bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate cancer cost-of-care and evaluation of traditional cost control measures.
Authors: Bansal Dhruv , Wong John 
Published: March 2019

163 Background: In the current era of rapid advances in cancer care, economic burden of these treatments is becoming increasingly apparent. Measures taken by Centers for Medicare & Medicaid Services (CMS) such as closely monitoring length of inpatient stay might be inadequate in their goal to curtail costs. SEER analysis shows a 5-year overall survival for prostate cancer of 98.2 % and incidence of 179.1 in 2000 versus 97.8 in 2015 per 100,000, respectively. This encouraging result comes at the cost of increasing healthcare costs. Methods: We used National Inpatient Sample (NIS) database to extract data for patients hospitalized with primary diagnosis of prostate cancer using ICD-9 code 185. The 15-year time from 2000 till 2014 was analyzed. The metrics focused on were mean length of stay (LOS), mean cost of hospitalization and rate of discharges. Results: Discharge rate was 32.2 +/- 1.3 in 2000 versus 20.4 +/- 0.8 in 2014 per 100,000, respectively. Mean LOS declined from 3.7 +/- 0.115 days in 2000 to 2.2 +/- 0.044 days in 2014. During this same time period mean hospitalization charges increased from $14,680 +/- 466 to $49,464 +/- 1,019. The average annual inflation rate during this time period was 2.26%. After adjusting for inflation, the cost of stay in 2000 was $20,072 versus $49,464 in 2014. This effect is magnified when analyzing the cost per day of hospitalization. Cost per day in 2000 was $5,424 versus $22,483 in 2014. Conclusions: The increase in cost of inpatient stay is likely due to the advances in multi-modality treatment in prostate cancer. With the aging population and focus on cost conscious allocation of resources, this increase in costs will remain a challenge for hospital decision makers and insurance companies. We have to apply models such as the Markov model that are increasingly used to justify exorbitant prices of individual drugs. Also, given the complexity of health care costs, more variables should be included to rationalize health care spending. Cost metrics such as LOS are out dated given costs of treatments will continue to exceed costs such as nursing care and room and board costs. These complex analyses might be feasible with advances in deep learning which enable consideration of multiple variables in the decision-making process.
Keynote-365 cohort C: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC).
Authors: Fong Peter C.C. , Retz Margitta , Drakaki Alexandra , Massard Christophe , Berry William R. , Romano Emanuela , De Bono Johann S. , Feyerabend Susan , Appleman Leonard Joseph , Conter Henry Jacob , Sridhar Srikala S. , Shore Neal D. , Linch Mark David , Joshua Anthony , Gurney Howard , Wu Haiyan , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y. 
Published: March 2019

171 Background: Pembro has antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). A study has suggested that pembro + enza after progression on enza may have clinical activity. KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort C combining pembro + enza in mCRPC. Methods: Patients who failed or became intolerant to ≥4 weeks of abi in the pre-chemotherapy mCRPC state were included. Pts also had to have progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Pts received pembro 200 mg intravenously Q3W with enza 160 mg per day orally, and response was evaluated by PSA levels Q3W and imaging Q9W for the first year and Q12W thereafter. Primary end points were safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points were investigator-assessed ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 69 pts initiated treatment (median age 69 years; PD-L1+ 30%; visceral disease 26%; measurable disease 36%). Median (95% CI) follow-up was 9 (7-13) mo. See efficacy outcomes in table. Treatment-related AEs occurred in 63 (91%) pts; most frequent (≥20%) were fatigue (30%), rash (23%), and nausea (22%). Grade 3-4 treatment-related AEs occurred in 28 (41%) pts; no deaths were due to treatment-related AEs. Conclusions: Early results from the pembro + enza combination show sustained activity in abi-pretreated frontline mCRPC. Observed safety profile for the combination treatment was consistent with the known safety profiles of pembro and enza. Clinical trial information: NCT02861573. [Table: see text]
Associations of cell cycle genetic variants with aggressive prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Authors: Huynh Melissa , Vyas Chirag , Penney Kathryn L. , Kibel Adam S. 
Published: March 2019

175 Background: The need to differentiate patients at risk for developing aggressive prostate cancer (CaP) from those at risk for less aggressive disease has led to efforts to identify genetic markers to predict disease course and personalize treatment. A study with participants from Johns Hopkins Medical Institutions (JHMI) and Washington University (WU) found single nucleotide polymorphisms (SNPs) in cell cycle genes were associated with risk of aggressive CaP. We sought to replicate those results in the European-American population of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We focused on variants associated with aggressive CaP in the JHMI and WU cohorts, which included 13 SNPs in 12 genes ( CCNC, CCND3, CCNG1, CCNT2, CDK2, CDK6, MDM2, SKP2, TERF2, WEE1, YWHAB, YWHAH). Variants were genotyped using the Pyrosequencing assay. Patients were classified into high risk (Gleason≥8, pT3b, N+, M+), low risk (Gleason≤7, ≤pT3a, N0, M0) or non-cancer control groups based on clinicopathologic characteristics. Logistic regression analysis was used to compare genotype frequencies of each variant between groups using the dominant model. Results: There were 108 aggressive and 1080 non-aggressive CaP patients, and 1155 controls . CDK6 ( rs8) was associated with increased risk of any CaP (OR 1.2, 95% CI 1.02-1.42; p = 0.032) and high risk disease (OR 1.63, 95% CI 1.09-2.42; p = 0.017) vs. controls. In contrast, the JHMI and WU cohort found CDK6 variants to be protective against aggressive CaP. CCNG1 ( rs11541970) approached significance (p = 0.052) between high risk and control groups, and CCNC conferred a protective effect consistent with the prior study, but did not reach significance (p = 0.101). No associations with any cell cycle gene variants were detected when comparing high and low risk patients. Conclusions: Our study did not replicate the results from the JHMI and WU cohorts. CDK6 predicted an increased risk of developing any CaP and high risk CaP. However, directionality was opposite to the prior study, indicating that this variant is unlikely to be a true predictor of increased risk of or protection from aggressive CaP.
Determining androgen inactivation status in prostate cancer by [18F] DHT PET.
Authors: Zhu Ziqi , Chung Yoon-Mi , Sergeeva Olga , Kepe Vladimir , Berk Michael , Li Jianneng , Ko Hyun-Kyung , Li Zhenfei , Petro Marianne , DiFilippo Frank , Lee Zhenghong , Sharifi Nima 
Published: March 2019

191 Background: Castration-resistant prostate cancer occurs in part due to increased tumor tissue testosterone (T) and dihydrotestosterone (DHT) that sustain tumor growth. T and DHT are converted to inactive T- and DHT-glucuronide (T/DHT-G) by uridine 5'-diphospho-glucuronosyltransferase family genes (UGT2B15 and UGT2B17) in glucuronidation-competent cells and excreted, but not in glucuronidation-deficient cells. Thus, low glucuronidation activity enables prostate tumors to preserve androgens, which increases hormone treatment resistance and may be detectable by functional imaging. Methods: We knocked out (KO) UGT2B15 and 17 in LNCaP cells and tested the DHT retention rate in the cell lines by pulse-chase using [3H]DHT as a probe. Free and DHT-G retention rates were separately determined after 5 to 60 min. To increase the signal difference between control and KO cells, we screened several ATP-binding cassette transporter inhibitors to block DHT-G excretion. We performed [18F]DHT PET/CT in castrated mice having a control and a KO xenograft on contralateral flanks ( n = 3). The ratio of the standard uptake value (SUV) in control to KO xenografts in each mouse was calculated. To increase the ratio between control and KO tumors, 50µg cyclosporin A (CSA) was injected 30 min before injecting [18F]DHT. Results: After 5 minutes of chase, control cells retained twice the DHT of KO cells. In control cells, 50%-70% DHT was glucuronidated. Almost no DHT-G was detected in KO cells, and free DHT was similar to control. Of the inhibitors, only CSA increased DHT-G (but not free DHT) in control cells, resulting in a 3-4-fold increase in overall signal. In vivo PET/CT showed control xenografts had higher peak SUV but also a higher elution rate. CSA increased the SUV ratio by 1.5-2. Conclusions: We developed a PET/CT modality to detect androgen inactivation in a prostate cancer xenograft model. Androgen-glucuronidation-proficient tumors give off a stronger signal that is increased by ATP transporter inhibition. Our method can provide a noninvasive means of determining androgen metabolism status and therefore could possibly predict effectiveness of potential therapies in a subgroup of tumors predisposed to androgen deprivation resistance.
Investigating a novel recombinant antibody to attenuate prostate cancer progression by targeting cell surface GRP78.
Authors: Al-Hashimi Ali , Won Kevin Doyoon , Pham Elizabeth , Mariano Natalie , Bailis Julie , Austin Richard , Shayegan Bobby 
Published: March 2019

206 Background: Prostate cancer (PCa) is characterized by increased activation of the procoagulant protein, tissue factor (TF) that drive tumour progression. We now show that this process is modulated by GRP78 on the cell surface (cs). In PCa GRP78 is a endoplasmic reticulum-resident chaperone that localizes to the cell surface where it functions as a signaling molecule with antigenic properties. In response to csGRP78 presentation, PCa patients produce autoantibodies (AutoAbs) against the N-terminus of GRP78. AutoAbs:csGRP78 complex acts as a potent driver of tumor growth via upregulation of the unfolded protein response (UPR) and TF activity. We hypothesize that inhibiting the binding of anti-GRP78 AutoAbs to csGRP78 will supress UPR and TF activity. Here we describe a recombinant anti-GRP78 antibody (AEP8587) that competes with the binding of AutoAbs to csGRP78 and may act as a novel therapeutic antibody with antitumor activity. Methods: Changes in TF activity or UPR markers were evaluated in vitro in the PCa cell line DU145 following treatment with anti-GRP78 AutoAbs or co-treatment with either enoxaparin, a low molecular weight heparin (LMWH), or AEP8587. Protein expression of TF and UPR markers was determined using western blotting and qRT-PCR. TF activity was determined using a real-time continuous assay. AutoAbs were purified PCa patients (St. Joseph’s Healthcare Hamilton). Results: Pre-prostatectomy PCa patients display high levels of anti-GRP78 AutoAbs (~60µg/ml), compared to healthy controls (~5µg/ml). Here, we show that anti-GRP78 AutoAb increases TF activation in vitro and leads to increased tumor progression in a DU145 xenograft model. In contrast, we show a co-treatment of anti-GRP78 AutoAb with either enoxaparin or AEP8587 completely abolishes the AutoAb-mediated increase in TF activity in vitro. Enoxaparin or AEP8587 co-treatment reversed the AutoAb effect on increased UPR markers. Conclusions: We have identified anti-GRP78 AutoAb as a driver of PCa progression. Our results indicate that a recombinant antibody, AEP8587, can bind to csGRP78 and prevent the binding of anti-GRP78 AutoAbs. This represents a potential novel means to manage PCa progression.
ARV7 and ARFL mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.
Authors: Marin Mercedes , Jiménez Natalia , Reig Òscar , Pereira Maria Verónica , Mila Maria , Benitez Daniel , Cabezón Raquel , González Azucena , Mengual Lourdes , Alcaraz Antonio , Ribal Maria Jose , García-Recio Susana , Juan Manel , Prat Aleix , Mellado Begona 
Published: March 2019

207 Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.
Impact of prostate specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients.
Authors: Freedland Stephen J. , Ramaswamy Krishnan , Lechpammer Stanislav , Mardekian Jack , Schultz Neil M. , Huang Ahong , Wang Li , Baser Onur , George Daniel J. 
Published: March 2019

211 Background: Prostate-Specific Antigen Doubling Time (PSADT) can help predict prostate cancer (PC) patient outcomes, particularly in hormone sensitive disease. However, PSADT has not been well validated in non-metastatic castration-resistant (nmCR) PC patients. This study examined the prognostic impact of PSADT on time to metastasis (TTM) and overall survival (OS) among nmCRPC patients in the Veterans Health Administration (VHA) database. Methods: VHA patients in this retrospective study were males with PC who had medical or surgical castration between Jan 1, 2012 and Dec 31, 2016. Patients actively receiving luteinizing hormone-releasing hormone treatment with ≥2 PSA post-castration increases were identified. The 3rd PSA value ≥25% and 2 ng/ml > the 1st PSA value was the CRPC (index) date; patients had continuous VHA enrollment for ≥12-months pre- to post-index date. Patients were followed until the earliest of death or disenrollment. PSADT was calculated as the natural log of 2 divided (Ln2) by the log slope of PSA using all PSA values after CRPC until metastases, and patients were categorized into 2-month cohorts. A demographically and clinically adjusted Cox regression model explored associations between PSADT cohorts and TTM and OS. Results: We identified 3,579 patients from which 1,389 (38.8%) progressed to mCRPC while 2,190 (61.2%) remained nmCRPC. Overall, patients averaged 73 years of age. PSADT was calculable in 2,800 patients with an average PSA value of 25.49 ng/mL. After a median follow-up of 820 days, the median PSADT was 17 months. Compared with the PSADT > 12 months cohort, PSADT ≤2, > 2 to ≤4, > 4 to ≤6, > 6 to ≤8, and > 8 to ≤10 month cohorts were associated with higher risk of metastasis (hazard ratio [HR]: 33.77, CI: 25.93-43.96; HR: 14.32, CI: 11.83-17.32; HR: 6.58, CI: 5.42-7.98, HR: 4.14, CI: 3.27-5.25; HR: 3.14, CI: 2.45-4.03, respectively) and death (HR: 12.27, CI: 9.20-16.35; HR: 5.32, CI: 4.26-6.64; HR: 3.50, CI: 2.74-4.47, HR: 2.29, CI: 1.68-3.14; HR: 1.64, CI: 1.14-2.37, respectively). Conclusions: Short PSADT strongly associated with TTM and poor OS in nmCRPC patients. Newer nmCRPC treatments are advisable for high-risk patients.
Immunogenomic landscape of neuroendocrine small cell prostate cancer.
Authors: Nappi Lucia , Kesch Claudia , Vahid Sepideh , Fazli Ladan , Eigl Bernhard J. , Kollmannsberger Christian K. , Gleave Martin , Zoubeidi Amina , Wyatt Alexander William , Chi Kim N. 
Published: March 2019

217 Background: Neuroendocrine small cell prostate cancer (NEPC) is a lethal variant of prostate cancer (PCa) unresponsive to hormone therapy and associated with poor prognosis. Cisplatin induces short-lived responses and therefore alternative novel therapeutic options are urgently needed. Methods: Prostate specimens from radical prostatectomy or transurethral resection (benign prostate specimens n = 4, primary untreated or neoadjuvant hormone-treated adenocarcinoma n = 30, castrate-resistant prostate cancer-CRPC n = 38 and NEPC n = 16) were evaluated for PD-L1 (SpringBio, M4420), AR, chromogranin A, synaptophysin, NSE and CD56 expression by immunohistochemistry (IHC). Archival tissue from liver, lymph nodes and prostate from 30 additional patients with de novo and treatment emergent NEPC were analyzed for PD-L1 expression by IHC. The intensity was assessed as percentage of positive cells / mm2 of tissue. Targeted and whole exome sequencing of the high-density tumor areas were performed and correlated to the PD-L1 status (PD-L1+ve: > 1% of positive cells). OS was calculated from the date of diagnosis of NEPC to death. We set out to define PD-L1 expression and immunogenomic characteristics of NEPC. Results: PD-L1 was expressed in 0%, 5%, 10% and 41% of benign, adenocarcinoma, CRPC and NEPC specimens, respectively. The PD-L1 expression intensity was significantly higher in patients with NEPC (mean: 40%, range: 5-100%) compared to benign, adenocarcinoma and CRPC samples (mean: 0%, 2% and 8%, respectively, P < 0.0001). There was a higher prevalence of biallelic DNA Repair Defects (DRD) in the PD-L1+ve vs PD-L1-ve patients (65% vs 0%, P = 0.005). The median OS of the NEPC patients was 8.5 months vs 10.5 months in PD-L1+ve vs PD-L1-ve tumors (HR 1.24, 95% CI: 0.59-2.75, p = 0.55). Conclusions: NEPC have greater PD-L1 expression than adenoCa and CRPC. Biallelic DRD was exclusively observed in PD-L1+ve patients. Since PD-L1 expression and DRD have been associated to response to PARP and PD1/PD-L1 inhibitors in prostate and other cancers, further studies evaluating the activity of those agents in NEPC patients are warranted.
Direct evidence of a clonal and tumor-directed T cell response to prostate cancer brachytherapy.
Authors: Williams Scott , Keam Simon , Halse Heloise , Mitchell Catherine , Caramia Franco , Byrne David , Haupt Sue , Ryland Georgina , Darcy Phil , Sandhu Shahneen Kaur , Blombery Piers , Haupt Ygal , Neeson Paul J 
Published: March 2019

22 Background: We characterised the immune response in human prostate cancer (PC) to high dose rate brachytherapy (HDRBT) using serial pre- and post-HDRBT biopsies. Methods: Prostate biopsies and peripheral blood samples were obtained from 9 men with clinically localised PC at baseline and again 14 days following a 10 Gy fraction of HDRBT. Immune infiltrates were characterised using multiplex immunohistology (T cell and pan-immune panels) and targeted gene expression profiling (Nanostring pan-cancer immune panel). T cell repertoire was assessed using T cell receptor (TCR) Vbeta CDR3 deep sequencing. Results: HDRBT induced profound but heterogenous immune responses. At the extremes, one patient had an extensive tumor-infiltrating lymphocyte (TIL) response post-HDRBT, comprising T cells (CD4+ > CD8+ > Treg), B cells, and PDL1+ antigen presenting cells (macrophages and CD11c+ dendritic cells); another had a substantial baseline immune infiltrate eliminated by HDRBT. TIL-hi cases (either before or after HDRBT) had a conserved signature of T cell activation, differentiation, and trafficking, with upregulation of checkpoint molecules PD1, IDO1, BTLA, CTLA4, ICOS, B7-H3 and FoxP3. Those TIL-hi specifically in response to HDRBT also had down-regulation of genes regulating myeloid differentiation and granulocyte chemotaxis pre-HDBRT. Conversely, a monocyte-like myeloid-derived suppressor cell signature was seen in the TIL-lo responders. The median number of dominant clones ( > 1% prevalence) determined by TCR sequencing was 24.5 and 26.5 pre- and post-HDRBT respectively. Only 2 clones (in 1 patient) were present at both time points with the T cell repertoire otherwise being completely new following HDRBT. A subset of PC-associated T cell dominant clones was also present in the PB in all patients, suggesting HDRBT can induce systemic immunity. Conclusions: We have shown that treatment of localized prostate cancer with HDRBT induces a marked clonal TIL infiltrate dominated by T cells likely to be operating under the control of multiple checkpoints. These first-in-human data may be able to inform the rational selection of immunotherapy to combine with HDRBT.