bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a six-gene signature for predicting prognosis in prostate cancer patients with lymph node metastasis.
Authors: Guo Jinan , Xie Wenzhuan , Huang Mengli , Gao Chan 
Published: May 2020

e17524 Background: Prostate cancer (PCa) patients with lymph node metastasis (LNM) always exhibit poor clinical outcomes. A gene signature that could predict survival in these patients would allow for earlier detection of mortality risk and will also guide individualized therapy. Methods: A prediction model was developed using a public cohort consisting of 623 patients with clinicopathologically confirmed PCa. Data were gathered from cBioPortal and UCSC Xena. Genes expressed differentially in patients with lymph node metastasis versus those without lymph node metastasis were identified. Uni-variate Cox regression analysis and LASSO Cox regression were applied to build a prediction model. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier curves were used to assess the prognostic capacity of the model, followed by external validation using the MSKCC dataset from cBioPortal. Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: We identified a six-gene signature (covering GSDMB, SSTR1, MX1, CCBE1, MYBPC1, and FAM3D) that could effectively identify a high-risk subset of PCa patients. ROC analysis indicated that the signature had a good performance (AUC > 0.7) in survival prediction in both the training and the testing/validation cohorts. Cox regression analysis showed that the six-gene signature could independently predict disease-free survival (DFS) as well, although with lower predictive power. Subgroup analyses showed that signature-based risk score may serve as a promising marker to predict DFS in different subgroups, including stage T2 (HR = 0.12, p < 0.001), stage T3 (HR = 0.29, p < 0.001), TP53-wild-type (HR = 0.22, p < 0.001), TP53-mutated (HR = 0.07, p < 0001), AR pathways-wild-type (HR = 0.2, p < 0.001) and AR pathways-mutated(HR = 0.16, p = 0.0419). The performance of the six-gene signature in LNM+ was stable for stratifying the patients according to risk of deatch (HR = 0.23, p = 0.0333). Moreover, GSEA revealed distinct pathway enrichment features in the different risk groups, where pathways related to DNA repair were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of androgen response. Conclusions: We developed a robust six-gene signature that can effectively classify PCa patients into groups with low- and high-risk group, which may help select high-risk patients who require more aggressive adjuvant target therapy or immune therapy.
Inhibition of PIM kinase with fractionated radiation and docetaxel in preclinical prostate cancer models.
Authors: Rajkumar-Calkins Anne , Sagar Vinay , Wang Jian , Bailey Shania , Anderson Philip , Abdulkadir Sarki , Kirschner Austin Noah 
Published: May 2020

e17534 Background: PIM kinases are highly expressed in high risk prostate cancer and are associated with aggressiveness and poor prognosis, presenting a therapeutic target. Methods: We studied PIM inhibition (PIMi) in both hormone-dependent (LNCaP) and -independent (DU145, 22Rv1) prostate cancer cell lines and mouse xenografts. We evaluated PIMi effects via Western blotting, immunofluorescence, and RNAseq of multiple relevant pathways, and performed radiosensitization analysis with colony formation assays. We also investigated xenograft tumor growth with PIMi +/- radiation (RT) or docetaxel. Results: Pretreating the cell lines with PIMi prior to RT caused marked changes in H2AX phosphorylation compared to no PIMi + RT, with most significant alteration in DU145. However, in colony formation assays, 22Rv1 showed greatest radiosensitization with colony survival reduced from 23% to 15% with PIMi. 22Rv1 xenografts were grown in castrated mice, which were randomized to 30 Gy in 15 treatments vs no RT over 3 weeks, -/+ PIMi on RT days. RT + PIMi eliminated gross tumor, compared to an average of 78% and 51% of initial tumor volumes remaining with PIMi alone and RT alone, respectively. Immunofluorescence and Western blotting of harvested tumors showed PIMi altered patterns in proteins involved with hypoxic response (COX-2), cell survival (MDM2), and androgen receptor and suggested interactions between RT and PIMi for both MDM2 and androgen receptor but not COX-2. RNAseq analysis of xenografts showed daily PIMi affected multiple pathways involved in metabolism, growth, and DNA repair. Finally, we tested PIMi -/+ docetaxel in castrated mice with hormone-sensitive (LNCaP) or -resistant (22Rv1) xenografts treated with PIMi -/+ docetaxel. With both xenografts, PIMi + docetaxel reduced tumor size best, with 22Rv1 xenografts most dramatically showing 74% volume reduction from baseline with PIMi + docetaxel compared to 50% and 25% reduction in volumes with PIMi alone and docetaxel alone, respectively. Conclusions: PIMi has multiple pathway effects in prostate cancer. PIMi significantly reduces disease burden, particularly in combination with RT or docetaxel. Our data provide rationale for testing PIMi in clinical trials for prostate cancer.
A web app nomogram based on real-life patients: Guide decision in first-line treatment for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vilbert Maysa Tamara Silveira , Pandolfi Natasha Carvalho , Cesca Marcelle Goldner , de Andrade Poliana , Calsavara Vinicius Fernando , Uchôa Bruno Cezar de Mendonça , Coelho Ricardo Lima , Corassa Marcelo , Rinck Jose A. , Dettino Aldo A. , Oliveira Thiago Bueno 
Published: May 2020

e17538 Background: mCRPC phenotype involves androgen-receptor signalling mechanisms that support the use of abiraterone/enzalutamide (Abi/Ez). These therapies improve overall survival (OS) and quality-of-life, with a favourable safety profile. There is no validated data defining the best drug or sequence to be used. Methods: A retrospective study evaluated if a nomogram helps the decision-making of first-line for mCRPC. The nomogram evaluated time-to-treatment failure (TTF) from Abi/Ez and Docetaxel (Doc) treatment and had C-índex of 0.726. Time from start of androgen deprivation therapy to Abi/Ez or Doc, pain, Gleason score, testosterone and the lowest PSA in castration-sensitive scenario were analysed. All patients (pts) in Doc group used second-line Abi/Ez. The outcomes were: to evaluate whether the nomogram scores were associated with TTF/OS in Abi/Ez population; to compare OS between Abi/Ez and Doc poor prognostic (PP) groups based on the nomogram scores. Kaplan-Meier and Cox-regression models were used for time-to-event analyses. The cut-off was defined by Log-Rank. Statistical significance was fixed at 0.05. Results: From May/12 to Feb/20, 123 pts were assessed (79 received first-line Abi/Ez and 44 Doc). Median follow-up was 25.7 months (1.6 to 93.7). Nomogram scores based on Abi/Ez treatment (medium score of 65, 0-225) were statistically associated with OS (HR 1.02, 95% CI 1.01-1.02, p < 0.001) and TTF (HR 1.02, 95% CI 1.02-1.03, p < 0.001). 79 pts who received Abi/Enz were stratified as having good (GP) (score < 46), intermediate (IP) (score 46-112) and PP (score > 112), and it was associated with 75%, 25-75% and 25% probability to 1-year free from treatment failure, respectively. Pts with GP (n = 24) had a median TTF of 29.8m (15.4-44.2), IP (n = 44) 9.8m (4.1-15.4) and PP (n = 11), 4m (2.5-5.5), p = < 0.001. Pts with GP achieved higher TTF than IP (HR 2.3 95% CI 1.3-4.2 p = 0.005) and PP (HR 8.9 95% CI 3.8-20.6 p < 0.001). The results were similar for OS, once the median for GP was 54.0m (30.5-77.6); IP 34.8m (32.2-37.5); and PP 13.6m (9.3-17.9), p = 0.023 (GP versus IP: HR 2.1 95% CI 1.01-4.4 p = 0.046; GP vs PP: HR 3.6 95%CI 1.4-9.6 p = 0.011). Pts with a higher score and PP from Abi/Ez group were compared with Doc pts at first-line (n = 44), showing worse OS (HR 2.4 95%CI 1.03-5.6 p = 0.042) when treated with Abi/Ez. Conclusions: The nomograns scores showed good correlation with TTF/OS. In PP groups, treatment with Doc was associated with better OS than Abi/Ez, suggesting a possible tool on the first-line decision making.
Addition of carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in post-second generation hormone therapy setting: Does it improve treatment response and survival outcomes?
Authors: Alamiri Jamal , Ahmed Mohamed E. , Andrews Jack R. , Alom Manaf , Motterle Giovanni , Higa Julianna , Karnes Jeffrey , Kwon Eugene D. , Bryce Alan Haruo 
Published: May 2020

e17540 Background: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after treatment with 2nd generation hormone therapy (2nd-HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing 2nd-HT. We sought to evaluate three common chemotherapy regimens in this setting. Methods: We retrospectively identified 150 patients with mCRPC with disease progression on enzalutamide or abiraterone. 92 patients were chemo-naïve, while 58 patients had previously received docetaxel chemotherapy prior to 2nd-HT. After failing 2nd-HT, 90 patients received docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). Favorable response was defined by ≥50% reduction in PSA level from baseline after a complete course of chemotherapy. Survival outcome was assessed for 30-month overall survival. Results: Mean (SD) age was 71.2 (8.28), 69.5(8.38) and 67.2 (8.36) for group (A), (B) and (C), respectively. Mean (SD) pre-chemotherapy PSA was 63.8 (138.18), 58.5 (118.15) and 53.7 (88.15) for group (A), (B) and (C), respectively. Mean (SD) Gleason score was 7.9 (1.1), 8.4 (0.88) and 8.1 (1.06) for group (A), (B) and (C), respectively. Patients in group (B) were 2.6 times more likely to have a favorable response compared to group (A) (OR = 2.625, 95%CI: 1.15 - 5.99) and almost 3 times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04 – 8.54) (p-value = 0.0442). We report a Hazard Ratio (HR) of 3.1 (95% CI 1.31-7.35; p = 0.0037) between patients in group (A) versus group (B), and a HR of 4.18 (95% CI 1.58-11.06; p = 0.0037) between patients in group (C) versus group (B). Thirty-month overall survival was 70.7%, 38.9%, and 30.3% for group (B), (A), and (C) respectively (p-value = 0.008). Conclusions: Our data demonstrate improved response and cancer-specific survival in patients with treatment-refractory mCRPC on docetaxel plus carboplatin compared to docetaxel or cabazitaxel alone. Selection bias is inherent in any retrospective study; however, our finding suggests that clinicians may consider docetaxel plus carboplatin in mCRPC patients who fail 2nd-HT. Further prospective studies are warranted.
Efficacy and safety of 177Lu-PSMA radionuclide treatment in patients with diffuse bone marrow involvement: A multicenter retrospective study.
Authors: Gafita Andrei , Fendler Wolfgang Peter , Wang Hui , Sandhu Shahneen Kaur , Weber Manuel , Esfandiari Rouzbeh , Czernin Johannes , Rathke Hendrik , Rauscher Isabel , Tauber Robert , Delpassand Ebrahim , Weber Wolfgang A , Herrmann Ken , Calais Jeremie , Eiber Matthias , Hofman Michael S 
Published: May 2020

e17543 Background: 177Lu-labelled prostate-specific membrane antigen (LuPSMA) radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC) is currently under investigation in phase III trial (VISION). However, patients with diffuse bone involvement, diagnosed with a superscan by bone scintigraphy at baseline, were excluded due to lack of efficacy and safety data. We therefore aimed to investigate the feasibility of LuPSMA in patients with diffuse bone marrow involvement on baseline PSMA-targeted PET/CT. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA and Australia were considered for inclusion.Eligible patients had 50% or greater bone involvement of the axial skeleton on the baseline PSMA PET. The primary endpoints were PSA response (PCWG3), toxicity (CTCAE v4.02), and overall survival (OS). Secondary endpoints included quality of life (assessed with Brief Pain Inventory-Short Form questionnaires) and radiological response (as measured by CT using RECIST 1.1). Results: 43 of 352 (12%) screened patients met inclusion criteria and were retrospectively analyzed. Median baseline PSA was 1000 (IQR 431-2151) ng/ml. PSA decline ≥50% was achieved in 26/43 (65%) patients, while median PSA progression-free survival was 4.8 (95%CI 2.4–7.1) mo. 15/42 (36%) evaluable patients exhibited pain progression with a median time-to-pain progression of 8.3 (95%CI 5.4–11.3) mo. After a median follow-up of 18.9 mo, median OS was 11.6 (95%CI 8.8-14.3) mo. Objective response in nodal or visceral disease was reported in 7/18 (39%) patients with evaluable target lesions on CT. Grade 3/4 anemia, thrombocytopenia and neutropenia occurred in 9/43 (21%), 10/43 (23%) and 3/43 (8%) patients, respectively. Of note, all patients had grade 1 anemia at baseline, with a median hemoglobin of 9.6 g/dl. 2/43 (5%) patients experienced an adverse event that required a reduction to the LuPSMA activity beginning with the third cycle. Conclusions: Patients with diffuse bone marrow involvement demonstrate similar LuPSMA efficacy and safety when compared to phase II evidence. Acceptable safety outcomes do not support exclusion of patients with a superscan from future LuPSMA treatment protocols.
Combinatorial expression of androgen receptor splice variants: No predictive value in castration-resistant prostate cancer patients treated with enzalutamide (enza) or abiraterone (abi).
Authors: Schlack Katrin , Seitzer Konstantin , Boegemann Martin , Krabbe Laura-Maria , Schrader Andres Jan , Grundmann Norbert , Tiedje Dorothee , Steinestel Julie , Bernemann Christof 
Published: May 2020

e17547 Background: Playing an important role in prostate cancer, androgen receptor (AR) signaling is a common therapeutic target. Novel hormonal treatment (NHT) using enza or abi prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, biomarkers predicting therapy response are limited. AR-V7, as the most abundant AR splice variant, has gained clinical interest. Nonetheless, current discussions on its predictive power are diverse. Given that AR-V7 as a sole biomarker is not efficient in predicting response to NHT, we aimed to increase the predictive potential by analysis of combinatorial AR splice variant (AR-V) expression in mCRPC patients undergoing NHT. Methods: We prospectively enrolled 60 patients who started on either abi or enza. Presence of circulating tumor cells (CTC) as well as expression of AR-V3, -7 and -9 were assessed. Outcomes in CTC-, CTC+/AR-V- and CTC+/AR-V+ patients were analyzed considering PSA reduction, PSA-PFS, PFS and OS. Results: PSA reduction of 50% was predominantly found in CTC- patients (78.5%) compared to CTC+/AR-V- (55.5%) and CTC+/AR-V+ (39.3%) without statistical significance (P = 0.059). When taking co-expression of two or more AR-V into account there was no difference in PSA response either (one AR-V 42.9%, two AR-V 33.3%, three AR-V 41.6%, P = 0.154). Median PSA-PFS was 17 months (95%CI 15.7 – 18.3), 13 months (95%CI 6.8 – 19.2) and 5 months (95%CI 3.6 – 6.4) for CTC- pts, CTC+/AR-V- pts and CTC+/AR-V+ pts, respectively (P = 0.005). However, comparing CTC- and CTC+ pts, differences become even more apparent (P = 0.004), CTC+/AR-V- and AR-V+ pts showed less statistically significant differences (P = 0.029). Median PFS and OS were not reached for CTC- pts. PFS was 10 months (95%CI 6.2 – 13.8) for CTC+/AR-V- pts and 9 months (95%CI 1.1 – 16.9) for CTC+/AR-V+ pts (P = 0.004, only CTC- vs. CTC+ P = 0.002). OS was 28 months (95%CI 16.8 – 39.2) for CTC+/AR-V- pts and 15 months (95%CI 7.9 – 22.1) for CTC+/AR-V+ pts (P = 0.014, only CTC- vs. CTC+ P = 0.006). Regarding PFS and OS, there was no difference comparing only CTC+/AR-V- and AR-V+ pts (P = 0.356 and P = 0.244). Conclusions: AR splice variants have prognostic power in stratifying mCRPC patients suffering from a more advanced stage of disease. Nonetheless, our study clearly demonstrates the lack of predictive power of AR splice variants for response to NHT. Additionally, we prove the importance of CTC analysis rather than AR-V expression being more valuable in mCRPC.
Treatment decision making in metastatic prostate cancer (mPC).
Authors: Schumacher Frank , Xu Jiahui , Oswald Laura , Lee Benjamin , Gonzalez Brian , Zhang Hui , Morgans Alicia K. 
Published: May 2020

e17552 Background: Multiple treatments with similar efficacy exist for mPC, leaving patients (pts) with complicated treatment choices. Shared decision-making (SDM) can facilitate treatment decisions. The extent to which SDM is used in mPC is unknown. We assessed mPC pt, caregiver, and physician perceptions of decision locus of control (DLOC) (SDM vs. physician- or pt-directed decisions), and the degree of agreement between groups. Methods: Pt/caregiver/physician triads completed surveys of decision-making practices between 12/2016 and 11/2017 after a clinic visit in which a decision occurred. Pts were included only if they had a caregiver present. To evaluate the degree of agreement between pt, caregiver, and physician perceptions of DLOC, we used the quadratic-weighted kappa coefficient (κ). Agreement was evaluated on an overall basis and by pt age group (5-year increments). Results: 50 pt/caregiver/physician triads participated, with median pt age of 72 yo. Most pts were white (96%) and married (90%). A majority of pts, caregivers, and physicians reported SDM (66%, 56%, and 52%, respectively). No group reported completely pt-directed decisions. Pts and physicians demonstrated agreement about DLOC for most encounters (weighted κ = 0.35; P = 0.01). Overall, pts and physicians agreed on the DLOC in 44% of cases, and SDM was the most common agreed-upon DLOC (36%). Relative to physicians, 34% of pts reported more pt influence on DLOC, and 22% of pts reported less pt influence on DLOC. In contrast, caregiver reports of DLOC were independent of physician reports (weighted κ = 0.23; P = 0.55). Overall, caregivers and physicians agreed on DLOC in 38% of cases, and SDM was the most common agreed-upon DLOC (32%). Relative to physicians, 46% of caregivers reported more pt influence on DLOC and 16% of caregivers reported less pt influence on DLOC. There was a statistically significant difference in the degree of agreement by pt age group between pts and physicians (P = 0.045) and caregivers and physicians (P = 0.002), although no specific pattern according to pt age was noted. Conclusions: A majority of pts, caregivers, and physicians reported SDM occurring in routine clinical visits for mPC. Pts reported a higher degree of agreement with their physicians in DLOC than caregivers. Both pts and caregivers perceived greater pt influence on treatment choice than physicians. Efforts to explore the association between SDM, pt satisfaction, and quality of life are ongoing.
Using longitudinal PSA values and machine learning for predicting progression of early stage prostate cancer in veterans.
Authors: Danciu Ioana , Erwin Samantha , Agasthya Greeshma , Janet Tate , McMahon Benjamin , Tourassi Georgia , Justice Amy 
Published: May 2020

e17554 Background: The ability to understand and predict at the time of diagnosis the trajectories of prostate cancer patients is critical for deciding the appropriate treatment plan. Evidence-based approaches for outcome prediction include predictive machine learning algorithms that harness health record data. Methods: All our analyses used the Veterans Affairs Clinical Data Warehouse (CDW). We included all individuals with a non-metastatic (early stage) prostate cancer diagnosis between 2002 and 2017 as documented in the CDW cancer registry (N = 111351). Our predictors were demographics (age at diagnosis, race), disease staging parameters abstracted at diagnosis ( Stage grouping AJCC, Gleason score, SEER summary stage) and prostate specific antigen (PSA) laboratory values in the last 5 years prior to diagnosis (last value, the value before last, average, minimum, maximum, rate of the change of the last 2 PSAs and density). The predicted outcome was disease progression at 2 years (N = 3469) and 5 years (N = 6325) defined as metastasis - taking either Abiraterone, Sipuleucel-T, Enzalutamide or Radium 223, registry cancer related death or PSA > 50. We used 4 different machine learning classifiers to train prediction models: random forest, k-nearest neighbor, decision trees, and xgboost all with hyper parameter optimization. For testing, we used two approaches: (1) 20% sample held out at the beginning of the study, and (2) stratified test/train split on the remaining data. Results: The table below shows the performance of the best classifier, xgboost. The top five predictors of disease progression were the last PSA, Gleason Score, maximum PSA, age at diagnosis, and SEER summary stage. The last PSA had a significantly higher contribution than the other predictors. More than one PSA value is important for prediction, emphasizing the need for investigating the PSA trajectory in the period before diagnosis. The models are overall very robust going from outcome at 2 years compared to 5 years. Conclusions: A machine learning based xgboost classifier can be integrated in clinical decision support at diagnosis, to robustly predict disease progression at 2 and 5 years. [Table: see text]
Real-world outcome with abiraterone low-dose plus prednisone in patients with mCRPC in a Brazilian Public Cancer Center.
Authors: Zucca Luis Eduardo Rosa , Neif Joao Antonio Junior , Preto Daniel D Almeida , Cordeiro Dias Isadora Clarissa , Araujo Hadson Silva , Carcano Flavio Mavignier ,   OncoGU
Published: May 2020

e17563 Background: Abiraterone acetate (AA) is a potent selective and irreversible inhibitor of CYP17 used as standard treatment for metastatic Castration Resistant Prostate Cancer (mCRPC). In the pivotal trial COU-AA 301, AA 1000 mg/day plus prednisone increased overall survival after docetaxel in patients with mCRPC. A recent trial demonstrated not inferiority with respect to PSA metrics in the reduced dose of 250mg/day AA associated with dietary intake, which is described as AA low dose (AALD). The introduction of generic AA in the Brazilian Pharma Market and after the endorsement of AALD from international guidelines, the use of AA in limited resourced hospitals became feasible. Since december 2018 our institution has incorporated AALD in patients with mCRPC in first or second line therapy, always after chemotherapy with Docetaxel (either in the sensitive or castration scenario). Methods: We retrospectively reviewed 49 patients with mCRPC that received AALD after chemotherapy with Docetaxel from December 2018 to January 2019. The primary end point was PSA response rate (decrease of ≥ 50% in the PSA concentration from pretreatment PSA value). Univariable analysis were performed to explore association between clinical and pathological features. Results: After a median follow-up of 5 months, 25 patients (51%) had PSA response rate ≥ 50%. Median age was 69 years-old and most patients (73.5%) were ECOG 0 and 1. Despite good ECOG, the population had aggressive disease characteristics with 57.1% being ISUP 4 and 5 and 69.4% being clinical stage IV at initial diagnosis. Seventeen patients (34.7%) were exposed to AALD at first line and 32 patients (65.3%) in second line. It was observed that patients in the first line had better PSA response rate them those treated in the second line (70,6% vs 40,6%. p 0.04). Conclusions: Despite the premature data, this retrospective analyses shows PSA response rate in about 50% of patients treated with AALD in the overall population and about 70% in those treated in first line therapy. Serum PSA response rate is known as a surrogate marker for overall survival in those patients. The protocol will for more mature data. AALD might be an alternative dose for treating patients in institutions with limited resources.