bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of glucocorticoid therapy on mortality in patients with rheumatoid arthritis and concomitant type II diabetes: a retrospective cohort study
Authors: Costello Ruth E. , Marsden Antonia , Movahedi Mohammad , Lunt Mark , Humphreys Jenny H. , Emsley Richard , Dixon William G.
Published: February 2020

Background

Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) and mortality risk. Patients with RA are also frequently prescribed glucocorticoids (GCs) which have been associated with increased risk of mortality. In addition, for patients who have concomitant diabetes mellitus (DM), GCs are known to worsen glycaemic control and hence may further increase CV and mortality risk. This study aimed to understand the relationship between GCs, DM and mortality in patients with RA.

Methods

This was a retrospective cohort study of patients with incident RA identified from UK primary care electronic medical records. Patients with linkage to Office for National Statistics (ONS) for mortality data (N = 9085) were included. DM was identified through Read codes, prescriptions and blood tests, and GC use was identified through prescriptions. Mortality rate ratios (RR) and rate differences (RD) were calculated across the different exposure groups. Cox proportional hazards regression models were used to estimate interaction on the multiplicative and additive scales.

Results

In those without DM GC use had a 4.4-fold increased all-cause mortality RR (95% confidence interval (CI): 3.77 to 5.07) compared to non-use, whilst those with DM had a lower RR for GC use (2.99 (95% CI: 2.32, 3.87)). However, those with DM had a higher RD associated with GC use because of their higher baseline risk. In those with DM, GC use was associated with an additional 44.9 deaths/1000 person-years (pyrs) (95% CI: 32.9 to 56.8) compared to non-use, while in those without DM GC use was associated with an additional 34.4 deaths/1000 pyrs (95% CI: 30.1 to 38.7) compared to non-use, while in those without DM GC use was associated with an additional 36.2 deaths/1000 pyrs (95% CI: 31.6 to 40.8). A similar pattern was seen for CV mortality. The adjusted Cox proportional hazards model showed no evidence of multiplicative interaction, but additive interaction indicated a non-significant increased risk. For CV mortality there was no interaction on either scale.

Conclusions

GC use was associated with higher mortality rates in people with comorbid DM compared to people without DM, despite apparently reassuring similar relative risks. Clinicians need to be aware of the higher baseline risk in patients with DM, and consider this when prescribing GCs in patients with RA and comorbid DM.
Evidence of inhibitory effect of Pseudomonas fluorescens CHA0 and aqueous extracts on tomato plants infected with Meloidogyne javanica (Tylenchida: Heteroderidae)
Authors: Moazezikho Ali , Charehgani Habiballah , Abdollahi Mohammad , Rezaei Rasool
Published: February 2020

Effects of Pseudomonas fluorescens L. (jimsonweed) (Pf) isolate and the two plant extracts, Datura stramonium and Myrtus communis, were investigated on hatching and juvenile (J2s) mortality of Meloidogyne javanica(Tylenchida: Heteroderidae) under laboratory conditions. After determining the values of LC30, LC50, and LC70 of each extract, four leaf stage seedlings of tomato were treated by 20 ml of Pf suspension at a concentration of 108 CFU/ml, using a soil drenching method. After 1 week, the tested plants were inoculated by 4000 eggs and (J2s) of M. javanica and simultaneously were treated by 100 ml of the selected concentrations of D. stramonium (1.1, 1.4, and 1.8%) and M. communis (1.8, 3 and 5.2%), as soil drench. Results showed that a combination of Pf and the leaf extract, D. stramonium at the rate of 1.8% or M. communis at the rate of 5.2%, respectively, reduced the number of eggs per root system and the reproduction factor by 68 and 45%, the number of galls by 64 and 33%, and the number of egg masses by 65 and 43%, than the control. In conclusion, combination of Pf and D. stramonium at the rate of 1.8% or M. communis at the rate of 5.2% can significantly reduce the damage of M. javanica on tomato, under greenhouse conditions.
Efficient electro-magnetic analysis of a GPU bitsliced AES implementation
Authors: Gao Yiwen , Zhou Yongbin , Cheng Wei
Published: February 2020

The advent of CUDA-enabled GPU makes it possible to provide cloud applications with high-performance data security services. Unfortunately, recent studies have shown that GPU-based applications are also susceptible to side-channel attacks. These published work studied the side-channel vulnerabilities of GPU-based AES implementations by taking the advantage of the cache sharing among multiple threads or high parallelism of GPUs. Therefore, for GPU-based bitsliced cryptographic implementations, which are immune to the cache-based attacks referred to above, only a power analysis method based on the high-parallelism of GPUs may be effective. However, the leakage model used in the power analysis is not efficient at all in practice. In light of this, we investigate electro-magnetic (EM) side-channel vulnerabilities of a GPU-based bitsliced AES implementation from the perspective of bit-level parallelism and thread-level parallelism in order to make the best of the localization effect of EM leakage with parallelism. Specifically, we propose efficient multi-bit and multi-thread combinational analysis techniques based on the intrinsic properties of bitsliced ciphers and the effect of multi-thread parallelism of GPUs, respectively. The experimental result shows that the proposed combinational analysis methods perform better than non-combinational and intuitive ones. Our research suggests that multi-thread leakages can be used to improve attacks if the multi-thread leakages are not synchronous in the time domain.
Vitamin C supplementation during chronic variable stress exposure modulates contractile functions of testicular artery and sperm parameters in male Wistar rats
Authors: Salami Shakiru Ademola , Salahdeen Hussein Mofomosara , Moronkola Oyinlola Toluwani , Murtala Babatunde Adekunle , Raji Yinusa
Published: February 2020

Background

Humans are exposed to identifiable multiple environmental stressors. However, there is paucity of studies assessing chronic variable stress (CVS) exposure together with antioxidant supplementation on reproductive function. This study investigates impact of vitamin C supplementation, during CVS exposure on contractile functions of testicular artery and sperm parameters. Twenty pubertal male Wistar rats (150–200 g) were grouped into four of five rats each consisting of control (normal saline), vitamin C treated (7 mg/kg bwt), chronic variable stress (CVS) + vitamin C, and CVS only. Animals were treated respectively for 8 weeks. Serum superoxide dismutase (SOD), catalase, malondialdehyde (MDA) activity, testosterone, and cortisol were assayed. Contractile responses of excised testicular artery to phenylephrine, potassium chloride, acetylcholine, and sodium nitroprusside were determined using Ugo Basile data acquisition system. Sperm parameters and histopathology of the testis were also determined. Statistical significance was taken at p < 0.05

Result

MDA activity was significantly increased in group exposed to chronic variable stress. However, groups supplemented with vitamin C during CVS exposure showed no significant increase. Serum SOD and catalase were enhanced in group exposed to CVS with vitamin C supplementation when compared to group exposed to chronic variable stress only. Chronic variable stress exposure increased serum cortisol level and this was attenuated with vitamin C supplementation. Vitamin C supplementation significantly increased serum testosterone level when compared to CVS only exposed group. Contraction responses of testicular arterial strips to phenylephrine and potassium chloride were attenuated in vitamin C supplemented groups when compared to CVS only exposed group. Vitamin C supplementation during CVS exposure also enhanced relaxation of testicular artery strip to sodium nitroprusside and acetylcholine. Sperm count and percentage motility were significantly reduced in CVS only exposed group when compared vitamin C supplemented group. Sperms cells with abnormal morphology were also significantly increased in chronic variable stress only exposed group when compared to control and vitamin C supplemented groups.

Conclusion

Chronic variable stress adversely impacts contractility of testicular artery, sperm parameters, cortisol, and testosterone level. Vitamin C supplementation modulated these by suppressing MDA and enhancing antioxidant enzyme activity.
Renal resistive index in non-alcoholic fatty liver disease as an indicator of early renal affection
Authors: Mahmoud Hossam El-Din A. , Yousry Wael A. , Saleh Shereen A. , El Badry Mohamed , Hussein Ahmed , Ali Mostafa Hassan , El-Hariri Hazem M.
Published: February 2020

Background

Nonalcoholic fatty liver disease (NAFLD) is a possible risk factor for chronic kidney disease (CKD). Renal resistive index (RRI) which is a ratio of peak systolic and end diastolic velocity can test arterial stiffness and endothelial renal dysfunction. The aim of the work is to detect the relation between NAFLD and RRI as an indicator of early renal affection and its relation to the disease severity. This study included 150 subjects divided into 3 groups: patients with NASH, simple steatosis, and control group (50 patients each). All patients were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound examination, and RRI measurement.

Results

6.0% of NASH patients had significant fibrosis by NAFLD fibrosis score. RRI was significantly higher in NASH patients with fibrosis (mean = 0.74) than NASH patients without fibrosis (mean = 0.65) and patients with simple steatosis (mean = 0.63). It was the lowest in normal controls (mean = 0.61). There were significant correlations between RRI and age, BMI, serum lipids, liver enzymes, and NAFLD fibrosis score. Multiple linear regression analysis found that age and serum cholesterol were significant independent factors of increased RRI (p < 0.0001). RRI showed low diagnostic performance in differentiation between NASH and simple steatosis using ROC curve.

Conclusion

RRI was significantly higher in NASH patients with and without hepatic fibrosis. RRI correlates significantly with NAFLD fibrosis score. RRI can be used as an indicator of early renal affection in patients with NAFLD.
Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): Five-year results of a randomized phase II trial.
Authors: Ost Piet , Reynders Dries , Decaestecker Karel , Fonteyne Valerie , Lumen Nicolaas , De Bruycker Aurélie , Lambert Bieke , Delrue Louke , Bultijnck Renée , Goetghebeur Els , Villeirs Geert , De Man Kathia , Ameye Filip , Billiet Ignace , Joniau Steven , Vanhaverbeke Friedl , de Meerleer Gert
Published: February 2020

10

Background: Multiple randomized phase II trials suggest that metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa) improves progression-free survival, but the majority of trials lack longer follow-up. We present the updated 5-year results from the STOMP-trial. Methods: In this multicentre, randomised, phase II study, asymptomatic PCa patients were eligible in case of a biochemical recurrence following primary PCa treatment with curative intent and presenting with up to 3 extracranial on choline PET-CT and a serum testosterone levels > 50 ng/ml. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions. Randomisation was balanced dynamically on two factors: PSA doubling time (≤3 vs. > 3 months) and nodal vs non-nodal metastases. The primary endpoint was androgen deprivation therapy (ADT)-free survival. Castrate resistant prostate cancer-free survival (CRPC) was a secondary endpoint. Tests were performed two-sided; p values less than 0.20 were deemed significant. Results: The 5-year ADT-free survival was 8% for the surveillance group and 34% for the MDT group (Figure 1, hazard ratio 0.57 [80% CI: 0.38-0.84], log-rank p = 0.06). There was no significant difference in effect for the different stratification factors (interaction test). The 5-year CRPC-free survival was 53% for the surveillance group and 76% for the MDT group (hazard ratio 0.62 [80% CI: 0.35−1.09]; log−rank p = 0.27). At a median follow for survival of 5.3 years (IQR 4.3-6.3), the 5-year overall survival was 85%, with 6 out of 14 deaths attributed to prostate cancer. Conclusions: The updated STOMP trial outcomes confirm the earlier reported significant difference in ADT free survival in favor of the MDT group compared to surveillance. Prostate-cancer related mortality is low within the first 5 years of diagnosis of oligorecurrent prostate cancer. Clinical trial information: NCT01558427.
Association of body composition with survival and efficacy of first-line treatment in patients with castration-resistant prostate cancer.
Authors: Joung Jae Young , Pak Sahyun
Published: February 2020

115

Background: We aimed to investigate the association of body composition with survival and efficacy of first-line treatments in patients with castration-resistant prostate cancer (CRPC). Methods: Records of CRPC patients who were treated with first-line docetaxel or androgen receptor signaling inhibitors (ARSi) between 2005 and 2018 were reviewed. Skeletal muscle index (SMI), visceral fat index, and subcutaneous fat index were evaluated using pretreatment computed tomography images. Results: Of the 230 eligible patients, 144 patients received docetaxel and 86 received ARSi as the first-line treatment for CRPC. SMIhi (based on median value) group had higher prostate-specific antigen (PSA) progression-free survival (median 13.5 vs. 8.3 months, p=0.030), radiologic progression-free survival (14.9 vs. 9.1 months; p<0.001), and overall survival (24.1 vs. 16.9 months, p=0.015) compared than SMIlo group. In multivariable analysis, SMI was independently associated with risk of PSA progression (HR=0.68; 95% CI, 0.50-0.93; p=0.017), radiologic progression (HR=0.54; 95% CI, 0.39-0.75; p=0.001), and overall survival (HR=0.72; 95% CI, 0.52-0.98; p=0.037), regardless of BMI. In docetaxel-treated patients, PSA progression-free survival (13.5 vs. 5.9 months, p=0.016) and radiologic progression-free survival (14.6 vs. 6.7 months, p<0.001) were higher in SMIhi than SMIlo group. However, PSA progression-free survival and radiologic progression-free survival were similar between two groups in ARSi-treated patients. Based on treatment-specific hazards of radiologic progression, patients with SMIlo are more likely to benefit from ARSi compared than docetaxel. Conclusions: High skeletal muscle mass may be associated with reduced risks of disease progression and mortality in patients with CRPC. However, the significance of these relationships is limited in patients treated with docetaxel. These results suggest that skeletal muscle mass may be helpful in treatment selection and predicting treatment response in CRPC. Further prospective studies are warranted.
The impact of the expression of the transcription factor MYBL2 on outcomes of patients with localized and advanced prostate cancer.
Authors: Yoshikawa Yuki , Wang Xin Victoria , Chen Yu-Hui , Mazzu Ying Zhang , Chakraborty Goutam , Jehane Lina E. , Rajanala Sai Harisha , Hirani Rahim , Nandakumar Subhiksha , Stopsack Konrad H. , Lee Gwo-Shu Mary , Davicioni Elai , Liu Glenn , DiPaola Robert S. , Carducci Michael Anthony , Kantoff Philip W. , Sweeney Christopher
Published: February 2020

149

Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]
Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with BRCA1 or BRCA2 (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Abida Wassim , Campbell David , Patnaik Akash , Sautois Brieuc , Shapiro Jeremy David , Vogelzang Nicholas J. , Bryce Alan Haruo , McDermott Raymond S. , Ricci Francesco , Rowe Julie Haewon , Zhang Jingsong , Loehr Andrea , Despain Darrin , Dowson Melanie , Golsorkhi Tony , Chowdhury Simon
Published: February 2020

178

Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]
CDK12-mutated prostate cancer (PC): Clinical outcomes to standard therapies and immune checkpoint blockade.
Authors: Schweizer Michael Thomas , Gulati Roman , Brown Landon Carter , McKay Rana R. , Dorff Tanya B. , Kilari Deepak , Vats Pankaj , Patel Vaibhav G. , Oh William K. , Armstrong Andrew J. , Montgomery Robert B. , Alva Ajjai Shivaram
Published: February 2020

191

Background: Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of PC, characterized by high neoantigen burden. Given that these mutations may define a clinically relevant PC subgroup, we sought to describe outcomes to both standard drugs and PD1 inhibitors. Methods: Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Multiple clinical grade sequencing assays were used to assess for CDK12 alterations. Descriptive statistics included PSA50 (≥50% decline in PSA from baseline) and clinical/radiographic progression-free survival (PFS). Results: Of 56 CDK12-mutated PC patients, 27 (48%) had biallelic CDK12 alterations. At diagnosis, 46 (82%) had Gleason grade group 4-5 disease, 52% had T3-T4 disease and 15 (27%) had M1 disease. Median follow up was 8.2 yrs (95% CI: 5.6-11.1) and 53 (95%) developed metastatic disease. Median overall survival (OS) from metastasis was 3.9 years (95% CI: 3.2-5.8). Nineteen patients received an anti-PD1 therapy. PSA50 responses to PD1 blockade were infrequent and overall PFS was short (Table); however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy naïve patients who received anti-PD1 therapy (P=0.004). Outcomes were similar in monoallelic vs. biallelic CDK12-mutated patients. Conclusions: CDK12-mutations define an aggressive PC subgroup, with a high rate of metastatic disease and short OS. Immune checkpoint inhibitors may be effective in a minority of these patients and exploratory analysis supports using anti-PD1 drugs early.[Table: see text]
Addition of abiraterone to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Model to estimate long-term survival, quality-adjusted survival, and cost-effectiveness.
Authors: Clarke Caroline Sarah , Brawley Christopher D. , Ingleby Fiona Caroline , Gabrio Andrea , Dearnaley David P. , Matheson David , Attard Gerhardt , Rush Hannah L. , Jones Robert J. , Clarke Noel W. , Parmar Mahesh K. B. , Sydes Matthew R. , Hunter Rachael Maree , James Nicholas D.
Published: February 2020

204

Background: Results from randomised trials show adding abiraterone acetate plus prednisolone (AAP) to standard of care (SOC) improves disease-free and overall survival in men with prostate cancer (PC) starting long-term hormone therapy for first time. Formal assessment is required of whether funding AAP here shows appropriate use of resources. This cost-effectiveness decision model tests if giving AAP to these patients is cost-effective using costs from English National Health Service, the largest nation where STAMPEDE recruited. Methods: Health outcomes and costs were modelled using patient data from AAP comparison of STAMPEDE (recruitment 2011-14). This included 1917 men with high-risk, locally advanced metastatic or recurrent PC starting 1st-line hormone therapy. SOC was hormone therapy for ≥2 years with radiotherapy in pre-selected patients. If allocated to research group, AAP (AA 1000mg/day, P 5mg/day) was added to SOC. The model makes lifetime predictions of survival, costs and quality-adjusted lifeyears (QALYs), with costs and QALYs discounted at 3.5% annually. Sensitivity analyses were performed. Results: The model predicted AAP would extend survival (discounted quality-adjusted survival) by 2.68y (1.46 QALYs) for metastatic patients and 0.30y (0.29 QALYs) for non-metastatic. The cost of AAP means it is not currently cost-effective in this setting, including with Patient Access Scheme costs for AAP and enzalutamide and similar reductions for cabazitaxel and Ra. If AAP’s price reduces after patent expiry as expected (90% reduction on BNF cost), it would be cost-effective in both patient groups, with incremental cost-effectiveness ratios below £10,000 (US$12,665) per QALY. AAP could also dominate in non-metastatic patients (i.e. lower costs and higher QALYs than SOC alone). Conclusions: AAP could be cost-effective for patients with non-metastatic and metastatic disease with expected future pricing and may be cost-saving in the former. Policymakers should encourage license submissions and generic price reductions to facilitate use of AAP given cost-saving potential in addition to improving survival. Clinical trial information: NCT00268476.
REACT: A feasibility study to test the integration of a cancer registry early case ascertainment process via electronic pathology reporting with an online clinical trial matching tool.
Authors: Borno Hala , Duffy Christine , Zhang Sylvia , Loya Zinnia , Golden Todd , Oh Debora , Odisho Anobel Y. , Gomez Scarlett Lin
Published: February 2020

207

Background: Representation of diverse patient populations in prostate cancer clinical trials is essential to ensure results are applicable to all men. However, underrepresentation among underserved populations remains a critical problem. Population-based cancer registries provide a potential platform to overcome problems with inclusion of diverse patient populations in clinical research when used as a source for recruitment. Methods: Leveraging statewide implementation of early-case ascertainment (ECA) via electronic pathology for cancer case identification, we performed a feasibility study within the Greater Bay Area Cancer Registry to (1) test a process using ECA to identify new cases of advanced prostate cancer for potential enrollment into clinical trials and (2) test the utility of an online clinical trial matching tool to improve matching of underrepresented patients into clinical trials. All study materials were translated into Spanish, and recruiters were Spanish-speaking. Results: A total of 419 cases were identified from 19 reporting facilities through ECA and sent invitation letters; 18 cases were excluded due to physician contraindication, and 68 (16%) declined participation. All enrolled participants (N=54) completed baseline surveys. To date, 40 participants completed follow-up surveys after using the online matching tool. Most participants were White (80%), of higher income (>$150,000; 41%), and college-educated (70%). Thirty-seven percent indicated awareness of cancer clinical trials, 69% stated interest in participating in clinical research, and 72% held a positive attitude towards cancer clinical trials. However, 46% indicated they would not participate in a randomized study. To assess utility of the matching tool, 65% indicated it increased their interest in participating in a clinical trial. Conclusions: ECA needs to ensure sociodemographic data are available to make it useful as a tool for clinical trials. Preliminary results indicate ECA used in combination with an online clinical trial matching tool may serve as an important recruitment vehicle for prostate cancer clinical trials.
Differential expression of PSMA and 18F-fluciclovine transporter genes in metastatic castrate-resistant and treatment-emergent small cell/neuroendocrine prostate cancer.
Authors: Chu Carissa , Alshalalfa Mohammed , Sjöström Martin , Zhao Shuang , Herlemann Annika , Chou Jonathan , Baskin Avi Lefridge , Mahal Brandon Arvin Virgil , Spratt Daniel Eidelberg , Cooperberg Matthew R. , Small Eric Jay , Aggarwal Rahul Raj , Wong Anthony C. , Porten Sima P. , Hope Thomas , Nguyen Paul L. , Schaeffer Edward M. , Carroll Peter , Feng Felix Y
Published: February 2020

24

Background: 18F-fluciclovine (Axumin) PET/CT imaging is recommended by the NCCN in the setting of biochemical recurrence, while prostate-specific membrane antigen (PSMA) PET/CT is preferred by the EAU. The utility of these methods in the post-androgen deprivation therapy (ADT) setting however, is less defined. Our objective was to compare relative gene expression of the molecular targets of these imaging modalities— fluciclovine transporter genes (LAT1-4, ASCT1-2) and PSMA—in metastatic castrate resistant prostate cancer (mCRPC) and treatment-emergent small cell/neuroendocrine prostate cancer (t-SCNC). Methods: Genome-wide expression profiles of five mCRPC cohorts (Aggarwal, Grasso, Kumar, Beltran, Robinson, et al) were used to characterize relative expression of fluciclovine transporter (LAT1-4, ASC1-2) and PSMA (FOLH1) genes. 3 cohorts (Kumar, Beltran, Aggarwal) were enriched with t-SCNC tumors. The GSE35988 cohort included primary tumors and mCRPC. RNA expression profiling methods were consistent within cohorts. Results: 518 mCRPC specimens were included. In the GSE35988 cohort, PSMA expression was downregulated in mCRPC when compared to primary localized tumors (p=0.01). PSMA expression was further depressed in t-SCNC when compared with mCRPC (p<0.001). Of the fluciclovine transporter genes, LAT1 and LAT4 were overexpressed in mCRPC when compared to primary tumors, while ASC2 was less expressed (p<0.001). LAT1 was further overexpressed in t-SCNC when compared to mCRPC, while LAT2 was less expressed (p<0.001). PSMA expression was negatively correlated with LAT1 (p<0.001) but positively correlated with LAT2 (p=0.006). Other fluciclovine transporters were not correlated. Conclusions: Expression of PSMA and a subset of fluciclovine transporter genes are inversely correlated in mCRPC and t-SCNC. These findings suggest that fluciclovine-based imaging may play a role in castrate resistant states. Clinical comparison between PSMA- and fluciclovine-based imaging modalities in mCRPC and t-SCNC is warranted.
A deep learning algorithm to predict coexisting metastatic disease using intraprostatic [F18]DCFPYL PSMA image alone in veterans with prostate cancer.
Authors: Nickols Nicholas George , Anand Aseem , Sjöstrand Karl , Jafari Lida , Ceccoli John , Lin Tess , Richter Jens , Rettig Matthew
Published: February 2020

25

Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent for prostate cancer. Independent of manual feature selection, a deep learning algorithm might offer additional insight into the disease biology. We explored the performance of a deep learning algorithm on PyL images of the primary tumor to predict co-existing distant metastases. Methods: 74 veterans with high risk primary prostate cancer tumors were imaged with both PyL PSMA PET/CT and conventional imaging (bone scan and CT or MRI of the abdomen/pelvis). 26% were confirmed with metastatic disease (M1) by conventional imaging. The PyL images of the primary tumor were analyzed with EXINI’s PyL-AI algorithm. Location of the prostate was defined on low dose CT via automatic segmentation using a deep convolutional network. The segmentations were used to map the PyL PET image of the prostate. The image based PyL-AI model was made up of a Conv3D layer of 4 kernels, a Conv3D layer of 8 kernels, a dense layer of 64 nodes followed by a final dense layer with 2 nodes. The model training was performed on the images using 5-fold cross validation with non-overlapping validation sets. The test predictions were compared with ground truth (M1); the area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of distant metastases. A logistical regression model from baseline clinicopathologic features of the primary tumor (baseline PSA, biopsy gleason score, percent cores positive, T stage) was created as a comparator. Results: The logistical regression model using clinicopathologic features had an AUC of 0.71, while the PyL-AI model based on intra-prostatic PyL Images alone had an AUC of 0.81 for prediction of metastatic disease as defined by conventional imaging. Adding clinical parameters in the image based PyL-AI model incrementally increased the AUC to 0.82. Conclusions: The image based PyL-AI deep learning model demonstrates a higher predictive accuracy over the logistic model using classical clinicopathologic features. The study is hypothesis generating observation that needs prospective validation in an independent data set.
Five-year results from a phase I/II study of moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancer including simultaneously integrated boost and pelvic lymph node (LN) coverage.
Authors: Ricco Anthony , Mukhopadhyay Nitai , Holdford Diane , Skinner Vicki , Saraiya Siddharth , Moghanaki Drew , Anscher Mitchell Steven , Chang Michael G. , Deng Xiaoyan
Published: February 2020

299

Background: This study reports the 5 year toxicity and efficacy data of a phase I/II trial of moderately hypofractionated intensity modulated radiation therapy (IMRT) for localized prostate cancer utilizing a simultaneous integrated boost and pelvic lymph node (LN) coverage. Methods: Men with localized prostate cancer were prospectively enrolled and received IMRT to the prostate +/- seminal vesicles (SVs) +/- LNs based on National Comprehensive Cancer Network (NCCN) guidelines. Low-risk (LR) patients received 69.6 Gy in 29 fractions to the prostate alone; intermediate-risk (IR) and high-risk (HR) patients received 72Gy to the prostate, 54Gy to the SVs, and 50.4Gy to LNs (if risk of LN involvement > 15% by the Roach formula) all in 30 fractions. IR and HR patients received androgen deprivation therapy. Results: Fifty-five patients were enrolled and 49 patients evaluable with a median follow up of 60 months. There were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Twenty-five patients (51%) received prostate and LN treatment. At 5 years, the cumulative incidence of late grade 2+ gastrointestinal (GI) and genitourinary (GU) toxicity was 22.6% and 38.2% respectively. Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8%, 3.9%, and 5.8% respectively. Late grade 2+ GI toxicities that did not resolve by 60 months included 3 out of 52 patients (5.8%). Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4%, 7.7%, and 13.5% respectively. There were 3 patients (5.8%) who experienced grade 3 GU toxicity and no grade 3 GI toxicities. The biochemical relapse free survival at 5 years for the cohort was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. Conclusions: Moderate hypofractionation of localized prostate cancer utilizing a simultaneous integrated boost and LN coverage produces excellent biochemical control and acceptable acute/late toxicity. This phase I/II trial adds to maturing data with 5 year outcomes which justify its use for cost and patient convenience factors. Clinical trial information: NCT01117935.
18-year prostate cancer-specific mortality after prostatectomy, brachytherapy, external beam radiation therapy, hormonal therapy, or monitoring for localized prostate cancer.
Authors: Herlemann Annika , Cowan Janet E. , Washington Samuel L. , Wong Anthony C. , Broering Jenny M. , Carroll Peter R. , Cooperberg Matthew R.
Published: February 2020

300

Background: The optimal treatment of localized prostate cancer (PCa) remains controversial. We compared long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (AS/WW) for localized PCa. Methods: Within the CaPSURE registry, we analyzed 12,062 men with localized PCa. PCa risk was assessed using the Stephenson preoperative nomogram and the Cancer of the Prostate Risk Assessment (CAPRA) score. Multivariable analyses were performed to compare prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) by primary treatment, adjusting for age and case-mix. An inverse probability weighted regression adjustment was used to reflect propensity for treatment assignment and any imbalances in censoring. Results: 6,357 men (53%) underwent RP, 1,351 (11%) BT, 1,716 (14%) EBRT, 1,605 (13%) PADT, and 1,033 (9%) AS/WW. During the 18-year follow-up period, 514 men died from PCa. Adjusting for clinical CAPRA score, the hazard ratios for PCSM relative to RP were 1.46 (95% CI, 1.00-2.12, p=0.050) for BT, 1.81 (95% CI, 1.43-2.30, p<0.001) for EBRT, 2.77 (95% CI, 2.18-3.51, p<0.001) for PADT, and 1.81 (95% CI, 1.23-2.66, p=0.003) for AS/WW. The greatest difference in PCSM between treatment modalities was observed for high-risk patients. Adjusting for age, comorbidity, and clinical CAPRA score, the hazard ratios for ACM were 1.46 (95% CI, 1.28-1.67) for BT, 1.38 (95% CI, 1.24-1.54) for EBRT, 1.89 (95% CI, 1.67-2.13) for PADT, and 1.60 (95% CI, 1.39-1.84) for AS/WW compared to RP (all p<0.001). Additional analyses using 100-Stephenson score or Fine-Gray competing risks analysis demonstrated similar results. Conclusions: In a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, risk of PCSM and ACM was lowest after RP. Mortality was significantly higher after EBRT and AS/WW, and highest after PADT. RP should be offered as part of the management paradigm for high-risk disease, AS/WW should be preferred for most low-risk PCa.
Adverse event profiles of apalutamide, enzalutamide, and darolutamide in SPARTAN, PROSPER, and ARAMIS: How confident are we about which drug is safest?
Authors: Drago Joshua Z. , Kantoff Philip W. , Stopsack Konrad H.
Published: February 2020

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Background: Apalutamide, enzalutamide, and darolutamide were approved for non-metastatic castration-resistant prostate cancer (nmCRPC) based on three randomized placebo-controlled trials that showed similar efficacy. Adverse event (AE) profiles have been invoked to differentiate the drugs but have only been informally compared. Methods: We accounted for baseline characteristics, AE collection and reporting, and statistical uncertainty when comparing AE risks in the drug and placebo arms of SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614). Results: Patients in SPARTAN, PROSPER, and ARAMIS had a similar median age (74 years in all studies), median PSA doubling time (3.7-4.7 months) and ECOG performance status (68-80% with ECOG 0). AEs were gathered consistently using CTCAE 4.0 or 4.03. However, PROSPER and ARAMIS reported AEs occurring in ≥5% of patients; SPARTAN reported AEs occurring in ≥15%. Trials also reported 5 to 14 ‘AEs of interest.’ Of 34 AE types reported overall, only 10 were reported in all three trials. Absolute risks of adverse events in the placebo arms differed considerably. Compared to the placebo arm of SPARTAN, AEs were on average 44% less common in the placebo arm of PROSPER (95% CI, 28-56%) and 54% less common in the placebo arm of ARAMIS (95% CI, 41-64%), a difference not explained by length of follow-up. With lower event numbers, relative risk estimates were less precise with wider confidence intervals. For example, comparing treatment vs. placebo arms, the relative risk for fatigue, the most common AE, was 1.45 (95% CI, 1.16-1.80) in SPARTAN, 2.37 (95% CI, 1.86-3.04) in PROSPER, and 1.39 (95% CI, 1.01-1.91) in ARAMIS. Across all AE types, compared to SPARTAN, relative risks from PROSPER were 23% less precise and relative risks from ARAMIS were 30% less precise. Conclusions: While conducted in similar patient populations, these trials had remarkable differences in AE reporting and in absolute AE risks between placebo arms. Rather than indicating better safety, low absolute adverse event numbers decrease confidence in AE profiles. Published data are insufficient to differentiate the AE profiles of these agents in nmCRPC.
Clinical outcomes and patient (pt) profiles in REASSURE: An observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Higano Celestia S. , Saad Fred , Sartor A. Oliver , Miller Kurt , Conti Peter , George Daniel J. , Sternberg Cora N. , Shore Neal D. , Sade Juan Pablo , Bellmunt Joaquim , Smith Matthew Raymond , Logothetis Christopher , Verholen Frank , Kalinovsky Jan , Bayh Inga , TOMBAL Bertrand F.
Published: February 2020

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Background: Ra-223 is a targeted alpha therapy that showed a survival advantage and favorable safety profile in the phase 3 ALSYMPCA trial in pts with mCRPC. REASSURE (NCT02141438) is evaluating the long-term safety of Ra-223 in routine clinical practice in pts with mCRPC over a 7-year follow-up period. Methods: In this global, prospective, single-arm, observational study, the second prespecified interim analysis (data cut-off March 2019) evaluated safety and clinical outcomes of Ra-223 in pts with mCRPC. Primary outcome measures were incidence of second primary malignancies (SPM), bone marrow suppression and short- and long-term safety in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: For 1465 pts in the safety analysis, median follow up was 11.5 months. Median PSA (n=1053), ALP (n=1048), and LDH (n=555) levels at baseline were 59 ng/mL, 135 U/L, and 269 U/L, respectively. 81% of pts had bone metastases only at baseline; 19% of pts had other metastatic sites, mostly in the lymph nodes. 19% of pts had <6 metastatic sites, 47% had 6–20 sites, 20% had >20 lesions but not a superscan, and 6% had a superscan. 45%, 38%, 37%, 9%, and 8% of pts received prior abiraterone, docetaxel, enzalutamide, cabazitaxel, or sipuleucel-T as prior therapies, respectively. Median number of Ra-223 doses received was 6; 67% of pts had ≥5 doses. SPM occurred in 1% of pts. The most common treatment-emergent drug-related adverse event (AE) of any grade was diarrhea (11%). 10% of pts had a bone-associated event, 5% had fractures, and 15% had a hematological AE. Median OS was 15.6 months (95% CI 14.6–16.5). Conclusions: In REASSURE, there was a low incidence of SPM, bone fractures, and bone marrow suppression after Ra-223 treatment, with no new AEs identified. This study confirms that in routine clinical practice, Ra-223 AE rates were low, and pts generally received ≥5 doses. Clinical trial information: NCT02141438. [Table: see text]
A systematic review and network meta-analysis of FDA approved treatment options in men with nonmetastatic, castration-resistant prostate cancer (M0CRPC).
Authors: Riaz Irbaz Bin , Asghar Noureen , Lang Daenielle K. , Yao Yuan , Riaz Anum , Almutairi Abdulaali , Wang Zhen , Abraham Ivo , Murad M. Hassan , Kohli Manish
Published: February 2020

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Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.
Loss of SNAI2 in prostate cancer and effect on patient response to androgen deprivation therapy.
Authors: Corcoran Niall , Cmero Marek , Kurganovs Natalie , McCoy Patrick , Costello Anthony , Ryan Andrew , Parente Phillip , Hovens Christopher
Published: February 2020

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Background: Androgen receptor (AR) signalling is important in prostate cancer progression, and therapies that specifically target this pathway are the mainstay of treatment for advanced disease. Treatment however is non-curative, and resistance develops inevitably with time. Although the mechanisms that drive castration resistant disease have been intensively analysed, how tumours survive and persist during the initial pathway inhibition is unclear. Methods: To track this process in detail we performed a Phase II neo-adjuvant study of a novel combination of AR targeting therapies (degarelix & abiraterone & bicalutamide) for 6 months prior to prostatectomy in men with high risk, localised disease. To determine what was driving tumour persistence in poorly responding patients, we comprehensively characterised pre- and post-treatment samples using both whole genome and RNA-sequencing, validating pertinent findings by qRT-PCR, IHC and FISH. Results: Despite universal ‘biochemical responses’, objective responses to treatment as measured by residual tumours volumes were highly variable. This state which we term ‘castration-persistence’, is molecularly distinct from ‘castration-resistance’, and is characterised by global transcriptional reprogramming leading to a transitional EMT state. Whole genome sequencing confirms tumour persistence is not associated with the emergence of a ‘driver’ lesion, rather treatment response is associated with regression of a ‘treatment sensitive’ subclonal population, defined by deletion of the EMT master regulator SNAI2. The extent of treatment response observed was determined by the prevalence of cells with loss of SNAI2 in pre-treatment biopsies. Conclusions: Cell plasticity with transition to a mesenchymal phenotype defines prostate cancer cell survival to acute AR signalling inhibition. Tumour response is determined by the proportion of cells present harbouring defects in this program.
Ability of the combined clinical cell-cycle risk score to identify patients that benefit from multi versus single modality therapy in NCCN intermediate and high-risk prostate cancer.
Authors: Tward Jonathan David , Schlomm Thorsten , Bardot Stephen , Freedland Stephen J. , Lenz Lauren , Cohen Todd , Stone Steven , Bishoff Jay
Published: February 2020

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Background: Prolaris combines RNA expression analysis of cell cycle progression genes with clinicopathologic information to create a combined clinical cell-cycle risk score (CCR). We evaluated the ability of CCR to predict metastasis (mets) in men for whom guidelines indicate that multimodality therapy (MTx) should be considered. Methods: A commercial cohort (N=15669) of National Comprehensive Cancer Network unfavorable intermediate-risk (UFI) and high-risk (HR) men revealed a distribution of 70.5% and 29.5% respectively. A CCR threshold of 2.112 was selected so that 29.5% of these men were above the threshold. MTx was defined as combined use of androgen deprivation therapy with radiation (RT) or surgery, or with adjuvant RT. Associations were evaluated in a 718-person retrospective, multi-institutional database of Prolaris-tested UFI and HR men. Kaplan-Meier (KM) analyses and Cox regressions were used to estimate the effects of prognostic covariates. Results: Median follow-up was 5.13 years. CCR predicted mets in the full cohort (HR =3.8 [2.7,5.2], p<10−15) and after accounting for CAPRA (HR=4.3 [2.7,7.0], p< 10−7). CCR also was a significant predictor of mets in patients who received STx, as a continuous predictor (HR=4.0 [2.6,6.1], p<10−9) and when dichotomized at the threshold (HR=15.9 [5.4,46.5], p< 10−9). The KM probability of mets by 10 years for those below and above the threshold was 4.3% and 20.4% respectively. MTx reduced patients’ risk of mets (HR=0.46 [0.22,0.97], p=0.04), and treatment benefit can be evaluated as a function of CCR score (Table). Conclusions: The CCR score prognosticates a clinically meaningful different risk of metastasis for those receiving MTx versus STx. Approximately 27% and 73% of people with HR or UFI risk cancer have CCR scores below the risk threshold and may consider STx after considering the difference in risk of mets.[Table: see text]