arm Phase 2 study (NCT03413995) in men with asymptomatic hormone-sensitive metastatic PCa who received rucaparib 600mg by mouth daily. During consenting, pts were informed and had to opt out of ADT-based therapy. Pts must have had a germline mutation in an HRD gene on clinical-grade testing. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 25% absolute increase in PSA50 response from a null of 50%. Results: 12 pts were enrolled, 7 with BRCA1/2 and 5 with CHEK2 muts. The confirmed PSA50 response rate to rucaparib was 41.7% (N=5/12, 95% CI: 19.3-68.1%), which did not meet the pre-specified efficacy boundary to enroll additional patients to 2nd stage. In pts with measurable disease, the ORR was 60% (N=3/5, all with BRCA2). Median rPFS on rucaparib was 10.3 months (95% CI: 4.0 mo - NR). At the time of the interim analysis, 3 pts remained on study. The majority of adverse events (AE) were Grade ≤2 and expected. Translational studies are ongoing. Conclusions: Rucaparib can induce clinical responses in a biomarker-selected PCa population without concurrent ADT. However, the pre-specified threshold of PSA50 response was not met. Although durable responses were observed in a subset of pts, PARPi without ADT in metastatic hormone sensitive PCa will not be pursued. Clinical trial information: NCT03413995 . [Table: see text]
Early outcomes from lutetium Lu-177 vipivotide tetraxetan treatment in patients selected for therapy with piflufolastat F-18 PET imaging.
Authors: Boike Thomas Pence , DiPippo Vincent A. , Austin Heather , Turnquist Wendy , Qamruzzaman Yusuf
Published: March 2023

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Background: The Vision trial utilized Ga 68 PSMA 11 imaging to select patients for treatment with Lutetium Lu 177 Vipivotide Tetraxetan. Current guidelines allow not only Ga 68 PSMA 11 PET but also Piflufolastat F 18 PET when selecting patients for Lutetium Lu 177 Vipivotide Tetraxetan but little is published on outcomes to this approach. Methods: Patients were enrolled on an IRB approved managed access protocol and were treated by a single investigator at a single institution. Eligible patients had mCRPC and had received previous treatment with at least one androgen receptor pathway inhibitor and at least one round of taxane based chemotherapy. Baseline imaging, demographics, treatment history, and tumor characteristics were collected. Patients were treated with 7.4 GBq of Lutetium Lu 177 Vipivotide Tetraxetan every 6 weeks for up to six cycles. Adverse events and PSA response were collected. Results: Fourteen patients were enrolled between August 2021 and August 2022. All patients had advanced mCRPC, were heavily pre-treated, and had failed both hormonal as well as chemotherapeutic options. The average number of androgen receptor pathway inhibitor courses for the cohort is 2.4 (range 1-4) and the average number of taxane courses for the cohort is 1.5 (Range 1-3). 11 patients underwent Piflufolastat F 18 PET and 3 patients had Ga 68 PSMA 11 PET. Baseline PSA varied significantly from 2.51 - 961.71 ng/mL. Declines of 50% in PSA were observed in 8/14 patients. 2 patients had greater than 80% PSA reductions. Conclusions: PSA treatment responses were similar to those reported in the Vision trial in this cohort of patients selected with either Piflufolastat F 18 PET or Ga 68 PSMA 11 PET supporting the guideline recommendations. Clinical trial information: NCT04825652 .
Real-world assessment of AR-LBD mutations in metastatic castration-resistant prostate cancer.
Authors: Antonarakis Emmanuel S. , Zhang Nicole , Saha Jayati , Nevalaita Liina , Shell Scott A. , Garratt Chris , Ikonen Tarja , Fizazi Karim
Published: March 2023

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Background: Treatment of men with metastatic castration-resistant prostate cancer (mCRPC) using drugs targeting the AR pathway is hampered by development of resistance including activating AR ligand-binding domain (LBD) point mutations. AR LBD mutations are found in approximately 10-20% of patients (pts) with mCRPC progressing on AR pathway inhibition (ARPi) therapy and may be associated with AR activation by alternative steroid hormones. We utilized the Guardant INFORM real-world database to explore the detection rate and clinical features associated with AR-LBD mutations in men with mCRPC. Methods: This observational study was conducted in a nationally representative clinical-genomic database of 200,000+ advanced cancer pts undergoing comprehensive ctDNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims. ctDNA samples of men with mCRPC were assessed for presence or absence of an activating AR-LBD mutation. The incidence of co-occurring genetic alterations was also investigated. Clinical outcomes were studied for matched cohorts comparing pts following first line (1L) or second line (2L) mCRPC therapy with or without AR-LBD mutations. Results: Of 15,705 prostate cancer pts included in the database, 8420 (53.6%) had mCRPC at the time of sample collection. 4122 (49.0%) of these mCRPC pts had prior treatment with an ARPi, of which 854 (21%) had an AR-LBD mutation. AR-LBD mutation prevalence was 15% in mCRPC pts untreated with an ARPi, 23% in those after 1 line, and 24% in those after 2 lines of ARPi treatment. AR L702H and T878A/S showed the greatest increase in prevalence post abiraterone, whereas AR L702H, T878S and F877L had the greatest increase in prevalence post enzalutamide. Prevalence of AR L702H and H875Y doubled (from 8.8% to 17.5%) for pts that received chemotherapy post ARPi, while AR F877L incidence declined by half (3.5% to 1.7%). Compared to pts without AR-LBD mutations, AR-LBD+ mCRPC pts were enriched for co-alterations in APC, CTNNB1, PTEN, BRCA2, and ARID1A. Rates of TP53 and RB1 alterations were comparable in the AR-LBD+ and ARLBD- cohorts. Matched mCRPC pts had similar time-to-treatment-discontinuation (TTD) and time-to-next-treatment (TTNT) between AR-LBD+ and AR-LBD- mCRPC pts in the 1L and 2L settings; however, AR-LBD+ pts exhibited worse overall survival from 1L mCRPC therapy (50.1 vs 60.7 months, log-rank P=0.013). Conclusions: In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.
Prognostic biomarkers and clinical outcomes in neuroendocrine prostate cancer (NEPC).
Authors: Gagnon Richard , Khosh Kish Ealia , Cook Sarah , Takemura Kosuke , Cheng Brian Yu Chieh , Bressler Kamiko , Heng Daniel Yick Chin , Alimohamed Nimira S. , Ruether Joseph D. , Lee-Ying Richard M. , Bose Pinaki , Kolinsky Michael Paul , Vasquez Catalina , Samuel Divya , Lewis John D , Faridi Rehan , Borkar Minal , Fairey Adrian S. , Bismar Tarek A. , Yip Steven M.
Published: March 2023

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Background: NEPC includes both pure small cell carcinoma and mixed tumors with varying degrees of adenocarcinoma and neuroendocrine histology. It arises de novo or is treatment associated (TA) post androgen deprivation therapy. Clinical outcome data and prognostic biomarkers are limited and were thus explored. Methods: Patients with high grade prostate cancer and morphologic and/or immunohistochemical (IHC) NEPC features were included in this retrospective multicentre study. Clinical stage, Gleason score, and serum biomarkers were recorded. Kaplan-Meier method and log-rank test calculated and compared overall survival (OS) from time of NEPC diagnosis.Cox proportional hazards regression assessed prognostic impact of serum biomarkers at diagnosis and de novo vs TA status, adjusting for clinical stage and castration resistance. Results: 135 NEPC cases were identified. 124 (92%) were mixed tumors. 56 (41%) arose de novo. 79 (59%) were TA. 77% of those with a Gleason score (N=85/110) were grade group 5. Median PSA pre-NEPC biopsy was 11.6 ng/mL. At NEPC diagnosis, 19 (14%) had localized disease (median OS 123.0 mo); 33 (24%) non-metastatic castrate-sensitive disease (median OS 42.3 mo); 6 (4%) non-metastatic castrate-resistant disease (median OS 14.3 mo); 35 (26%) metastatic castrate-sensitive disease (median OS 17.6 mo); and 42 (31%) metastatic castrate-resistant disease (median OS 9.6 mo). Median OS for those with visceral metastases was 8.6 mo (95% CI 6.0 – 14.6), compared to patients with non-visceral metastases (11.1 mo; 95% CI 13.7 – 21.5) and no metastases (42.3 mo; 95% CI 47 – 89). Anemia (adjusted HR 1.66; 95% CI 1.05 - 2.16, p = 0.031) and NLR >3 (adjusted HR 1.51; 95% CI 1.01 - 2.52, p = 0.045) were associated with increased risk of death. De novo disease, elevated LDH, serum PSA, and Gleason score were not prognostic. Conclusions: This study identifies NEPC clinical outcomes by stage, with survival poorer than expected in pure prostate adenocarcinoma. Anemia and elevated NLR >3 are prognostic biomarkers that may help risk stratify and guide treatment intensification, including platinum-based chemotherapy. Further biomarker characterization of NEPC through IHC-staining pattern and genomic analysis is currently underway by this group.