bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary resistance in docetaxel and androgen deprivation therapy in metastatic castrate sensitive prostate cancer patients.
Authors: Pouptsis Athanasios , Germanou Styliani , Waldron Nick , Young Thomas , Khan Madeha , Hughes Simon , Josephs Debra Hannah , Rudman Sarah Maria , Enting Deborah , Chowdhury Simon 
Published: February 2018

342 Background: Docetaxel chemotherapy combined with androgen deprivation therapy (ADT) has become the new standard of care in patients with metastatic castrate sensitive prostate cancer as it has shown significant benefit in terms of overall survival (OS) and response rates (Sweeney 2015, James 2016). However a subgroup of patients still experience early progression. Methods: We searched the hospital database for patients treated with docetaxel in the castrate sensitive setting. Eligible patients included those with newly diagnosed metastatic prostate adenocarcinoma and also patients with relapsed metastatic disease post radical radiotherapy or radical prostatectomy. Patients starting chemotherapy > 12 weeks after commencing ADT were excluded. Results: We identified 72 patients treated with docetaxel and ADT between August 2014 and September 2017. The median age was 66 years (49-84 years). Of the 72 patients, 63 (88%) had bone metastases, 5 (7%) had visceral metastases and 45 (63%) had pelvic lymph node disease. Seven patients (9.7%) had relapsed metastatic disease post radical treatment. All patients had ≤6 cycles of docetaxel. Median time from diagnosis of metastatic disease to commencing castrate resistant treatment was 13 months (2-41 months). Median duration of follow-up was 16 months (5-39 months). Six patients (8%) had biochemical, radiological or clinical progression during, or at completion of docetaxel chemotherapy. One patient terminated treatment before completion of six cycles due to disease progression. The median presenting PSA in this group was 49.5 ug/L (9.04-2290 ug/L) and 2 patients had visceral disease. Of these 6 patients, 2 have died, and the median OS for the group was 11.5 months (8-22 months). Five patients were subsequently treated with enzalutamide and 1 with abiraterone. Conclusions: Despite the improvement in OS and response rates with the use of early docetaxel, a clinically significant number of patients developed disease progression during treatment, and these patients have a particularly poor prognosis. These patients should be the focus of future clinical trials.
Clinical experience with PSMA-Actinium-225 (Ac-225) radioligand therapy (RLT) in end-stage metastatic castration-resistant prostate cancer (mCRPC) patients.
Authors: van der Doelen Maarten Johannes , Mehra Niven , Smits Minke , van Oort Inge M. , Janssen Marcel J.R. , Haberkorn Uwe , Kratochwil Clemens , Gerritsen Winald 
Published: February 2018

344 Background: Prostate-specific membrane antigen (PSMA) is an ideal target for RLT in mCRPC patients (pts). Alpha-emitting radioisotope Actinium-225 (Ac-225) may be more efficacious than beta-emitting Lutetium-177, due to higher rates of double-strand DNA breaks in prostate cancer cells, with less tissue penetration and minimal bystander effects in PSMA-negative cells. Limited data is available on the clinical efficacy and side effects of PSMA-Ac-225 RLT in mCRPC pts. Here we describe our clinical experience so far. Methods: Between February 2016 and October 2017, 11 pts underwent PSMA-Ac-225 RLT in Heidelberg, Germany. Prostate-specific antigen (PSA) responses were measured every two weeks. Pts underwent PSMA PET/CT prior to and after RLT. Consenting pts had tissue and blood collected for translational biomarker studies, including targeted-next generation sequencing and whole genome sequencing to discover biomarkers and mechanisms of RLT resistance. In addition, pts received structured questionnaires on quality of life and xerostomia evaluation. Results: All pts were heavily pre-treated, with a median of four therapies prior to PSMA-Ac-225 RLT. Pts underwent a median of three RLT cycles (range 1-4 cycles) of median 8 MBq (range 6-10 MBq). Five pts (45%) had died at time of analysis. Median overall survival since start of RLT was 12.6 months (95% CI 5.0-20.1). Median baseline PSA was 878 µg/L (range 6-2249). Eight of eleven pts had > 50% PSA response, with median change in PSA reduction of 87%. Six pts were evaluable according to PCWG3 criteria with 5/6 (83%) pts showing partial responses, and one patient with stable disease following RLT. No grade 3-4 hematologic toxicity occurred. Grade 2-3 xerostomia was mentioned by all pts. Pts with features of neuro-endocrine prostate cancer (NEPC) showed less response to RLT, with blood-based NEPC biomarkers increasing during RLT. Conclusions: PSMA-Ac-225 RLT resulted in remarkable clinical, biochemical and radiological responses in end-stage mCRPC pts, and may be considered a promising therapy for mCRPC pts.
Are prostate cancer treatments correlated to sleep distress?
Authors: Mitteldorf Darryl , Nelms Jerrod 
Published: February 2018

347 Background: Sleep distress associated with prostate cancer due to emotional issues like anxiety is well documented. But there have been no investigations focused on sleep distress correlated to specific types of prostate cancer treatments. Methods: During a ten day period in July, 2016, 963 men diagnosed with prostate cancer completed an online survey containing demographic and treatment history questions, the Pittsburg Sleep Quality Index (PSQI) and a current state of health self-assessment. The subjects were randomly chosen from the Malecare prostate cancer support network in the United States and completed the survey. 27% of survey subjects reported being initially diagnosed with Gleason 8 or higher. 42% reported using either androgen deprivation therapy, Zofigo, Xtandi or Xofigo within three months of our survey. Only 5% had been continually on active surveillance. We compiled the PSQI Component score and correlated the scores to a specific prostate cancer treatments, adjudicating for pre-existing conditions such as emotional disorders or apnea. We stratified for race, age, sexual orientation and if the subject had a sleep partner. Results: The PSQI handout says that a total score of 5 or greater indicates sleep distress worthy of consultation with a healthcare provider. Our investigation also considered a “4” to indicate poor sleep quality among participants. Only 398 (41.33%) of our participants scored less than 5 on the PSQI, while only 232 (24.09%) scored less than 4. From these statistics, we showed that over 75% of our study sample suffered sleep distress. However, our analysis failed to disclose significant correlations between specific types of prostate cancer treatments and extent of sleep distress. We did not see correlations regarding subject’s age, race, sleep co-habitation, time from diagnosis to survey and other treatment and demographic stratifications. Conclusions: Sleep distress is well established and broadly experienced by prostate cancer patients. Our study showed there is no advantage to any specific prostate cancer treatment in terms of sleep distress. We also found that severity and instances of sleep distress are distributed without significance across age, race, sexual orientation and time to treatment after diagnosis.
Disseminated intravascular coagulation secondary to advanced prostate cancer: Clinical characteristics, management, and prognosis.
Authors: Ni Benny , Wang Jue 
Published: February 2018

355 Background: Although disseminated intravascular coagulation (DIC) is a recognized complication of prostate cancer, little is known about the clinical features and optimal management of these patients. Although anecdotal case studies indicating that the prognosis of prostate cancer associated with DIC might improve with chemotherapy, the clinical data from single case report are far from sufficient for establishment of a standardized treatment strategy. The main objective of this study was to determine the clinical features, treatment and prognosis clinical outcome of patients with prostate cancer complicated by DIC. Methods: We conducted a pooled analysis of 85 prostate cancer patients diagnosed with DIC, two treated in our institution and 83 patients from published literature between January 1976 and June 2017. Results: Eighty-five patients were included in final analysis. The median age was 68 years (range, 44 to 92 years). The majority of patients (98%) has adenocarcinoma. Two (2%) patients with small cell carcinoma. The median of PSA was 614 ng/ml (range: 0.8 – 8138). A Gleason score of 8 or higher was found in 67% of patients. Distant metastasis was reported in 98% of patients. At diagnosis of DIC, the median platelet count was 75 *109 /L (range: 3-205). Regarding the presenting symptoms of DIC, subcutaneous bleeding was reported in 64% of cases; hematuria in 27%. Invasive procedure including prostate biopsy might have been the provoking events of DIC in 25% of the cases. Seventy-one patients received cancer directed therapy including various androgen deprivation, chemotherapy, and novel androgen signaling inhibitor, whereas 13 patients received only best supportive care (BSC). The median overall survival (OS) of the entire cohort of patients was 10 months (95% confidence interval [CI], 5.3-14.7). Significantly prolonged OS was observed in the cancer therapy group, with a median survival of 12 months compared to 2 weeks in the BSC group (p < 0.001, log-rank test). Conclusions: Our analysis showed that patients with prostate cancer complicated by DIC had very poor prognosis, and active cancer therapy might improve OS of these patients.
Treatment outcome of everolimus against neuroendocrine prostate cancer (NEPC).
Authors: Shimomura Tatsuya , Kurauchi Takashi , Sakanaka Keigo , Egawa Shin 
Published: February 2018

365 Background: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection. The treatment strategy against NEPC is not yet established. Some clinical trials are ongoing now. Recently, clinical trial (RADIIANT4) showed that treatment with everolimus was associated with significant improvement in survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. And FDA approved new indication for everolimus for progressive, nonfunctional GI and lung neuroendocrine tumors last year. In this study we tried to introduce everolimus against pathologically proven NEPC and investigated the clinical outcomes of this agent. Methods: Total of seven cases were included in this study. All cases were proven the existence of neuroendocrine prostate cancer pathologically. Everolimus (10mg/d) were introduced into all cases. We investigated the neuroendocrine tumor markers (neuron-specific enolase: NSE, and pro-gastrin-releasing peptide: pro GRP), radiologic examination and survival. Results: The median follow up period was 6 months. At least one of the tumor markers increased above normal limit in all cases. NSE increased in four cases, pro GRP increased in five cases and both markers increased in two cases. Tumor markers decreased in five of seven (71.4%) cases (NSE: 2 of 4 cases, pro GRP: 4 of 5 cases) after introduction of everolimus. Median decreasing rate were 67.1% in NSE and 65.5% in pro GRP. Two of seven (28.6%) cases progressed in radiologic examination and died from prostate cancer. One case was very advanced disease and everolimus was introduced after failure of systemic chemotherapy (CDDP + etoposide). Another case was advanced disease with bone marrow carcinomatosis. In terms of adverse event, 4 cases had stomatitis and one case had hyperglycemia. Conclusions: In this study, evelolimus showed efficacy against NEPC. It decreased tumor markers and stabilized the tumor status. Although this study was retrospective and number of cases was limited, there is a possibility that evelolimus would be a one of the treatment options against NEPC.
Prognostic and predictive role of CTCs and AR-V7+ CTCs expression in metastatic catrate resistant prostate cancer (mCRPC): A feasibility study.
Authors: Maruzzo Marco , Rossi Elisabetta , Basso Umberto , Facchinetti Antonella , Anile Giuseppe , Pierantoni Francesco , Galuppo Sara , Evangelista Laura , Pizzirani Enrico , Zamarchi Rita , Zagonel Vittorina 
Published: February 2018

367 Background: Circulating tumor cells (CTC) counts ≥ 5/7.5 mL predict shorter survival in patients (pts) with mCRPC. Moreover, the presence of androgen receptor splice variant-7 mRNA (AR-V7) in CTCs is thought to play a relevant role in the development of primary or acquired resistance to enzalutamide (E) or abiraterone (A). We developed a new immunofluorescence-based assay for AR-V7+ CTCs and tested its association with PFS and OS. Methods: We performed a single-centre observational prospective trial enrolling pts with mCRPC candidate to receive E or A. CTC samples have been collected at baseline, after 1 month (mo) and every 3 mos thereafter until progression or at 12 mos without progression. CTCs have been enumerated with CellSearch System. We integrated the standard assay with a mAb able to recognize the AR-V7 protein. Slides from samples underwent automated immunofluorescent staining and AR-V7+ CTCs were enumerated. Results: Since Sep 2016, 31 pts have been enrolled (Table). We compared CTC counts between standard and the integrated assay and found no differences in the mean total CTC number ± (Wilcoxon Signed Rank test, p= 0.31). 16 out of 28 evaluable pts (57%) had ≥ 1 CTCs at baseline, 9 pts (32%) had ≥ 5 CTCs/7.5 ml, 4 pts (14.3%) were AR-V7+ before any exposure to A or E. After a median follow-up time of 8.1 mos, 6 pts have progressed and 4 died. No association has been found between CTCs ≥ 5/7.5 mL and survival. The presence of at least 1 AR-V7+ CTC at baseline did not correlate with PSA response, but had a weak association with shorter PFS (log-rank test, p = 0.055) and a significant impact (p = 0.02) on OS. Conclusions: We developed a new integrated assay for AR-V7+ CTCs, based on an automated platform that permits serial sampling with low inter- / intra-test variability. The clinical utility in anticipating the resistance to E or A is under study. [Table: see text]
Germline pathologic mutations and cancer family history in prostate cancer patients.
Authors: Moses Marcus Marie , Ledet Elisa , Ernst Emma M. , Cotogno Patrick , Schiff Joshua , Lewis Brian E. , Sartor A. Oliver 
Published: February 2018

378 Background: Prostate cancer (PCa) patients (pts) with metastases and/or strong family history (FH) of cancer (Ca) are at higher risk of a germline mutation. The identification of alterations in PCa pts may be important for risk stratification as well as personalizing treatment options. The goal of this study was characterization of FH and pathogenic variants (PV) detected in PCa pts, with both localized and metastatic disease. Methods: 300 PCa pts from Tulane Cancer Center underwent germline testing. 265 Caucasian (C) and 35 African-Americans (AA) were tested and met the NCCN criteria for testing and/or had distant metastases (mets). Germline genetic testing was done via commercial panels (30-80 genes) (Invitae. San Francisco, Ca). PCa pts had extensive FH screening. Clinical annotation included age at diagnosis (dx), race, and presence of mets at any time. Chi square tests were used to compare clinical correlates and PVs. Results: Of the 300 pts tested, 182 pts (60.6%) had mets and 118 (39.4%) did not. 41 pts (13.6%) had ≥ 1 germline pathogenic variant (PV) and 161 pts (53.6%) had ≥ 1 germline variant of uncertain significance (VUS). PVs were detected in BRCA2 (n = 10), MUTYH (n = 8), CHEK2 (n = 6), BRCA1 (n = 4), ATM (n = 4), TP53 (n = 3), PMS2 (n = 2), BLM (n = 2), MITF (n = 2), NBN (n = 1), and RAD51D (n = 1). MUTYH and MITF are not known to be linked to prostate cancer. There was no significant relationships in FH PCa and FH non-PCa in regard to likelihood of a PV (p = .86 and p = .18). Of the 300 pts tested, 136 pts (45.3%) had PCa FH, 131 pts (43.6%) had breast Ca FH, 61 pts (20.3%) had lung Ca FH, 61 pts (20.3%) had colon Ca FH, 37 pts (12.3%) had pancreatic Ca FH, and 32 pts (10.6%) had ovarian Ca FH. 45.6% of C men (n = 121) and 42.8% of AA men (n = 15) had PCa FH. Pts with a non-PCa FH (n = 255) were 1.37 times more likely to develop mets (p = .01168). The median age of dx were 61 for PV pts, 62 for VUS pts, and 61 for negative pts (non-significant). 21/182 pts with mets (11.5%) had a PV; 8/182 (4.4%) pts with mets had a BRCA2 PV. Conclusions: In metastatic patients, FH of prostate cancer alone cannot predict those with PV. The most common Cas observed in these pts were breast, lung, colon and pancreatic. A larger cohort is needed to fully characterize and understand the co-segregation of PCa with other Cas.
An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi , Snyder Lawrence B , Willard Ryan R , Vitale Nicholas , Raina Kanak , Pizzano Jennifer , Gordon Deborah A , Bookbinder Mark , Macaluso Jennifer , Dong Hanqing , Liu Zheng , Ferraro Caterina , Wang Gan , Wang Jing , Crews Craig M , Houston John , Crew Andrew P , Taylor Ian 
Published: February 2018

381 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC that leads to ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, DMPK, toxicology and preclinical efficacy studies. Results: This AR PROTAC completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. The AR PROTAC degrades all clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, the AR PROTAC demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.
Interim analysis of a prospective randomized trial of dietary carbohydrate restriction for men with a rising PSA after failed primary treatment: Carbohydrate and Prostate Study 2 (CAPS2).
Authors: Freedland Stephen J. , Allen Jenifer , Armstrong Andrew J. , Moul Judd W. , Sandler Howard M. , Levin Dana , Howard Lauren E. , Lin Pao-hwa 
Published: February 2018

382 Background: Nearly one third of men treated with curative intent for localized prostate cancer (PC) will develop a rising PSA. The rate of PSA rise (PSA doubling time aka PSASDT) is a predictor metastases and PC death. In laboratory mice, an extreme low carbohydrate diet slows PC growth. We tested whether this diet could slow PSADT in men with recurrent PC. Methods: We are conducting a 6-month multi-center randomized phase II trial of dietary carbohydrate restriction vs. no diet intervention control. Men had to have a BMI ≥24 kg/m2, received radical prostatectomy or definitive local radiation for PC, had a PSA 0.4-20.0 ng/ml (3-20 if prior radiation therapy) within the past 3 months, and current PSADT 3-36 months. The intervention arm was instructed to eat < 20 grams/carbs/day with no other limits. The control arm was told to make no diet. In this interim analysis, we present the efficacy of the dietary intervention with regards to weight loss. Arms were compared using rank-sum. Total anticipated enrollment is 60. The primary outcome is differences in PSADT between arms. Secondary outcomes include weight loss, and dietary make-up. Results: To date, 28 patients (14 in each study arm) have completed the study. Characteristics were well-balanced at baseline. At the 6-month dietary assessment, calorie consumption was similar between the two study arms (p = 0.090) among the 16 patients (7 low-carb, 9 control) with diet information. Subjects in the low-carb arm ate fewer carbs (29 vs. 188 g, p = 0.008) and more protein (125 vs. 73 g, p = 0.044) but similar amounts of fat (75 vs. 67 g, p = 0.672) vs. subjects in the control arm. Six months on the low carb diet resulted in greater weight loss (median: 31.7 vs. 0.8 lbs, p < 0.001), lower BMI (24.4 vs. 29.6 kg/m2, p < 0.001), and smaller waist circumference (95.7 vs. 108.9 cm, p = 0.002). Conclusions: In this interim analysis of an on-going dietary study for men with a rising PSA after definitive local treatment, an extreme low carbohydrate diet results in dramatic weight loss in 6 months. Whether this weight loss slows PC growth is an on-going question. Clinical trial information: NCT01763944.