bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is PI-RADS 3/total lesion ratio associated with clinically-significant prostate cancer in patients with equivocal-risk lesions on multi-parametric MRI?
Authors: Ghabili Kamyar , Swallow Matthew , Suarez-Sarmiento Alfredo , Syed Jamil , Leapman Michael , Weinreb Jeffrey , Sprenkle Preston 
Published: February 2018

149 Background: Prostate imaging reporting and data system (PI-RADS) category 3 (P3) provides an equivocal assessment of prostate cancer (PCa). We aimed to investigate imaging parameters including the ratio of P3-to-total regions of interest (ROI) that may assist in identifying P3 lesions harboring clinically-significant PCa (csPCa). Methods: We retrospectively queried our institutional MRI-ultrasound fusion biopsy database to identify patients without a prior diagnosis of PCa and with at least one P3 lesion on multi-parametric MRI (mpMRI) who underwent fusion biopsy during Feb 2015-Oct 2017. mpMRI findings were assessed, including prostate and P3 volumes, number of ROIs, and P3-to-total ROIs ratio (P3 lesion volume/total ROIs volumes). Logistic regression and area under the curve (AUC) were used to assess the ability of clinical and mpMRI characteristics to predict csPCa, defined as any grade group (GG)≥2 cancer or GG 1 cancer in > 2 cores or > 50% of any positive core from targeted biopsy of the P3 lesion. Results: Of 127 men with at least one P3 lesion, 29 (22.8%) had csPCa on the biopsy of P3 lesions. Patients with csPCa in P3 lesions had smaller prostate volumes (42.1mL vs 56mL, p = 0.003), lower P3/total ROIs ratios (0.46 vs 1.00, p < 0.001), and higher numbers of total ROIs (2 vs 1, p = 0.004). Compared with patients who had a P3/total ROIs ratio > 0.58, men with ratios < 0.58 were more likely to be diagnosed with csPCa in a P3 lesion (57.1% vs 9%, p < 0.001). Using a threshold of 0.58, P3/total ROIs ratio was 76.1% sensitive and 80.6% specific for csPCa in a P3 lesion. On multivariate analysis, smaller prostate volume (OR1.04, 95%CI 1.01-1.07, p = 0.01) and lower P3/total ROIs ratio (OR1.04, 95%CI 1.02-1.07, p = 0.003) were associated with an increased risk of csPCa in P3 lesions. P3/total ROIs ratio (AUC 0.73) and prostate volume (AUC 0.70) were superior to PSA density (AUC 0.65) for the prediction of csPCa in P3 lesions. Conclusions: Our data indicated that prostate volume and P3/total ROIs ratio outperformed PSA density in and were associated with detecting csPCa in P3 lesions. P3/total ROIs ratio could be used to avoid 80.6% of unnecessary biopsies of a P3 lesion in men with multiple ROIs.
Definitive radiation therapy and survival in clinically node-positive prostate cancer.
Authors: Alex Bryant , Kader A. Karim , McKay Rana R. , Einck John Paul , Mell Loren K. , Mundt Arno James , Kane Christopher J. , Efstathiou Jason A. , Murphy James Don , Rose Brent Shane 
Published: February 2018

168 Background: The survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared to ADT alone for clinically lymph node-positive prostate cancer remains controversial. Methods: We identified clinically node-positive, non-metastatic prostate cancer patients diagnosed between 2000-2015 and treated with ADT (n = 450) or ADT/RT (n = 198) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable Cox regression, controlling for potential confounders. All tests of statistical significance were two sided. Results: Compared to ADT alone, ADT/RT was associated with improved ACM (hazard ratio [HR]: 0.56, 95% CI 0.41-0.76, p < 0.001) and PCSM overall (HR 0.65, 95% CI 0.43-0.97, p = 0.03). We noted a significant interaction between ADT/RT and pre-treatment PSA for PCSM (p for interaction = 0.005) and ACM (p for interaction < 0.001). ADT/RT was associated with improved PCSM among patients with PSA less than (HR 0.43, 95% CI 0.24-0.78, p = 0.004) but not greater than the median of 26 ng/mL (HR 1.01, 95% CI 0.60-1.71, p = 0.96). ADT/RT was also associated with improved ACM among patients with PSA less than (HR 0.38, 95% CI 0.25-0.57, p < 0.001) but not greater than the median (HR 0.91, 95% CI 0.60-1.38, p = 0.66). Conclusions: Definitive treatment with ADT/RT is associated with improved ACM and PCSM among patients with clinically node-positive prostate cancer. The survival benefit of ADT/RT is only apparent among patients with lower baseline PSA. Patients with clinically node-positive disease appear to be a heterogeneous cohort, with a subset that may achieve long-term survival with combined radiation and androgen deprivation therapy.
DNA repair gene panel mutations in young onset prostate cancer cases in the.
Authors: Eeles Ros A. , Leongamornlert Daniel , Saunders Ed , Wakerell Sarah , Whitmore Ian , Dadaev Tokhir , Borrella Clara Cieza , Govindasami Koveela , Brook Mark , Lophatananon Artitaya , Muir Kenneth , Conti David V , Kote-Jarai Zsofia 
Published: February 2018

18 Background: Prostate cancer (PrCa) is the most common solid tumour in men in the Western world. There is substantial evidence that PrCa predisposition is due both to common and rare germline variation. Methods: We screened 167 genes from DNA damage response and repair pathways, within a UK based cohort of young onset cases (diagnosed at < 65 years) and controls. Samples were sequenced using a custom Agilent SureSelectXT bait library and Illumina HiSeq technology and processed using a BWA/GATK 2.8 pipeline. Following sample QC, data were analysed from 1,285 PrCa cases and 1,163 controls. Results: We identified 5,086 single nucleotide variants (SNVs) and 175 indels; 233 unique protein truncating variants (PTVs) with MAF < 0.5% in controls were found in 97 genes of the screening panel. The total proportion of PTV carriers in cases was higher than in controls (14.5% vs. 11.6%, P = 0.036; OR = 1.29, 95% CI 1.01-1.64). This enrichment was greater within the previously reported BROCA gene set of 22 tumour suppressor genes (4.5% vs 2.2%, P = 2.5x10-3; OR = 2.07, 95% CI 1.28-3.34). To identify genes which best to distinguish PrCa cases from controls, we applied the adaptive combination of P values algorithm, ADA, for genes with at least 2 carriers of PTVs. This analysis selected 10 genes, (OR = 3.37, 95% CI 2.05-5.66, PADA= 5.99x10-3); men with PTVs in these were about 3.4-fold more likely to have PrCa (5.8% vs. 1.8%). We subsequently compared aggressive cases (Gleason score ≥ 8, n = 204) with non-aggressive cases (Gleason score ≤ 7, n = 1049) and lethal PrCa cases (cause of death PrCa, n = 183) with indolent cases (Gleason score ≤ 6, n = 563) to evaluate genes associated with poor clinical prognosis. Using ADA, 4 genes were selected for aggressive PrCa ( PADA= 0.006) and 2 of these also for lethal PrCa ( PADA= 0.057). Conclusions: These gene sets provide an 11 gene panel which could be used for clinical testing and will help to facilitate the development of a PrCa specific sequencing panel with both predictive and prognostic potential.
Abiraterone acetate (AA) plus prednisone (P) 5 mg QD in metastatic castration-naïve prostate cancer (mCNPC): Detailed safety analyses from the LATITUDE phase 3 trial.
Authors: Fizazi Karim , Tran Namphuong , Fein Luis Enrique , Matsubara Nobuaki , Bjartell Anders , Galli Luca , Lee Jae-Lyun , Mazhar Danish , North Scott A. , Olmos David , Suttmann Henrik , Zou Qing , Li Susan , Martin Jason L. , Park Youn C. , Sulur Giri , Deprince Kris , De Porre Peter , Chi Kim N. 
Published: February 2018

182 Background: AA + P added to androgen deprivation therapy (ADT) improves overall survival (OS) in newly diagnosed mCNPC patients (pts). AA has been previously coadministered with P (10 mg QD). As a lower dose of P (5 mg QD) was used in LATITUDE, we conducted additional safety analyses. Methods: 1199 pts with newly diagnosed, high-risk mCNPC (≥ 2 of 3 risk factors: Gleason ≥ 8, ≥ 3 bone lesions, visceral metastases) were randomized 1:1 to AA (1 gm QD) + P (5 mg QD) + ADT or placebos (PBOs) of AA and P + ADT: median treatment duration 24 and 14 mo, respectively. Safety analyses focused on key mineralocorticoid excess (ME)-related adverse events (AEs): hypertension (HTN) and hypokalemia. Results: Increased HTN with 5 mg/d P with AA + ADT (relative risk, 1.6 [95% CI, 1.4-1.9]) was similar to prior studies using 10 mg/d P (COU-AA-301: 1.4 [0.9-2.0]; COU-AA-302: 1.6 [1.2-2.1]). Of Gr 3/4 HTN events, 87% (109/126 [AA + P + ADT]) and 83% (52/63 [PBOs + ADT]) resolved to Gr ≤ 2. There were few cerebrovascular events: AA + P + ADT, 5; PBOs + ADT, 9. The protocol allowed increasing dose of P to 10 mg for ME-related AEs, but most Gr 3/4 HTN events were managed only by supplemental antihypertensives. Prior use of antihypertensives at study entry was predictive of Gr 3/4 HTN in both treatment arms (RR: 1.85; 95% CI, 1.14-3.01). Gr 3/4 hypokalemia increased with AA + P + ADT (10.4% [62/597]) vs PBOs + ADT (1.3% [8/602]); 89% (55/62) and 100% (8/8) of these events improved to Gr ≤ 2. Less than 1% of pts in either arm discontinued therapy for ME-related AEs. Conclusions: In-depth analysis of LATITUDE data confirms the safety of 5 mg/d P with AA + ADT and helps provide practical treatment guidance for managing mCNPC. Clinical trial information: NCT01715285. [Table: see text]
Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy.
Authors: Yokomizo Yumiko , Hayashi Narihiko , Takizawa Akitoshi , Kobayashi Kazuki , Ohta Jun-ichi , Kitami Kazuo , Kishida Takeshi , Tsuchiya Futoshi , Yao Masahiro , Uemura Hiroji 
Published: February 2018

183 Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.
Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer (mPC).
Authors: Zhang Tian , Austin Rebecca Garland , Park Sally E , Runyambo Daniella , Boominathan Rengasamy , Rao Chandra , Bronson Elizabeth , Anand Monika , Healy Patrick , George Daniel J. , McNamara Megan Ann , Armstrong Andrew J. 
Published: February 2018

191 Background: Most immune checkpoint inhibitors have shown limited efficacy in unselected men with mPC, and there is limited understanding about which immune checkpoints (ICs) are relevant in mPC. We evaluated ICs on the cell surface of circulating tumor cells (CTCs) in patients with mPC. Methods: Patients were enrolled prospectively at the Duke Cancer Center in three cohorts: A) mCRPC starting the novel androgen receptor inhibitors abiraterone acetate (AA) or enza with or without sipuleucel-T, B) mCRPC with disease progression after AA or enza, and C) metastatic castration sensitive PC. The Cellsearch platform was used to capture EpCAM- and CK-expressing CTCs and analyzed for PD-L1, PD-L2, B7-H3, and CTLA-4 expression at baseline, 12 weeks, and at further disease progression. Results: Through August 2017, we enrolled 4 subjects in cohort A, 7 in cohort B, and 3 in cohort C. CTCs were detectable in every cohort. At baseline, B7-H3 was the most prevalent IC on a per-patient basis (mean 96% in cohort A, and 100% in cohort B, and 88% in cohort C). PD-L1 was detected less frequently (cohort A mean 8%, cohort B mean 42%, and cohort C mean 67%), with evidence of heterogeneity of CTC PD-L1 expression between and within patients. PD-L1 was expressed on 8% of CTCs in cohort C and cohort A, as compared to 28% of CTCs in cohort B, while CTLA-4 expression was not identified in cohort C, 3% of cohort A, and 15% of cohort B. B7H3 was expressed on 68% of cohort C, 91% of cohort A, and 98% of cohort B. PD-L2 was expressed on 0-7% of CTCs overall. Conclusions: Patients with mPC can have detectable and heterogeneous ICs on CTCs, particularly PD-L1 and B7-H3, and these characteristics can be monitored over time. B7-H3 was the most prevalent IC on CTCs, regardless of disease state. Our preliminary data suggests that men with mCRPC post-enza/AA have higher levels of PD-L1 and CTLA-4 expression on their CTCs as compared with men with mHSPC and mCRPC prior to enza/AA. Patient enrollment and analysis are ongoing.
Tumor fraction in circulating free DNA as a biomarker of disease dynamics in metastatic prostate cancer.
Authors: Choudhury Atish Dipankar , Werner Lillian , Ha Gavin , Freeman Samuel , Rhoades Justin , Reed Sarah , Gydush Greg , Rotem Denisse , Lo Christopher , Taplin Mary-Ellen , Harshman Lauren Christine , Zhang Zhenwei , O'Connor Edward P , Boehm Jesse , Getz Gad , Meyerson Matthew , Love J. Christopher , Hahn William C. , Adalsteinsson Viktor 
Published: February 2018

195 Background: Quantification of circulating free DNA (cfDNA) has been proposed both as a prognostic biomarker and as a biomarker of response and resistance to therapy. However, dynamics of cfDNA derived from both tumor and non-cancerous tissues through dense longitudinal monitoring over the course of treatment with multiple therapeutic modalities have not been well described. Methods: CfDNA isolated from banked and prospectively collected plasma samples from pts with metastatic castration-resistant prostate cancer (mCRPC) was subject to ultra-low pass (~0.1x coverage) whole genome sequencing (ULP-WGS). The fraction of cfDNA derived from tumor rather than non-cancerous tissues (i.e. the tumor fraction, or TFx) in each sample was estimated using a novel computational tool called ichorCNA, and was correlated with clinical features and response to therapy. Results: 663 plasma samples from 140 pts were included (median 3 samples/pt; range 1-20). TFx was correlated with the number of bone metastases (median TFx = 0.014 with no bone mets, 0.047 with 1-3, 0.190 for 4+), and with the presence of distant visceral mets (p < 0.0001). In multi-variate analysis, TFx was positively correlated with Alk Phos (p = 0.0227) and negatively correlated with Hgb (p < 0.001), but was not correlated with PSA (p = 0.75). All new treatment starts leading to > = 30% PSA decline at > = 6 weeks were associated with a decline in TFx from baseline when baseline TFx was > 7% (median TFx change -92.2%, range -70.3% to -100%); however, TFx in patients being subsequently maintained on secondary hormonal therapy without radiographic progression was quite dynamic. The total yield of cfDNA derived from both tumor and non-cancerous tissues tracked closely with TFx, and did not markedly change with initiation of therapies expected to lead to generalized tissue damage, such as chemotherapy and radiation, over the time scales examined. Conclusions: Decline in TFx is a promising biomarker for initial response to therapy, but subsequent temporary rises in TFx do not necessarily indicate the cessation of clinical benefit from secondary hormonal therapies. Analysis of cfDNA may allow a window into short-term tumor dynamics not easily assayed through other methods.
Hepatic effects assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials.
Authors: Beer Tomasz M. , Chowdhury Simon , Saad Fred , Shore Neal D. , Higano Celestia S. , Iversen Peter , Fizazi Karim , Miller Kurt , Heidenreich Axel , Kim Choung Soo , Phung De , Barrus Jeffrey Kent , Nikolayeva Natalia , Krivoshik Andrew , Waksman Javier , Tombal Bertrand F. 
Published: February 2018

199 Background: Androgen receptor inhibitor enzalutamide (ENZA) improves survival in patients with metastatic CRPC. As the liver is the main route of ENZA elimination, this post hoc analysis evaluated the hepatic effects of ENZA versus comparators in controlled CRPC trials. Methods: Safety data from two large Phase 3, placebo (PBO)- (PREVAIL, NCT0121299; AFFIRM, NCT00974311) and two smaller Phase 2, bicalutamide (BIC)-controlled (STRIVE, NCT01664923; TERRAIN, NCT01288911) ENZA trials in men with CRPC were assessed for hepatic impairment-related adverse events (AEs) using the following standardized narrow MedDRA queries V19.1: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, non-infectious; and liver-related investigation, signs, and symptoms. Liver-related laboratory test results were also evaluated. Data were summarized as follows: patients receiving ENZA in Phase 3 trials (n = 1671); patients receiving ENZA in Phase 2 trials (n = 380); patients receiving PBO (n = 1243); patients receiving BIC (n = 387); and combined ENZA-treated patients (n = 2051). Results: Percentages of hepatic impairment-related AEs ranged between 2.9% and 4.5% with ENZA, and were 2.7% with PBO and 5.4% with BIC (Table). The most common hepatic impairment-related AEs were increased aspartate (AST) and alanine aminotransferase (ALT; Table). Within each trial, the incidences of grade ≥3 AEs were similar, and dose reductions or discontinuations due to hepatic impairment-related AEs were low (Table). When adjusted for treatment exposure, AEs per 100 patient-years were lower with ENZA versus either PBO or BIC (Table). Conclusions: This combined analysis of CRPC trials demonstrates no hepatic safety signal with ENZA and thus routine liver tests are not required. Clinical trial information: NCT0121299; NCT00974311; NCT01664923; NCT01288911. [Table: see text]
Clinical experience with 100 consecutive patients treated with Lu-177-labeled PSMA-I&T radioligand therapy for metastatic castration-resistant prostate cancer.
Authors: Heck Matthias Michael , Schwaiger Sebastian , Knorr Karina , Retz Margitta , Maurer Tobias , Janssen Friederike , D´Alessandria Calogero , Wester Hans-Juergen , Gschwend Juergen E. , Schwaiger Markus , Tauber Robert , Eiber Matthias 
Published: February 2018

206 Background: To report our clinical experience with 177Lutetium-labeled prostate-specific membrane antigen-ligand (177Lu-PSMA-I&T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: All patients were treated under a review board-approved compassionate use protocol. Eligibility criteria for 177Lu-PSMA-I&T therapy included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or unsuitability for taxanes as well as positive 68Ga-PSMA tracer uptake of metastases in a prior PET-scan. Intravenous treatment with 177Lu-PSMA-I&T was given 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles in patients without clinical or radiographic progression. We report prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS) and overall survival (OS) as well as toxicity. Results: Median age was 72 years (range 46-85) and median PSA level was 164 ng/ml (range 0-6178). Bone, lymph node and visceral metastases were present in 94%, 85% and 33% of patients, respectively. The median number of previous treatment regimens for mCRPC was 3 (range 1-6) and 84% of patients were pretreated with chemotherapy. At the time of evaluation, 286 cycles with 177Lu-PSMA-I&T were applied (median 2 cycles per patient, range 1-6), while treatment was still ongoing in 27% of patients. Overall, 4 and 6 cycles were applied in 33 and 15 patients, respectively. PSA decline ≥30%, ≥50% and ≥90% was achieved in 40%, 32% and 9% of patients, respectively. Median PSA-PFS was 3.4 months (95%CI 2.7-4.0), median cPFS was 4.1 months (95%CI 2.5-5.7) and median OS was 12.2 months (95%CI 8.8-15.7). Treatment-emergent hematologic grade 3/4 toxicities were anemia in 7%, thrombocytopenia in 5% and neutropenia in 4% of patients. Grade 3/4-non-hematologic toxicities were not observed. The main non-hematologic grade 1/2 toxicities were dry mouth in 18%, fatigue in 16% and loss of appetite in 9/% of patients. Conclusions: Radioligand therapy with 177Lu-PSMA I&T appears to be safe and active in late-stage mCRPC.
Occurrence of pathologic stage T3 disease at radical prostatectomy with isup grade group 1 (Gleason 3+3=6) prostate cancer.
Authors: Greenwald David Theodore , Wang Alice Y. , Huang Jason , Wadhwa Harpreet , Nimeh Tony , Cohen Justin J. , Yonover Paul 
Published: February 2018

21 Background: Treatment of ISUP Grade Group 1 (Gleason 3+3 = 6) disease continues to evolve in the modern era. We examined our surgical database to investigate patterns of behavior in this pathologic subset. Methods: We reviewed the results of 1127 consecutive radical prostatectomies performed by our surgeons from 2012−2015 at various community and academic medical centers in Chicagoland. Specifically, we examined the ISUP Grade Group 1 (Gleason 3+3 = 6) patients in our database, 314 patients overall. Results: A review of our database revealed that of ISUP Grade Group 1 (Gleason 3+3 = 6) patients (n = 314), only 3.82% had pT3 disease (11 patients stage pT3a and 1 stage pT3b). The only patient of these 12 to have lymphovascular invasion (LVI) was the singular pT3b patient. Overall, ISUP Grade Group 1 (Gleason 3+3 = 6) pT3 disease represents only 1.06% of all prostatectomies in our database. Conclusions: In our large prostatectomy cohort, ISUP Grade Group 1 (Gleason 3+3 = 6) prostate cancer was rarely associated with extra−prostatic extension (pT3) or lymphovascular invasion (LVI), suggesting that it has very low metastatic potential. These findings give further support to the trend of increased utilization of active surveillance for low risk prostate cancer.