bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute decompensated pulmonary hypertension
Authors: Savale Laurent , Weatherald Jason , Jaïs Xavier , Vuillard Constance , Boucly Athénaïs , Jevnikar Mitja , Montani David , Mercier Olaf , Simonneau Gerald , Fadel Elie , Sitbon Olivier , Humbert Marc
Published: March 2019

Acute right heart failure in chronic precapillary pulmonary hypertension is characterised by a rapidly progressive syndrome with systemic congestion resulting from impaired right ventricular filling and/or reduced right ventricular flow output. This clinical picture results from an imbalance between the afterload imposed on the right ventricle and its adaptation capacity. Acute decompensated pulmonary hypertension is associated with a very poor prognosis in the short term. Despite its major impact on survival, its optimal management remains very challenging for specialised centres, without specific recommendations. Identification of trigger factors, optimisation of fluid volume and pharmacological support to improve right ventricular function and perfusion pressure are the main therapeutic areas to consider in order to improve clinical condition. At the same time, specific management of pulmonary hypertension according to the aetiology is mandatory to reduce right ventricular afterload. Over the past decade, the development of extracorporeal life support in refractory right heart failure combined with urgent transplantation has probably contributed to a significant improvement in survival for selected patients. However, there remains a considerable need for further research in this field.
Reconstruction of evolutionary trajectories of chromosomes unraveled independent genomic repatterning between Triticeae and Brachypodium
Authors: Wang Zhenyi , Wang Jinpeng , Pan Yuxin , Lei Tianyu , Ge Weina , Wang Li , Zhang Lan , Li Yuxian , Zhao Kanglu , Liu Tao , Song Xiaoming , Zhang Jiaqi , Yu Jigao , Hu Jingjing , Wang Xiyin
Published: March 2019

Background

After polyploidization, a genome may experience large-scale genome-repatterning, featuring wide-spread DNA rearrangement and loss, and often chromosome number reduction. Grasses share a common tetraploidization, after which the originally doubled chromosome numbers reduced to different chromosome numbers among them. A telomere-centric reduction model was proposed previously to explain chromosome number reduction. With Brachpodium as an intermediate linking different major lineages of grasses and a model plant of the Pooideae plants, we wonder whether it mediated the evolution from ancestral grass karyotype to Triticeae karyotype.

Results

By inferring the homology among Triticeae, rice, and Brachpodium chromosomes, we reconstructed the evolutionary trajectories of the Triticeae chromosomes. By performing comparative genomics analysis with rice as a reference, we reconstructed the evolutionary trajectories of Pooideae plants, including Ae. Tauschii (2n = 14, DD), barley (2n = 14), Triticum turgidum (2n = 4x = 28, AABB), and Brachypodium (2n = 10). Their extant Pooidea and Brachypodium chromosomes were independently produced after sequential nested chromosome fusions in the last tens of millions of years, respectively, after their split from rice. More frequently than would be expected by chance, in Brachypodium, the ‘invading’ and ‘invaded’ chromosomes are homoeologs, originating from duplication of a common ancestral chromosome, that is, with more extensive DNA-level correspondence to one another than random chromosomes, nested chromosome fusion events between homoeologs account for three of seven cases in Brachypodium (P-value≈0.00078). However, this phenomenon was not observed during the formation of other Pooideae chromosomes.

Conclusions

Notably, we found that the Brachypodium chromosomes formed through exclusively distinctive trajectories from those of Pooideae plants, and were well explained by the telomere-centric model. Our work will contribute to understanding the structural and functional innovation of chromosomes in different Pooideae lineages and beyond.
Young pregnant women and risk for mental disorders: findings from an early pregnancy cohort
Authors: Lockwood Estrin Georgia , Ryan Elizabeth G. , Trevillion Kylee , Demilew Jill , Bick Debra , Pickles Andrew , Howard Louise Michele
Published: March 2019

Background

Young women aged 16–24 are at high risk of common mental disorders (CMDs), but the risk during pregnancy is unclear.

Aims

To compare the population prevalence of CMDs in pregnant women aged 16–24 with pregnant women ≥25 years in a representative cohort, hypothesising that younger women are at higher risk of CMDs (depression, anxiety disorders, post-traumatic stress disorder, obsessive–compulsive disorder), and that this is associated with low social support, higher rates of lifetime abuse and unemployment.

Method

Analysis of cross-sectional baseline data from a cohort of 545 women (of whom 57 were aged 16–24 years), attending a South London maternity service, with recruitment stratified by endorsement of questions on low mood, interviewed with the Structured Clinical Interview DSM-IV-TR.

Results

Population prevalence estimates of CMDs were 45.1% (95% CI 23.5–68.7) in young women and 15.5% (95% CI 12.0–19.8) in women ≥25, and for ‘any mental disorder’ 67.2% (95% CI 41.7–85.4) and 21.2% (95% CI 17.0–26.1), respectively. Young women had greater odds of having a CMD (adjusted odds ratio (aOR) = 5.8, 95% CI 1.8–18.6) and CMDs were associated with living alone (aOR = 3.0, 95% CI 1.1–8.0) and abuse (aOR = 1.5, 95% CI 0.8–2.8).

Conclusions

Pregnant women between 16 and 24 years are at very high risk of mental disorders; services need to target resources for pregnant women under 25, including those in their early 20s. Interventions enhancing social networks, addressing abuse and providing adequate mental health treatment may minimise adverse outcomes for young women and their children.

Declaration of interest

None.
Validation of MSKCC pre-prostatectomy nomogram in men who undergo MRI-targeted prostate biopsy prior to radical prostatectomy.
Authors: Glaser Zachary A , Gordetsky Jennifer , Bae Sejong , Nix Jeffrey , Porter Kristin K , Rais-Bahrami Soroush
Published: March 2019

14

Background: The Memorial Sloan Kettering Cancer Center (MSKCC) Pre-Prostatectomy nomogram is a widely used resource using clinical factors to predict the likelihood of adverse pathology at radical prostatectomy. The increasing adoption of magnetic resonance imaging (MRI) and MRI-targeted biopsy (TB) permits optimized detection of clinically-significant cancer over systematic biopsy sampling alone. We aim to validate the prognostic utility of the MSKCC Pre-Prostatectomy nomogram with TB pathology results. Methods: Men who underwent systematic extended-sextant prostate biopsy (SB) followed by MRI TB who later underwent radical prostatectomy at our institution were included. Patient information was entered into the MSKCC Pre-Prostatectomy nomogram using five biopsy reporting schemes (SB alone, TB alone reported each of two ways (individual core (IC) technique or aggregate cores (AG) technique combining cores from a single MRI targeted lesion), and SB with TB combined with TB reported by both IC and AG methods. The likelihood of extracapsular extension (EPE), lymph node involvement (LNI), and seminal vesicle invasion (SVI) as predicted by the nomogram for each biopsy reporting schema were compared to radical prostatectomy pathology. Results: We identified 63 men from January 2014 to November 2017. On ROC analysis, IC-TB, AG-TB, SB plus IC-TB, and SB plus AG-TB exhibited similar, if not improved, AUC compared to SB alone in predicting EPE (0.671, 0.674, 0.658, and 0.6613 versus 0.6085). For LNI, superior AUC was observed for AG-TB (0.647) compared to IC-TB (0.571) and SB alone (0.524) Equivocal SVI prediction was observed for SB plus IC-TB compared to SB alone (0.727 versus 0.733). Conclusions: Using TB pathology results either alone or combined with SB pathology results for the MSKCC Pre-Prostatectomy nomogram appears comparable, if not improved, in prognosticating adverse pathologic features on radical prostatectomy compared to using SB core data alone from which the nomogram was developed.
Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650).
Authors: Sharma Padmanee , Pachynski Russell Kent , Narayan Vivek , Flechon Aude , Gravis Gwenaelle , Galsky Matt D. , Mahammedi Hakim , Patnaik Akash , Subudhi Sumit Kumar , Ciprotti Marika , Duan Tao , Saci Abdel , Hu Sarah , Han G. Celine , Fizazi Karim
Published: March 2019

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Background: Immune checkpoint inhibitor monotherapy has shown limited clinical benefit in patients (pts) with prostate cancer, likely due to an immunologically “cold” tumor microenvironment. We report preplanned interim efficacy/safety for NIVO + IPI in pts with mCRPC from CheckMate 650. Methods: Asymptomatic/minimally symptomatic pts who progressed after 2nd-generation hormone therapy and have not received chemotherapy for mCRPC (cohort 1) and pts who progressed after taxane-based chemotherapy (cohort 2) were included. Treatment was NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses, then NIVO 480 mg every 4 weeks. Coprimary endpoints: objective response rate (ORR) and radiographic PFS per PCWG2. Safety is a secondary endpoint. Exploratory endpoints include correlation of biomarkers with efficacy. Results: 78 pts had a minimum follow-up of 6 months; among pts with baseline measurable disease, ORR was 26% and 10% in cohorts 1 and 2 (Table). In both cohorts, ORR was higher in pts with PD-L1 ≥1%, DNA damage repair (DDR), homologous recombination deficiency (HRD), or above-median tumor mutational burden (TMB). Of all PSA responding pts (Table), 4 had PSA <0.2 ng/mL. Grade 3–4 treatment-related adverse events occurred in 39% and 51% of pts in cohorts 1 and 2; one grade 5 event occurred in each cohort. Conclusions: In a malignancy where immune checkpoint inhibitor monotherapy has previously shown limited success, NIVO + IPI demonstrated activity in pretreated pts with mCRPC, particularly in a biomarker-enriched population, with a safety profile consistent with this dosing schedule. Further study is warranted. Clinical trial information: NCT02985957. [Table: see text]
Assessment of circulating tumor cell number as a transitional surrogate endpoint for survival in phase II trials for metastatic castration-resistant prostate cancer.
Authors: Scher Howard I. , Mccormack Robert Thomas , Molina Arturo , Smith Matthew Raymond , Dreicer Robert , Saad Fred , De Wit Ronald , Fizazi Karim , Aftab Dana T. , Limon Ana , Fleisher Martin , De Bono Johann S. , Kelloff Gary J. , Heller Glenn
Published: March 2019

143

Background: Short-term measures of response that reflect clinical benefit are a critical unmet need for clinical trials for mCRPC. Using data from 5 randomized mCRPC trials, we showed that a response endpoint (RE) based on a change in CTC number using the FDA cleared CellSearch® (Menarini) platform from any, (≥ 1, CTC any) to 0 (CTC0) per 7.5 ml of blood was associated strongly with overall survival (OS). Here we explored whether different CTC and PSA REs could serve as “transitional surrogates” defined as a biomarker validated in phase 2 but not in phase 3 trials for overall survival (OS), using the baseline and week 13 prostate-specific antigen (PSA) level and CTC counts. Methods: Four 13-week REs were studied: (i) PSA50 (≥ 50% PSA decline from baseline), (ii) CTC0 (≥ 1 CTC/7.5 ml of blood at baseline and 0 CTCs at week 13), (iii) both PSA50 and CTC0, and (iv) either PSA50 or CTC0. The relative effectiveness of these REs as transitional surrogates for OS was evaluated at the patient level by discrimination, the separation between responder and non-responder survival curves, and at the trial level using explained variation, the accuracy in predicting k-month survival in a trial with the response proportion. Results: A total of 6081 pts were enrolled of whom 5660 (93%) survived until week 13 and among these patients 3080 (54%) had a baseline CTC count ≥ 1 and baseline PSA ≥ 5 ng/ml. At the patient level, separation between responder and non-responder survival curves over time was greater using CTC0 than PSA50 (average difference in survival probability 0.35 vs. 0.29, respectively). At the trial level, explained variation in survival over time was also greater for CTC0 than PSA50 (average R-squared 0.67 vs. 0.58, respectively). CTC/PSA combination REs did not improve on CTC0 at either level. Conclusions: The CTC0 RE provides stronger discrimination than PSA50 at the patient level and greater observed explained variation at the trial level. The results suggest that for the individual patient, a decrease in CTCs to zero at week 13 is a stronger indicator of longer term OS than the more widely used PSA50 and serves as a reasonably likely surrogate for OS in clinical trials.
Targeting mediator subunits CDK8/CDK19 for treatment of advanced prostate cancer.
Authors: Hupe Marie C. , Offermann Anne , Becker Finn , Joerg Vincent , Vogel Wenzel , Braegelmann Johannes , Perner Sven , Merseburger Axel Stuart
Published: March 2019

152

Background: The mediator complex plays a pivotal role in the regulation of gene transcription. The subunits CDK8 and CDK19 are overexpressed in advanced prostate cancer (PCa) and promote migration and invasion, as shown previously by our group. The aim of this study was to analyze if CDK8/CDK19 inhibition can impede PCa progression. Methods: Immunohistochemistry for CDK8 and CDK19 was performed on a large PCa cohort (376 radical prostatectomy (RP) specimens, 39 locally advanced tumors, 32 lymph node metastases, 24 distant metastases, 73 benign prostatic specimens). PCa cell lines (DU145, PC3) were treated with CDK8/CDK19 small molecule inhibitors followed by MTT assay, wound healing assay, and Western Blot for epithelial/mesenchymal markers. Results: CDK19 is higher expressed in primary PCa vs. benign specimens and locally advanced PCa/distant metastases vs. primary PCa. CDK8 and CDK19 are higher expressed in castration-resistant specimens vs. hormone-naive specimens. CDK19 significantly correlates with grade group in RP specimens. Biochemical recurrence free survival rates are lower for patients with high vs. medium vs. no/low CDK19 expression in the tumor. CDK19 predicts recurrence free survival independently from grade group and PSA. CDK8/CDK19 inhibition results in decreased migration, while there is no effect on proliferation. Mesenchymal markers are reduced while epithelial markers are induced following CDK8/CDK19 inhibition. Conclusions: CDK19 qualifies as a prognostic marker predicting biochemical recurrence following RP. CDK8/CDK19 inhibition leads to decreased migratory potential and mesenchymal phenotype. CDK8/19 expression increases during progression to castration-resistance. Collectively, CDK8/CDK19 represents a new target for treatment of advanced and/or castration-resistant PCa.
A circulating tumor cell RNA assay for dynamic assessment of androgen receptor signaling inhibitors sensitivity in metastatic castration-resistant prostate cancer.
Authors: Jan Yu Jen , Yoon Junhee , Chen Jie-Fu , Chen Pin-Jung , Teng Pai-Chi , Yao Nu , Cheng Shirley , Lozano Amber , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin M.
Published: March 2019

157

Background: Tissue-based gene signatures can predict clinical behavior in prostate cancer (PC). Our objective was to extend their application to circulating tumor cells (CTCs) and to show that changes in the signature were associated with changes in clinical behavior. Methods: Our approach combined the Thermoresponsive(TR)-NanoVelcro CTC purification system with the Nanostring nCounter system for cellular purification and transcriptomic analysis. The Prostate Cancer Classification System (PCS) panel was modified for use in CTCs. We selected 31 blood samples from 23 PC patients receiving androgen receptor signaling inhibitors (ARSI) and measured the PCS1 Z score (probability). These findings were compared with clinical outcome data (responsiveness/resistance). Results: A modified, 16-gene PCS1 signature was established and validated through a rigorous bioinformatics process. We performed analytical validation of our combined CTC-RNA system to ensure reproducibility and specificity. In patient bloods, ARSI-resistant samples (ARSI-R, n = 14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n = 17) (Rank-sum test, P = 0.003). The analyzed bloods contained samples from 8 patients who developed resistance to an ARSI allowing for dynamic measurement of gene expression. Our analysis found that the PCS1 Z score increased at the time that ARSI-resistance emerged (Pairwise T-test, P = 0.016). Conclusions: Using this new methodology, contemporary, clinically-relevant gene signatures such as PCS could be measured non-invasively in CTCs. These findings can be used to relate gene expression to clinical drug response. This approach also allowed for measurement of dynamic variations of gene expression in individual patients over time that correlated to ARSI sensitivity.
A Genome-wide association study of metastatic prostate cancer.
Authors: Teerlink Craig , Hahn Andrew W , Esther John , Rathi Nityam , Farnham James M , Agarwal Neeraj , Cannon-Albright Lisa
Published: March 2019

160

Background: There are no biomarkers currently used in clinical practice that can predict which men will develop metastatic prostate cancer (mPrCa). Germline genetic variants that are highly associated with metastatic disease could be used for such prediction and may be identifiable from genome-wide association analyses (GWAS) conducted in appropriately scaled mPrCa case-control datasets. Methods: 451 mPrCa cases sequentially sampled from University of Utah/Huntsman Cancer Institute clinics were genotyped on the Illumina OmniExpress SNP platform and population-matched via principal components analysis to 1043 controls from dbGaP study phs000733 genotyped on the Illumina 5M SNP platform. The mPrCa cases and controls were analyzed via genome-wide association to identify SNPs highly associated with mPrCa. The dataset was then merged and re-analyzed with 176 lethal prostate cancer cases (identified in the Utah SEER Tumor Registry with a linked Utah death certificate including prostate cancer as a cause of death) in an attempt to identify a larger number of potential candidate SNPs associated with metastatic or lethal prostate disease. Results: The GWAS of mPrCa cases identified 4 significant SNPs at the 8q24.21 locus (p < 5e-8), as well as 9 SNPs in 6 previously unreported regions (5q14.1, 6p24.1, 8q21.3, 15q13.3, 15q22.2, and 17q25.1) with suggestive evidence for association (p < 1e-6). In addition, 30 SNPs with nominal evidence (p < 0.001) in the mPrCa-only GWAS appeared with more extreme p-values when the 176 lethal subjects were included in the analysis, and may be appropriate candidate variants to test in external datasets. Conclusions: In this case-control GWAS study of 627 men with mPrCa or lethal PrCa, germline SNPs at the 8q24.21 locus and 6 previously unreported regions may be associated with mPrCa. These findings should be validated in external datasets of men with mPrCa.
A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases.
Authors: Uemura Hiroji , Matsubara Nobuaki , Uemura Hirotsugu , Nagamori Satoshi , Suzuki Hiroyoshi , Kimura Go
Published: March 2019

164

Background: TAS-115, a novel multi-kinase (eg, MET, VEGFR) inhibitor has also shown to inhibits Feline McDonough Sarcoma oncogene (FMS) kinase, Anti-tumor activity against bone metastases was observed in the preclinical and phase1 study. In this phase 2 study, the efficacy and safety of TAS-115 were evaluated in castration-resistant prostate cancer (CRPC) patients (pts) with bone metastases. Methods: This was a phase 2, open-label, multi-arm study for CRPC pts with bone metastases to evaluate the clinical anti-tumor activity of TAS-115. Pts who had visceral metastases were ineligible for this study. TAS-115 was given orally, once daily, and schedule of 5 days on/2 days off each week was repeated. This study had 2 cohorts (A and B). In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. In cohort B, CRPC pts who had symptomatic bone metastases, post or unfit to docetaxel, were randomized in a 1:1 to 400 or 600 mg/day of TAS-115. The primary endpoint was bone scan index (BSI) response rate at week 12, defined as ≥ 30% decrease of BSI from baseline. BSI is a quantitative assessment of bone scan data calculated by software (BONE NAVI). Results: From Nov 2016 to Jul 2018, a total of 50 pts received TAS-115 (24 pts in cohort A and 26 pts in cohort B). BSI response rate at week 12 and best BSI response was 20.8 % and 37.5% in cohort A, and 15.4 % and 19.2% in cohort B, respectively. Any reduction of BSI was observed in 70.8% of cohort A and 61.5% of cohort B. In cohort B, pain was assessed using the Brief Pain Inventory short form and improvement was observed in 61.5% of pts. Furthermore, the reduction of bone-turnover marker (BAP, P1NP, NTx and TRACP-5b) were observed in both cohorts, but not PSA response. The major (≥ 10%) Grade 3/4 treatment-related adverse drug reactions were hypophosphataemia (21%) in cohort A, and anemia (23%), hypophosphataemia (12%) and neutrophil count decreased (12%) in cohort B. Conclusions: Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases. Clinical trial information: JapicCTI-163448.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A multicenter randomized phase II trial (OCUU-CRPC study).
Authors: Iguchi Taro , Tamada Satoshi , Kato Minoru , Yasuda Sayaka , Machida Yuichi , Ohmachi Tetsuji , Ishii Keiichi , Iwata Hiroyuki , Yamamoto Shinji , Kanamaru Tomohiro , Morimoto Kazuya , Hase Taro , Tashiroro Koichiro , Harimoto Koji , Deguhi Takashi , Adachi Takahisa , Iwamoto Katsuki , Takegaki Yoshinori , Nakatani Tatsuya ,   OCUU-CRPC STUDY Group
Published: March 2019

168

Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely administered for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The objective of the OCUU-CRPC study was to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative AAT after CAB therapy that included bicalutamide in patients with CRPC. Methods: A total of 104 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day) and flutamide (375 mg/day) groups. The primary endpoint for the drug efficacy was the response rate of prostate-specific antigen (PSA; i.e., declined by ≥50%) at 3 months. Results: Between January 2015 and February 2018, 103 patients were randomly assigned, 52 to enzalutamide and 51 to flutamide. 25 (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 13.4 months (IQR 9.6–23.8) in the enzalutamide group and 17.0 months (9.7–24.4) in the flutamide group. Enzalutamide resulted in significant improvements in the response rate of PSA at 3 months (84.6% vs 31.4%; p< 0.001). Enzalutamide significantly improved in all secondary endpoints: the PSA progression rate at 3 months (HR, 0.17; 95% CI, 0.05 to 0.47; p< 0.01) and at 6 months (HR, 0.22; 95% CI, 0.09 to 0.50; p< 0.01); and PSA response rate at 6 months (75.0% vs 29.4%; p< 0.01); and time to PSA progression (median: not reached vs 6.6 months; HR, 0.29; 95% CI, 0.15 to 0.54; p< 0.01). The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusions: Enzalutamide significantly reduced risk of progression compared with flutamide in patients with CRPC after CAB therapy with bicalutamide. This trial is registered with ClinicalTrials.gov, number. Clinical trial information: NCT02346578.
Plasma AR status and cabazitaxel in heavily-treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Castro Elena , Jayaram Anuradha , Wetterskog Daniel , Scarpi Emanuela , Romero-Laorden Nuria , Olmos David , Gurioli Giorgia , Lolli Cristian , Puente Javier , Medina Ana , Querol Rosa , Arranz Jose Angel , Saez Maria Isabel , Fornarini Giuseppe , Basso Umberto , Mellado Begona , Gonzalez-Billalabeitia Enrique , Attard Gerhardt , De Giorgi Ugo
Published: March 2019

203

Background: Plasma androgen receptor ( AR) copy number status has been identified as a potential biomarker of response in mCRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR status in the context of cabazitaxel therapy is unknown. Methods: Between September 2011 and January 2018, pre-therapy plasma samples were collected from 155 patients treated with second or third-line cabazitaxel at standard or reduced dose in different biomarker protocols. Droplet digital PCR was used to identify plasma AR gain and normal samples, with the primary objective to evaluate associations of plasma AR status with treatment outcome. In an exploratory analysis, a comparison between plasma AR status and treatment type was investigated by incorporating updated data from our prior study of 85 post-docetaxel patients receiving abiraterone or enzalutamide. Results: We observed a shorter median overall/progression-free survival (OS/PFS) in AR-gained compared to AR-normal patients (OS 10.5 versus 14.1 months, hazard ratio (HR) 1.44, 95% confidence interval (CI) 0.98-2.13, P = 0.064), and (PFS 4.0 versus 5.0 months, HR 1.47, 95%CI 1.05-2.07, P = 0.024). In mCRPC patients receiving second-line therapies, a significant treatment interaction was observed between plasma AR and cabazitaxel versus AR-directed therapies for OS (P = 0.041) but not PFS (P = 0.244). In an exploratory analysis, AR-gained patients treated with initial reduced-dose of cabazitaxel had a significantly shorter median OS (7.3 versus 11.5 months, HR 1.95, 95%CI 1.13-3.38, P = 0.016), and PFS (2.7 versus 5.0 months, HR 2.27, 95%CI 1.39-3.71, P = 0.001). Conclusions: Plasma AR status has a potential clinical utility in patients being considered for cabazitaxel. Validation of these findings in prospective trials are warranted.
A multidisciplinary team-based approach to mitigate the impact of androgen deprivation therapy in prostate cancer: A randomized phase II study.
Authors: Pollock YaoYao Guan , Zhang Li , Rodvelt Tammy J. , Ma Brian , Macaire Greta , Weinberg Rami , Kenfield Stacey , Chan June M. , Topp Kimberly , Van Blarigan Erin , Friedlander Terence W. , Lin Amy M. , Fong Lawrence , Kim Won , Hough Jeffrey , Lee Mina , Ryan Charles J. , Small Eric Jay , Aggarwal Rahul Raj
Published: March 2019

204

Background: Androgen deprivation therapy (ADT) is associated with numerous metabolic toxicities that are potentially modifiable. We sought to evaluate the impact of participation in a multidisciplinary clinic (MDC) designed to provide individualized lifestyle modification and management of ADT-related side effects. Methods: This phase II study recruited men with prostate cancer who had started ADT < 6 months prior to enrollment, and in whom ADT was planned for at least 12 months following enrollment. Patients were randomized in a 1:1 ratio to either the MDC or standard of care (SOC). Patients randomized to the MDC were provided monthly multidisciplinary assessment and counseling on exercise, nutrition, and symptom management for 12 months on a rotating schedule. Endpoints included feasibility endpoints (proportion of visits completed), and efficacy endpoints, including mean change from baseline to 12 months in blood pressure (BP), weight, waist circumference, percent body fat, hemoglobin A1C (HbgA1C), insulin resistance, and fasting lipids. Results: 25 men were randomized to MDC, and 23 were randomized to SOC. Overall 91% (295/325) of MDC visits were completed. 72% (18/25) of patients completed all 12 months of MDC, and 80% (20/25) completed the first 6 months. Compared to SOC, patients in the MDC arm had a trend towards more favorable mean percent change from baseline to 12-month follow up in systolic BP (6.5% vs. 10.3%), diastolic BP (-3.9% vs.10.0%), waist circumference (2.5% vs. 4.0%), HbA1C (-2.4% vs. -1.7%), insulin resistance (0.5% vs. 1.9%), and fasting lipids (total cholesterol: 7.0% vs. 21.8%; LDL: -2.9% vs. 7.6%; triglyceride: 15.5% vs. 37.2%). Conclusions: Individualized and comprehensive management of toxicities of ADT in a multidisciplinary clinic is feasible, and appears to provide some benefit over SOC. Larger randomized studies are warranted to investigate whether this intervention will provide lasting benefit. Clinical trial information: NCT02168062.
External beam radiation therapy and brachytherapy boost versus radical prostatectomy and adjuvant radiation therapy for high-risk prostate cancer.
Authors: Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Yang David Dewei , Leeman Jonathan Eric , D'Amico Anthony Victor , Nguyen Paul L. , Orio Peter F. , King Martin T.
Published: March 2019

21

Background: Previous studies have suggested that combination external beam radiation therapy (EBRT) with brachytherapy boost (BT) for high-risk prostate cancer is associated with equivalent overall survival (OS) compared with radical prostatectomy (RP). However, it is not known whether RP with post-operative radiation therapy (PORT) can offer improved OS compared with combination RT (EBRT + BT + androgen deprivation therapy [ADT]) for patients with Gleason 9-10 high-risk disease. Methods: We identified all patients diagnosed with clinical T1-T3, Gleason 9-10, prostate-specific antigen (PSA) 0-40 ng/mL, and clinically node negative disease between 2004 and 2014 from the National Cancer Database. We divided patients into 4 treatment groups: EBRT + ADT, combination RT (EBRT + BT + ADT), RP, and RP + PORT. Only patients who received PORT within 360 days of surgery were included within the RP + PORT group. We compared OS utilizing inverse probability of treatment-weighted multivariable Cox proportional hazards regression modeling after accounting for clinical and demographic factors, including Gleason grade (9 versus 10), T-stage (T1, T2, T3), age, Charlson-Deyo comorbidity score (0, 1, versus 2), education quartile, income quartile, geographic location within the US, insurance status, facility volume, and race. Results: Median follow-up in the entire cohort was 4.5 years. The numbers of patients treated with EBRT + ADT, EBRT + BT + ADT, RP, RP + PORT were 6778, 924, 7111, and 1929, respectively. There were no significant differences in 5-year OS when comparing combination RT to RP (85.0% vs 85.7%, adjusted hazard ratio (AHR) 0.92, 95% confidence interval [CI] 0.77-1.10, p = 0.36) or RP + PORT (85.0% vs 85.6%, AHR 0.89, 95% CI 0.71-1.12, p = 0.34). Combination RT was associated with superior 5-year OS compared to EBRT + ADT alone (without BT boost) (85.0% vs 79.4%, AHR 1.26, 95% CI 1.07-1.48, p < 0.01). Conclusions: Our study suggests that for patients with Gleason 9-10 tumors, multi-modality surgical therapy is equivalent to combination RT.
Final analysis of a phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabozantinib.
Authors: Desai Arpita , Brewer Jamie Renee , Medved Milica , Oto Aytekin , Gao Guimin , Karrison Theodore , Shevrin Daniel H. , Karczmar Greg S. , Stadler Walter Michael , Szmulewitz Russell Zelig
Published: March 2019

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Background: Cabozantinib (C) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. C trials have shown significant improvements in bone pain and bone scintigraphy in mCRPC patients (pts). We hypothesized that functional imaging using MRI could elucidate underlying biological processes by demonstrating an early decrease in vascular permeability (decrease in transfer consant - Ktrans) and subsequent decrease in cell density (increase in apparent diffusion coefficient - ADC) within bone metastases. Methods: mCRPC pts received C 60 mg daily. The primary endpoint was change in Ktrans at 2 weeks (wks) of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and correlation with bone scan, PSA, RECIST, and changes in reported pain. All pts underwent MRI at baseline, day 0, day 15 and every 12 wks. Results: 17 pts were treated at two sites. Median age: 68 yrs (range:51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events, and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 wks, Ktrans decreased an average 35%, 0.074 to 0.048 min-1 (SD=0.016, p<0.0001). There was no change in Ktrans between wk 2 and end of study. There was an increase in median ADC of 150 at wk 12. There were no RECIST or 50% PSA responses. Conclusions: Ktrans decreased significantly after 2 wks of treatment, consistent with antiangiogenic properties of C. Compared to wk 2, K trans at disease progression is unchanged, which could signify that adaptive vascular change is not the primary mechanism of tumor resistance to the drug. Contrary to our hypothesis, ADC increased during the trial, which perhaps correlates with the short median time to progression. Still, MRI of bone metastases could benefit drug development for other agents in mCRPC or interrogation of bone metastases, notoriously challenging for disease response analysis, in other cancers. Clinical trial information: NCT01599793.
An updated analysis evaluating skeletal related events (SREs) in CTRIAL-IE 13-21: Phase II trial of radium-223 (R223) in combination with enzalutamide (ENZA) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Greene John Patrick , Lim Marvin Chang Jui , Baird Anne-Marie , Deignan Olwyn , McCaffrey John , Prior Lisa Mary , Parker Imelda , Bowes Alison , Teiserskiene Ausra , Feeney John , Thirion Pierre Guillame , Finn Stephen P. , Kelly Paul J. , McDermott Ray
Published: March 2019

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Background: This phase II single arm study, previously reported on the safety and tolerability of the combination of R223 and ENZA in pts with mCRPC. R223 in combination with ENZA was well tolerated with acceptable safety and toxicity profiles. Methods: This study enrolled pts with mCRPC to bone with or without visceral/lymph node involvement progressing on ADT. Pts received 6 cycles of R223 (55 kBq/kg IV Q4W) in combination with ENZA (160mg/day), followed by ENZA alone. Bone health agents were initiated as per treating clinician choice. SREs were defined as: a pathologic fracture, spinal cord compression (SCC), necessity for external beam radiation (EBRT) or surgery to bone. SREs during the combination period and after completion of R223 are reported here. An unplanned retrospective analysis of all scans performed on each patient for any fracture was performed and is included. Results: From July 2015 to July 2017, 45 pts were enrolled. 42 pts (93.3%) received all 6 cycles of combination therapy. 16 pts (35.5%) remain on ENZA alone. In total, 6 pts (13.3%) had SREs. 4 developed pathological fractures (femur = 1, vertebrae = 3) while 3 had EBRT for pain. Of these 6 pts, 2 developed SCC requiring EBRT. The average time from starting R223 to SRE was 615 days. 2/6 pts were not receiving bone protection. One pt who developed a pathological fracture has subsequently died related to progressive disease (time to death = 292 days). In the retrospective analysis, 4 pts (8.8%) developed fractures which were associated with a history of trauma (radius = 1, tibia = 1 ribs = 2). 11 pts (24.4%) developed asymptomatic insufficiency fractures (ankle = 1, femur = 1, sacrum = 2, vertebrae = 4, ribs = 4). The average time to insufficiency fracture was 354 days. No interventions were required. The majority of pts (75.5%) on the study were receiving bone health agents. Conclusions: SREs were in keeping with previously published data. In an unplanned retrospective analysis, there was a higher incidence of asymptomatic insufficiency fractures in this cohort of patients, however no interventions were required. Clinical trial information: NCT02225704.
Circulating tumor (ct) DNA-based genomic profile of prostate cancer (PCa) patients with elevated carcinoembryonic antigen (CEA).
Authors: Malalur Pannaga G. , Gourdin Theodore Stewart , Roberts Ali , Lilly Michael B.
Published: March 2019

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Background: Neuroendocrine (aggressive variant) PCa patients often have elevated CEA (40-85%), which is associated with poor outcomes. We used ctDNA analysis to identify a genomic pattern for PCa patients with elevated CEA (CEA+ PCa). Methods: We analyzed ctDNA-based genomic profiles (Guardant 360) from 32 patients with CEA+ PCa. Profiles were compared with genomic profiles from the TCGA database, ctDNA profiles for 50 consecutive PCa patients with normal CEA levels (CEAnl PCa), and ctDNA profiles for GI tumors associated with elevated CEA. Results: CEA+ PCa patient profiles showed concordance with TCGA database genomic profiles for neuroendocrine PCa. There was high similarity in genes amplified; however many more single-nucleotide variants (SNVs) were detected with ctDNA analysis. For ctDNA profiles of CEA+ PCa, the most commonly amplified genes were AR, PIK3CA, MYC, CDK6, BRAF, MET; the most common clonal SNVs were in TP53, PTEN, APC, PIK3CA, and MET. Serial ctDNA analyses were done in 23 CEA+ PCa patients, of which 8 showed conversion from CEAnl to CEA+ PCa. This change was accompanied by emergence of new amplifications (62.5%; AR, MET, MYC, BRAF, EGFR, CDK6) or SNVs (tumor suppressor genes [ APC, TP53] or mitogen signaling pathways [ BRAF, ERBB2, KRAS, MET, PIK3CA]). Clonal mutations present in CEAnl PCa frequently persisted after emergence of a CEA+ phenotype. CEA+ PCa differed from CEAnl PCa by the higher prevalence of AR amplifications (p = 0.033), higher AR copy number (p = 0.004), and lower number of AR clonal mutations (p = 0.0017). AR amplification was significantly more frequent in CEA+ PCa (50%) than in another CEA+ malignancy, colon cancer (3%). AR amplification copy number was also much higher in CEA+ PCa than in colon cancer (p = 0.0023). Conclusions: ctDNA analysis shows AR amplifications as highly associated with CEA+ and neuroendocrine PCa. New amplifications occur during evolution from CEAnl to CEA+ PCa. Genomic profile obtained using ctDNA (within limits) is comparable to TCGA database. AR amplification is characteristic of CEA+ PCA and may distinguish this entity from other cancers with elevated CEA.
Discovery of targetable mutational signatures in advanced prostate cancer (aPC) using machine learning and next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Lin Edwin , Hahn Andrew W , Sonpavde Guru , Lilly Michael B. , Nussenzveig Roberto , Ledet Elisa , Pal Sumanta K. , Grivas Petros , Rich Thereasa A. , Raymond Victoria M. , Sartor A. Oliver , Yandell Mark , Agarwal Neeraj
Published: March 2019

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Background: Alterations (alts) of the AR gene are common in aPC and are associated with reduced responses to AR-axis inhibitors; optimal treatment is unknown. Genomic sequencing of ctDNA from aPCs may recapitulate truncal and branching alts across metastatic sites in heavily pretreated progressive aPC and facilitates identification of AR and other alts that contribute to aPC progression. Such data could lead to better understanding of aPC molecular biology and guide development of novel treatments. Methods: Two unsupervised machine learning algorithms, hierarchical clustering and principal components analysis, were used to evaluate mutational profiles of 2,679 plasma samples from 2,309 men with aPC. Samples were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA). Indels, amplifications, and fusions are evaluated in a subset of genes with high sensitivity and specificity. Chi-squared residual analysis and gene ontology enrichment were used to identify significantly co-altered molecular pathways. Results: Distinct, non-overlapping mutational signatures were observed in tumors with only AR amplification (amp) vs. only AR mutation (mut). Tumors with only AR amp, and those with both AR amp and mut, were strongly enriched for amps in the MAPK pathway (P = 3.62E-10, 4.92E-05, resp.). Tumors with only AR mut, and those with no AR alts, were strongly enriched for muts in negative regulators of cell proliferation (P = 1.09E-05, 3.30E-09, resp.). Muts further stratified to oxidative stress response in AR mut (P = 4.37E-05), and cell aging in no AR alts (P = 8.31E-07). Conclusions: In men with aPC, machine learning of ctDNA NGS data revealed recurrent mutational signatures that stratified according to the type of AR alts. These hypothesis-generating data require external validation but suggest that aPC may progress due to distinct mechanisms dependent on AR status. Future efforts to develop novel therapeutic approaches for aPC may need to consider the impact of the type of AR alt present and explore the interplay of AR with other altered pathways identified in this analysis.
TP53 mutations in circulating tumor DNA in men with metastastic castration-resistant prostate cancer mCRPC.
Authors: Chapman Lynne , Ledet Elisa , Ranasinghe Lahiru , Manogue Charlotte , Cotogno Patrick , Moses Marcus Marie , Christensen Bryce Raymon , Steinwald Peter , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver , Barata Pedro C.
Published: March 2019

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Background: Genes involved in mCRPC, including the tumor suppressor gene TP53, can be monitored with ctDNA but implications are unclear. Methods: Between 8/6/15 to 9/19/18, patients with mCRPC with available ctDNA genomic data using Guardant360 (Guardant360, Redwood City, CA) were included. Relationships between various lines of therapy and TP53 mutational status were analyzed. Patients positive for TP53 mutants were categorized using mutant allelic fraction of > 0%, ≥0.5%, ≥1% and ≥5%. Results: This study included 215 patients with mCRPC, median age 70 (41-90), and 80% Caucasians who had ctDNA after one line treatment for CRPC that included abiraterone (55%), enzalutamide (22%), and sipuleucel T (21%). Frequent co-alterations with TP53 mutants after 1 line of CRPC therapy included AR (14%), NF1 (5%), EGFR (4%), and PIK3CA (4%). See Table for relationships between lines of therapy and mutant TP53 allelic fraction. Conclusions: In this cohort of men with mCRPC, a higher mutational burden of TP53 in ctDNA was frequent and particularly associated with multiple lines of therapy. [Table: see text]
Performance of the 17-gene genomic prostate score test in men with prostate cancer (PCa) managed with active surveillance (AS): Results from the Canary Prostate Active Surveillance Study (PASS).
Authors: Lin Daniel W. , Zheng Yingye , McKenney Jesse , Brown Marshall , Lu Ruixiao , Crager Michael , Boyer Hilary , Brooks James D. , Dash Atreya , Fabrizio Michael , Gleave Martin , Liss Michael A. , Morgan Todd Matthew , Thompson Ian M , Wagner Andrew , Tsiatis Athanasios , Pingatore Andrea , Lawrence H. Jeffrey , Nelson Peter S , Newcomb Lisa F
Published: March 2019

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Background: The 17-gene Genomic Prostate Score (GPS) test (scale 0-100) predicts adverse surgical pathology (AP) and recurrence in newly diagnosed low- and intermediate-risk PCa. Studies of the predictive value of the GPS test in men initially managed with AS are limited. Methods: Diagnostic biopsy tissue was obtained from 634 men enrolled at 8 sites in PASS. Time to AP (Gleason Grade Group (GG) ≥3, ≥pT3a, or N1) in men who underwent radical prostatectomy (RP) was the primary endpoint. All diagnostic biopsies and RP specimens were centrally reviewed. Multivariate regression models for interval censored data were used to evaluate the association between time to AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Association between GPS and time to Gleason score upgrade on surveillance biopsy was also evaluated using a Cox Proportional Hazards model. Results: GPS results were obtained for 432 men (median follow-up 4.6 [IQR: 2.9-6.2] years); 374 and 58 with GG 1 or 2 cancer, respectively; median PSA density (PSAD) was 0.11 [IQR: 0.08-0.15]; 101 men underwent RP with central pathology after a median of 2.1 [IQR: 1.3-4.3] years surveillance, and 52 (52%) men undergoing RP had AP. 167 men upgraded at a subsequent biopsy. No clinico-pathologic covariates were significantly associated with AP other than PSAD. GPS was significantly associated with time to AP (hazards ratio [HR]/20 GPS units: 1.96 [95% CI = 1.17-4.28]; p = 0.030), when adjusted for diagnostic GG, or for dichotomous PSAD ( < vs ≥ 0.15; HR: 1.83, 95% CI = 1.04-3.62; p = 0.046). GPS was not significantly associated with AP (HR: 1.61, 95% CI = 0.87-2.98; p = 0.12) when adjusted for continuous PSAD. No association, either univariable or multivariable, was observed between GPS and subsequent biopsy upgrade. Conclusions: In a cohort of men on AS, GPS was associated with time to AP when adjusted for diagnostic GG or dichotomous PSAD. GPS was not associated with surveillance biopsy GG upgrading or AP at surgery after adjustment for continuous PSAD, although a trend was seen for AP, suggesting an association may be seen in a larger study.
Alkaline phosphatase (ALP) value at diagnosis of CRPC and response to primary androgen deprivation therapy may predict metastasis in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Keiichiro Mori , Kimura Takahiro , Egawa Shin
Published: March 2019

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Background: Numerous therapeutic options are available for metastatic castration-resistant prostate cancer (mCRPC). However, current therapeutic options remain inadequate for non-metastatic CRPC (nmCRPC); furthermore, there is a paucity of clear evidence to show who may be targeted for aggressive therapy among nmCRPC patients. Therefore, the objective of this retrospective study was to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of nmCRPC patients who may benefit from aggressive therapy. Methods: A total of 115 patients with CRPC who had no metastasis at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University Hospital. The primary outcome measure was metastasis-free survival (MFS) from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox model. Results: The median observation period after diagnosis of CRPC in these patients was 30 months. Kaplan-Meier analysis revealed a median MFS of 76 months in these patients. Multivariate analysis demonstrated that low ALP values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS ( P = 0.011, and 0.031, respectively). Conclusions: Study results suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict metastasis in patients with nmCRPC. Further prospective studies will be required in more patients to confirm our findings. Univariate/multivariate analysis of factors contributing to MFS in nmCRPC patients. [Table: see text]