bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic rule of programmed cell death protein 1 expression in resectable upper tract urothelial carcinoma.
Authors: Hayakawa Nozomi , Kikuchi Eiji , Mizuno Ryuichi , Oya Mototsugu 
Published: September 2018

e16090 Background: Programmed cell death protein (PD-1) expressed on active T cells are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the rule of PD-1 expression on clinical outcome have not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 155 patients who had been surgically treated for UTUC without previous history of bladder cancer. At a magnification of 400x, PD-1 protein expression was estimated and the positive cells was graded as weak and strong. The protein expression of PD-1 was evaluated in the most invasive part of the cancer with tumor periphery and inside separately. Results: The PD-1 expression was weak in 67 (43.2%) and strong in 88 (56.8%) in tumor periphery. On the other hands, the staining was weak in 117 (75.5%) and strong in 38(24.5%) in tumor insides. Regarding to pathological features, high grade (p = 0.026) and pT2≤ (p = 0.008) related to strong PD-1 expression in tumor inside, and high grade (p = 0.002), pT2≤ (p < 0.001) and positive LVI (p = 0.008) were associated with strong PD-1 expression in tumor periphery. The 5-year caner-specific survival (CSS) in patients with strong PD-1 staining in tumor periphery was 79.4%, which was significantly lower than those in their counterparts (86.0%, p = 0.044). The 5-year CSS in patients with strong PD-1 staining in tumor inside was 73.3%, which was significantly lower than those in their counterparts (85.1%, p < 0.021). Multivariate Cox regression analysis demonstrated that positive LVI (HR; 3.92, p < 0.001) and strong PD-1 expression in tumor inside (HR; 2.30, p < 0.036) were independent predictors for CSS. Conclusions: PD-1 expression, especially in tumor inside, may be a novel indicator for identifying a worse prognosis in UTUC patients with radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC, especially aggressive UTUC.
Evaluating the impact of bone-targeted agents in the era of novel androgen targeted therapy for metastatic castration-resistant prostate cancer.
Authors: Li Haoran , Kamel Dalia , Fernandes Ricardo , Bosse Dominick , Vo Dong , Souied Osama , Kumar Vikaash , Ong Michael 
Published: September 2018

e16500 Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) often develop bone metastases, resulting in a risk of symptomatic skeletal events (SSE). Bone-targeted agent (BTA) has been integrated into the overall treatment strategy, but its role in the era of novel androgen-targeted therapy (ATT) is still unclear. Methods: A retrospective analysis of real-world practice from 2010 to 2015 was conducted. Patients diagnosed with mCRPC and bone metastases who received systemic therapy (docetaxel/abiraterone/enzalutamide) with or without BTA (zoledronic acid/denosumab/alendronate) were included. Results: We obtained data from 299 patients with a median follow-up of 75.5 months. Compared with no BTA, concomitant BTA was associated with decreased incident of SSE (3.8% vs. 19.2%, p< 0.001), especially in the need for bone radiation (1.9% vs. 15.8%, p< 0.001). Compared to patients without SSE, patients with SSE were more likely to have previous fracture history (10.8% vs. 9.7%, p= 0.047), steroid use history (2.4% vs. 1.4%, p= 0.019), smoking history (53.0% vs. 38.9%, p= 0.009), diabetes (19.3% vs. 8.8%, p= 0.012) and reduced baseline mobility (9.6% vs. 4.2%, p= 0.002). Among those who received first-line novel ATT (n = 152), concurrent ATT+BTA significantly decreased the incident of SSE (2.8% vs. 27.3%, p= 0.004) and prolonged the time to SSE (24.3 vs. 3.2 mo, p< 0.001), when compared to ATT alone. But there was no difference in overall survival between two groups (134.2 vs. 138.9 mo, p= 0.99). In patients who responded to systemic treatment with PSA declining, the SSE rate (2.4% vs. 14.3%, p= 0.037) was lower and the time to SSE was longer (49.6 vs. 32.3 mo, p= 0.026) than those who did not respond. Smoking history (adjusted HR = 1.46, p= 0.013) and PSA response (adjusted HR = 0.19, p< 0.001) are independent risk factors for SSE. Conclusions: This real-world database suggests that concomitant BTA with novel ATT was associated with reducing SSEs. PSA decrease might be used as a predictive factor for those under BTA treatment. Further studies are warranted to validate the role of PSA response.
Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa.
Authors: Mahalingam Devalingam , Salih Hanni , Fountzilas Christos , Michalek Joel , Sarantopoulos John , Datta Paromita , Romero Ofelia , Mulampurath Achutan Pillai Sureshkumar , Kuhn John G. , Pollak Michael N. , Thompson Ian Murchie 
Published: September 2018

e16502 Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. In diabetes, metformin (MET) decreases glucose & insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: Men with biochemical relapse or advanced PCa due to receive ADT were randomized 1:1 in a double blind manner to MET (500mg TID) or placebo (P). Subjects required normal oral glucose tolerance test at baseline, with fasting serum insulin/glucose, PSA, MET, weight and waist circumference (WC) monitored at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of MET vs P. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: 36 men were randomized to MET or P, mean age 68.4; biochemical failure (n = 15) & metastatic disease (n = 21). Mean weight, WC and insulin at baseline in MET cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in P cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At wk 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. 4 men randomized to MET had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in MET and 53.3% in P cohort achieved undetectable PSA at wk 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusions: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Clinical trial information: NCT02620423.
How do patterns of progression influence treatment selection after chemohormonal therapy in patients with metastatic hormone sensitive prostate cancer?
Authors: Aguado De La Rosa Carlos , Garcia Carbonero Iciar , De Velasco Guillermo , Alonso Teresa , Villalobos Maria L. , Garrido Maria , Gallegos Isabel , Martin Almudena , Pinto Alvaro , Maximiano Alonso Constanza , Rodriguez-Moreno Jf , Rodriguez Laura , Sereno Maria , Perezagua Carmen , Marrupe David , Riquelme Alejandro , Cassinello Javier , Grande Enrique , Puente Javier , Gajate Pablo 
Published: September 2018

e16504 Background: In the CHAARTED and STAMPEDE clinical trials, Docetaxel combined with androgen-deprivation therapy (ADT) increased overall survival in mHSPC patients. Despite the increasing use of this strategy in clinical practice, there is a lack of information about the best treatment choice after progression. Methods: We retrospectively analyzed 96 patients with mHSPC treated with Docetaxel plus ADT in 18 Spanish centers (July 2014 to December 2016). The objectives of the study were to describe baseline and progression characteristics, as well as second-line treatment choice and its outcomes. Results: The median age was 66.7 years. 33.3% patients had visceral metastases at diagnosis and 81% had a Gleason Score 8-10. After a median follow-up of 12.2 months, 35.4% of patients developed castration-resistant prostate cancer (CRPC). The median time to CRPC was 15.4 months. 36.3% of patients had visceral progressive disease. 27 patients received subsequent treatment after progression: 9 (33.3%) were treated with chemotherapy (2 docetaxel, 6 cabazitaxel, 1 carboplatin-etoposide), and 18 (66.6%) received androgen receptor axis-targeted agents (12 enzalutamide, 6 abiraterone). Median progression-free survival was similar with hormonal therapies (4.3 months) than chemotherapy (3.5 months) as second line. Treatment choice was influenced by pattern of progression (visceral vs non visceral) and time to develop CRPC (≤ 12 vs > 12 months). Hormonal therapies were more frequent for non-visceral disease (75% vs 25%) or patients with longer time to develop CRPC (89% vs 11%). Chemotherapy was preferred in patients with visceral progressive disease (83.3% vs 16.7%). In patients with a time to CRPC less than 12 months both treatments were used equally (44.5 vs 55.5%). Conclusions: In our cohort, androgen receptor axis-targeted agents were used more frequently than chemotherapy after progression to chemo-hormonal therapy. Despite the low number of patients that received treatment at progression, our results suggest that the characteristics at the time of progression, such as pattern of progression and time to develop CRPC, could influence treatment choice.
Bone scan index at baseline as a tool for predicting hematologic toxicity in metastatic castration-resistant prostate cancer patients eligible for radium-223 treatment.
Authors: Kothari Shalin , Sharif-Tabrizi Ahmad , Attwood Kristopher , Lamonica Dominick M , Levine Ellis Glenn , George Saby 
Published: September 2018

e16513 Background: The prognosis of castration-resistant prostate cancer with skeletal metastasis (CRPCSM) is poor. The ALSYMPCA trial led to the approval of radium-223 (Ra223) in such patients. Factors that could predict hematologic toxicities associated with Ra223 remain poorly defined. We analyzed the utility of bone scan index (BSI) at baseline (BSI-B) as a predictive marker for such toxicities. Methods: This is a retrospective study of CRPCSM patients without visceral metastasis who received Ra223 at Roswell Park Cancer Institute from 2013 to 2015. BSI was defined utilizing the estimation of a numerical index (max, 70.8% for diffuse skeletal involvement) that expresses the fractional involvement of each bone by tumor. BSI-B values were classified into < first quartile ( < Q1), between first and third quartile (Q1-Q3), and > third quartile ( > Q3). The associations between BSI-B and different hematologic parameters [hemoglobin (Hgb), platelets (Plt), absolute neutrophil count (ANC)] over the Ra223 treatment duration were evaluated using linear mixed models. Results: A total of 79 patients were included in this analysis. The median Gleason score was 8 (range: 4-10) and the median age at first Ra223 was 71 years. Seventy percent of patients received 5 or more doses of Ra223. There was a significant association between BSI-B and Hgb (p = 0.005) and Plt (p = 0.011) levels at baseline and at all time points. The > Q3 BSI-B was associated with a greater drop in Plt from an elevated baseline with subsequent treatments of Ra223 [drop from a mean of 293.5±21.3 x109/L (n = 19) to 132.2±48.8 x109/L (n = 9) after sixth Ra223]; while such a decline was not observed for lower BSI-B (p < 0.001). The ANC decreased with each Ra223 in patients with > Q3 BSI-B but not in the ones with lower BSI-B (p = 0.003). Conclusions: Our work demonstrates that hematologic parameters at baseline and during Ra223 treatment are associated with higher BSI-B values, raising the possibility of BSI-B as a valuable tool for predicting the risk of cytopenias before initiating Ra223 in CRPCSM patients. Prospective validation is needed to confirm the utility of our findings.
Characterisation and treatment of patients with castration-resistant metastatic prostate cancer (mCRPC) developing neuroendocrine clonal divergence (NCD): A case series.
Authors: Bauernhofer Thomas , Belic Jelena , Pichler Martin , Bezan Angelika , Heitzer Ellen , Geigl Jochen Bernd , Stoger Herbert , Speicher Michael , Smolle Maria Anna 
Published: September 2018

e16520 Background: The introduction of Abiraterone (Abi) and Enzalutamide (Enza) into treatment of mCRPC has led to a survival benefit. However, in a subset of patients treated with Enza/Abi, rapidly progressive disease with atpical metastatic spread develops. According to Eric Small et al. (ASCO 2015 Abstract 5003), 39% of metastases in mCRPC-patients treated with Enza/Abi have small cell neuroendocrine or mixed type histologies. Based on these findings we aimed at characterising NCD in a case series of 8 patients using 1) clinical, laboratory, radiological parameters, 2) molecular features generated by liquid biopsy and 3) to present outcome variables after treatment of these patients with combination chemotherapy carboplatin/etoposide (CE). Methods: Clinical, radiological, laboratory parameters, whole-genome sequencing of cfDNA (PlasmaSeq) and ctDNA taken at different time points during treatment were ascertained from 8 mCRPC-patients with NCD. Results: All patients presented with rapid tumour progression and atpical metastatic spread (3x liver, 3x lungs, 1x skin, 1x adrenal glands) during treatment with Enza/Abi. Laboratory findings revealed marked increase in CRP, AP and LDH levels and elevation of NSE ( > 5x times upper normal limit), whilst PSA levels were low or declining. All patients received Carboplatin AUC5 day 1 and Etoposid 100 mg/m3 day 1-3 q3w. In 7 out of 8 patients, initially high levels of CRP, LDH, AP and NSE decreased under CE therapy. Very good partial response on radiological examination was observed after 3-6 cycles of CE in these patients. One patient had progressive disease. Copy number profiles of ctDNA taken peri-interventionally revealed loss of androgen receptor and a clonal shift in comparison to profiles taken during endocrine treatment phase. Conclusions: Rapid clinical and radiologic progression, atypical metastases and sharp rise in LDH, CRP, AP and NSE levels combined with low PSA are indicative of NCD. For these patients, CE-based chemotherapy is a promising treatment option. In order to identify clonal shift from adenocarcinoma to neuroendocrine cancer, genetic profiling using ctDNA may be of use.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) pts receiving a new agent (NA)- based third line treatment: Final results from a multicenter Italian study.
Authors: Caffo Orazio , Bria Emilio , De Giorgi Ugo , Tucci Marcello , Biasco Elisa , Fratino Lucia , Facchini Gaetano , Iacovelli Roberto , Lo Re Giovanni , Scagnoli Simone , Morelli Franco , D'Angelo Alessandro , Verderame Francesco , Campadelli Enrico , Ricotta Riccardo , Napolitano Martina , Sartori Donata , Borsellino Nicolo , Sperduti Isabella , Maruzzo Marco 
Published: September 2018

e16521 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.
Expression of NY-ESO-1 cancer testis antigen in prostate cancer.
Authors: Jain Rohit K. , Xu Bo , Mehta Rutika Jitesh , Pop Elena , Mohler James , Odunsi Kunle , Chatta Gurkamal S. 
Published: September 2018

e16544 Background: Poor outcomes in castrate resistant prostate cancer (CRPC) patients is a growing concern urging the need for innovative treatments. Cancer testis antigens (CTAs) like NY-ESO-1 are aberrantly expressed in several cancers including prostate cancer (PC). Given its tumor-restricted expression and ability to elicit spontaneous cytotoxic & antibody-mediated immune responses, NY-ESO-1 shows promise as an immunotherapy target. With the expertise of RPCI in NY-ESO-1 targeted therapeutics and limited information on NY-ESO-1 expression in CRPC, we sought this study. Methods: Immunohistochemical expression of NY-ESO-1 was analyzed in a series of PC samples from 2 different institutions. Two TMAs consisted of triplicate cores from 37 patients with localized PC (with cores from cancerous areas & the normal tissue adjacent to it), and 36 mCRPC patients. We also included 17 mCRPC whole sections for analyses. Intensity and percentage of NY-ESO-1 staining were recorded. The intensity was characterized as low (0-1+) and high (2-3+). Results: The median age in this cohort was 62 years. NY-ESO-1 IHC was positive for cytoplasmic staining in 33 of 111 (26.4%) evaluable cases including 41% in localized PC, 22.6% in benign areas adjacent to tumor, and 35.5% in CRPC. 23 (18.4%) had 1+, 7 (5.6%) had 2+ and 3 (2.4%) had 3+ cytoplasmic staining intensity. No statistical difference was noted in cytoplasmic staining with tumor grade. Gleason grade 8 -10 tumors (33 of 103 [35.4%]) correlated with lower intensity staining (0-1+) pattern (p = 0.028). NY-ESO-1 expression did not correlate with age, race, disease free or overall survival in this cohort. Conclusions: Heterogeneous NY-ESO-1 expression in PC and other tumors is linked to DNA methylation status of its promoter and tumor cells. We noted NY-ESO-1 expression in a third of the patients with CRPC, making it a credible immunotherapeutic target. NY-ESO-1 expression has been shown to be induced and upregulated in cancer by treatment with demethylating agent. Thus targeting NY-ESO-1 in concert with epigenetic modulation maybe therapeutically meaningful in patients with CRPC. Additional efforts at validating NY-ESO-1 expression in CRPC with CLIA approved IHC and qPCR assays (Omniseq) are ongoing and will be reported.
Variation in radiation oncology referral and adjuvant radiotherapy use following prostatectomy: A population-based study of health system performance.
Authors: Jin Chunzi Jenny , Hanna Timothy , Cook Earl Francis , Miao Qun , Brundage Michael Donald 
Published: September 2018

e16551 Background: Evidence-based guidelines confirm a survival advantage of adjuvant radiotherapy (ART) for prostatectomy (RP) patients with high-risk pathology. The efficacy of deferred salvage RT is under evaluation as an alternative strategy, and guidelines recommend radiation oncology (RO) referral for discussion of options. We report RO referral patterns, ART use, and factors associated with these patterns in a contemporary population-based RP cohort. Methods: Electronic treatment records were linked to Ontario's cancer registry. Multivariable regression was used to evaluate clinical and health systems factors associated with RO referral and ART use ≤ 6 months post-RP. Results: From January to November 2012, 2,663 prostate cancer patients received RP in Ontario. Among 1,261 with adverse pathology, 492 (39%) were referred to RO ≤ 6 months post-RP, of which 51% received ART. Multivariable analysis demonstrated that RO referral was more frequent for cases of T3b/T4 disease [OR 17.87; p < 0.0001], T3a disease [OR 5.24; p < 0.0001], Gleason score 8-10 disease [OR 11.32; p < 0.0001], Gleason score 7 disease [OR 4.18; p < 0.0001], at least one non-apex margin positive [OR 4.20; p < 0.0001], an apex only positive margin [OR 2.60; p < 0.0001], RO referral prior to RP [OR 1.95; p < 0.0001], low RP volume hospitals [OR 2.50; p < 0.0001], and increased distance of patient residence from cancer center [OR 1.73; p = 0.01]. There was wide geographic variation in RO referral rates (range 6%-66%; p < 0.0001). Among patients seen by RO, only T3b/T4 disease [OR 5.37; p < 0.0001], T3a disease [OR 2.72; p < 0.0001], at least one non-apex positive margin [OR 2.81; p < 0.0001], and an apex only positive margin [OR 1.32; p < 0.0001] remained predictive of ART on multivariable analysis. Conclusions: Nonmedical factors are important determinants of whether patients are referred for discussion of ART post-RP. Post-RO consultation, treatment decisions are correlated with pathologic findings. Large inter-center variations persist in referral and treatment post-RP, suggesting that further understanding of the reasons for variation could improve access to potentially curative RT in this setting.