bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can we avoid radiotherapy with 18FCH PET/CT?
Authors: Iorio Julieta , Eleta Martin , Bambacci Florencia , Cuneo Lucrecia , Montenegro Constanza , Brisco Maria Agustina 
Published: March 2019

282 Background: The aim of this study was to assess the utility of 18 fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) in detecting local recurrence in patients with prostate carcinoma treated with radical prostatectomy surgery. Methods: 432 patients with prostate cancer were enrolled in our institution between July 2015 and August 2018. 176 were treated with radical prostatectomy surgery and presented elevated levels of PSA (0.02-1600 ng/ml). All of them underwent “Dual phase” PET-CT consisting of initial pelvis starting 20 minutes after the injection of 18 F-Choline followed by 1 hour delayed PET of the whole body. 18 F-Colina PET/TC findings were compared with other imaging techniques and/or clinical monitoring. Patients were divided in three subgroups according to PSA levels: <1 ng/ml; ≥1-5ng/ml y >5 ng/ml. Results: 39 (22%) patients had PSA levels <1 ng/ml; 90 (51%) had between 1-5 ng/ml and 47 (27%) >5 ng/ml. 120 (68%) patients showed radiotracer uptake, on the other hand, 56 (32%) patients had negative PET-CT. 153 lesions showed increased uptake on FCH-PET, only 36 (23%) of them were interpretated as local recurrence the rest of them were interpretated as extraprostatic involment (table). Conclusions: 18 FCH PET/CT has clinical implications in patients with prostate carcinoma treated with radical prostatectomy surgery not only because it avoids unnecessary radiotherapy in the surgical wound, but also, it has the ability to detect local recurrent disease and lymphatic/haematogenous involvement. [Table: see text]
Utilization and outcomes of surgical castration in comparison to medical castration in metastatic prostate cancer.
Authors: Garje Rohan , Chennamadhavuni Adithya , Mott Sarah L , Chambers Isaac Matthew , Gellhaus Paul , Zakharia Yousef , Brown James A. 
Published: March 2019

288 Background: Androgen deprivation therapy (ADT) is the gold standard for metastatic prostate cancer (mPC) which can be achieved either by surgical or medical castration (SC, MC). In this study we evaluate the trends of utilization of SC and also assess survival difference compared to MC. Methods: National Cancer Database was used to identify patients with mPC from 2004 to 2014. Logistic and Cox regression models were utilized to estimate the odds of utilization of SC and effect of treatment on overall survival (OS). Results: A total of 33712 pts with mPC were identified; 31722 (94.1%) had MC and 1990 (5.9%) underwent SC. There was significant decline in the trend of utilization of SC from 8.5% in 2004 to 3.1% in 2014. On multivariable analysis, being a non-caucasian race, lower household income levels, having non-private insurance and earlier years of Dx were found to be associated with increased odds of choosing SC over MC. Notably, the odds of SC were lower at academic centers. On univariate analysis, a survival difference between ADTs was evidenced (p<0.01); 5-yr OS for MC and SC was 24.8% and 18.2%. However, on multivariate analysis there was no OS difference between SC and MC (p=0.14). Conclusions: In this large contemporary analysis, the utilization of SC has declined overtime with no OS difference when compared to MC. With rising health care costs, changing the practice by utilizing SC can help reduce healthcare expenditure. [Table: see text]
A survey to determine patients’ (pts) opinions of a clinical trial (CT) comparing intermittent (int) versus continuous (cont) androgen receptor signaling inhibitor (ARSi) therapy for the treatment of advanced prostate cancer.
Authors: Phillips Cameron , Delos Santos Seanthel , Mason Robert , Emmenegger Urban 
Published: March 2019

295 Background: Several therapies have shown a survival benefit and improvements in pt-reported quality of life in metastatic prostate cancer (mPC) including ARSis, such as abiraterone (A) and enzalutamide (E). While both are fairly well tolerated, there is a wide range of side effects associated with them. In addition, both of these medications are costly. The purpose of this study was to obtain pts’ opinions regarding potential participation in a randomized CT comparing int to cont treatment with A and E. Methods: We approached ambulatory pts diagnosed with mPC between August 2018 and October 2018 to complete a questionnaire eliciting their preferences regarding participation in a CT comparing int to cont treatment with A or E. A total of 105 patients completed the survey. We collected information regarding pts’ current/prior therapies, their interest in being treated with an int strategy and reasons for or against participating in a randomized CT with int versus cont treatment. Results: The median age of our pts was 72 years (IQR: 67 -78). 30% of patients had prior experience with an ARSi (A 10%, E 20%). 51% of pts were receiving either A (28%) or E (23%) at the time of the survey. 76% of pts indicated that they would generally be interested (27%) or very interested (49%) in participating in CTs, and 65% of patients were interested (19%) or very interested (46%) in participating in a CT involving int ARSi therapy. The reasons for participating include the prospect of less side effects (49%), less medication burden (39%), and cost-savings (15%). The reasons for not participating include the possibility of the cancer worsening off treatment (55%), the possibility of worse overall survival (48%), and the possibility of developing cancer-related symptoms in the off-phase (39%). Conclusions: The majority of pts surveyed would be interested in participating in a randomized CT that would include int versus cont treatment with an ARSi. In a complementary study, we are surveying oncologists to determine the ideal patient cohort for such a study, as well as acceptable triggers for treatment interruption and resumption.
Effect of IL-6 and related mediators on resistance to abiraterone acetate (abi) and enzalutamide (enza) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Adashek Jacob J. , Won Haejung , Moreira Dayson , Duttagupta Priyanka , Twardowski Przemyslaw , Jones Jeremy , Kortylewski Marcin , Pal Sumanta K. 
Published: March 2019

296 Background: IL-6 is an upstream regulator of various moieties, including STAT3, that are associated with a poor prognosis in mCRPC. The specific association between these moieties and outcomes with enza and abi are as yet undefined. Methods: Pts receiving abi or enza in the course of routine clinical care were consented for blood collection at weeks 0, 4, 8, and 12 of therapy, and at the time of progression (based on PCWG3 criteria). PBMCs were isolated within 4 hours of blood collection and plasma samples were assessed for 30 soluble immune mediators using Luminex analysis. Flow cytometric analysis was used for characterization of CD3, CD4, CD8 and PD-1. CellSearch was used for CTC enumeration. Results: Of 36 patients consented, 21 received abi and 15 received enza. Median age in the cohort was 71 (range, 54-84). Median PSA was 21.9 ng/dL (range, 0-918.3) and mean CTC count was 158 (range, 0-2126). Median duration of therapy (DOT) with abi or enza was 10.5 mos (range, 1-53); pts were divided into two groups around median DOT. Median DOT in Group A and B were 4 mos (range, 1-10) and 49 mos (range, 11-53), respectively. Patients in Group A had higher levels of pre-treatment levels of IL-6, IL-10, GM-CSF, MIG and FGF, and higher expression of PD1 and FoxP3 on CD4+ T cells (P < 0.05 for each). In an exploratory analysis, patients with > 5 CTCs/7.5 mL of blood at baseline had higher levels of IL-6, although this was not statistically significant (P = 0.08). Conclusions: Elevated levels of IL-6 and several other cytokines are seen in patients with relative resistance to abi/enza for mCRPC. Surface expression of PD-1 and FoxP3 on CD4+ T-cells is also higher in the setting of resistance. The dual combination of elevated pro-inflammatory cytokines along with elevated immunosuppressive signals supports ongoing trials assessing checkpoint inhibition with abi/enza, as well as efforts by the current investigators to develop therapies antagonizing STAT3 (Moreira D et al CCR 2018).
Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bailis Julie , Deegen Petra , Thomas Oliver , Bogner Pamela , Wahl Joachim , Liao Mike , Li Shyun , Matthes Katja , Nägele Virginie , Rau Doris , Rattel Benno , Raum Tobias , Kufer Peter , Coxon Angela 
Published: March 2019

301 Background: mCRPC is a disease of high unmet medical need, especially for patients who fail novel hormonal therapies and chemotherapy. BiTE molecules provide an off the shelf therapy that activates a patient’s own immune system and redirects T cells to kill tumor cells. The BiTE mechanism of action is distinct from other immunotherapies and may unlock immune response in mCRPC. PSMA is a compelling BiTE target that is highly expressed on PCa compared to normal tissue and has increased expression in mCRPC. Methods: AMG 160 is a fully human, half-life extended (HLE) BiTE that targets PSMA on tumor cells and CD3 on T cells. AMG 160 comprises two tandem single chain variable fragments fused to an Fc domain. Results: AMG 160 binds human and non-human primate (NHP) PSMA and CD3, leading to T cell activation and proliferation and cytokine production. AMG 160 redirects T cells to kill PSMA-positive cancer cell lines in vitro, including those with low PSMA levels or androgen-independent signaling. Weekly dosing of AMG 160 induces significant antitumor activity in established PCa xenograft model. The pharmacokinetics (PK) and pharmacodynamics of AMG 160 were tested in NHP. AMG 160 treatment led to BiTE target engagement in vivo, including transient T cell activation and cytokine release in blood, and mixed cellular infiltrates in multiple organs known to express PSMA. AMG 160 treatment was well tolerated. Cytokine release associated with the first dose could be attenuated using a step dose regimen. The half-life of AMG 160 in NHP was about one week. Based on allometric scaling, the PK profile of AMG 160 may be projected to enable dosing every other week in humans. Conclusions: AMG 160 is a potent HLE BiTE with specificity for PSMA-positive tumor cells. A Phase 1 study is planned to evaluate the safety and efficacy of AMG 160 in patients with mCRPC.
The effect of androgen receptor splice variant 7 on the growth of castration-resistant prostate cancer and the efficacy of taxane chemotherapy.
Authors: Shimizu Yasuomi , Kato Minoru , Takeyama Yuji , Hamada Kosuke , Iguchi Taro , Tamada Satoshi , Nakatani Tatsuya 
Published: March 2019

302 Background: Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as a mechanism associated with the development of castration-resistant prostate cancer (CRPC), but a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. We clarify the relationship between AR-V7 expression and resistance to taxanes. Furthermore, we assess the inhibitory effect of EPI-002, an antagonist of AR amino-terminal domain (NTD), to an AR-V7 driven CRPC cell line with acquired resistance to docetaxel. Methods: LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel, was developed. WST-1 assay or BrdU ELISA assay was performed to evaluate the inhibitory effect of drugs. We examined alterations of AR and AR-V7 signaling using Western blot analyses, real-time RT-qPCR and reporter gene assay. Results: LNCaP95-DR cells showed cross-resistance to cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002 had an inhibitory effect on the proliferation of LNCaP95-DR cells that was similar to that achieved with the parental LNCaP95 cells, whereas enzalutamide had no effect on the proliferation of either cell line. Conclusions: Our results suggest that EPI-002 may be an option for the treatment of AR-V7-driven CRPC that is resistant to taxanes.
Biochemichal recurrence in prostate cancer after salvage surgery in correlation to the site of reccurrent disease.
Authors: Pfister David , Pullankavumkal Jasmin , Haidl Friederike , Heidenreich Axel 
Published: March 2019

306 Background: Due to improved diagnostic tools salvage surgery is getting more popular after failure of primary local treatment as radical prostatectomy or radiotherapy. We analyzed PSA progression free survival (PFS) after radical prostatectomy and or radiotherapy in accordance to the location of the recurrence and the performed salvage surgery. Methods: We retrospectively analyzed 274 patients with salvage surgeries. 142, 18, and 114 patients underwent salvage radical prostatectomy (SPRE, Group1), locoregional recurrences mainly in seminal vesical remnants (SVR, Group2) or salvage lymph node dissection (SLND, Group3). All patients were diagnosed either by Choline- or more lately PSMA-PET CT. All surgeries had been done open. In Group1 radical prostatectomy and lymph node dissection, in Group 2 the seminal vesicals and in Group3 an ipsilateral pelvic lymph node dissection had been performed due to imaging results. Results: Median age at time of surgery was 67(62-72)years. Median PSA was 3.1(1.45-5.45)ng/ml. Radiotherapy or hormone therapy before salvage surgery in Group 1,2,3 was done in 100%, 61,1%, 54,39% and 12,6%, 27,8%, 18,42% of the patients. Median progression free survival in Group 1, 2, 3 is 41(11.104), 29 (8-47) and 8 (2-21) months (p < 0.001). PSA PFS in Group1/2 and Group 1/3 differed significantly with an HR of 1.85 (95%CI;1,0-3.44) and HR of 2.72 (95%CI; 1,84-4,04). Only age at time of surgery and interval from primary treatment to salvage procedure in months were significant predictors in an univariate Cox regression analysis. Conclusions: We demonstrate that the best biochemical control in salvage surgeries is achieved in patients with isolated recurrence in the prostate after radiotherapy. The effect of salvage surgery decreases with increasing distance of the site of recurrence to the prostate.
Germline heterozygous BLM mutations and prostate cancer risk.
Authors: Ledet Elisa , Antonarakis Emmanuel S. , Pritchard Colin , Isaacs William B. , Sartor A. Oliver 
Published: March 2019

321 Background: The BLM gene encodes a RecQ DNA helicase that is involved in homologous recombination. Biallelic BLM inactivation leads to Bloom syndrome, an inherited genetic disorder marked by chromosomal instability and multiple cancer susceptibilities. Conflicting studies have suggested that heterozygous BLM mutation carriers may have an increased risk of various cancers. Here we explored the role of germline pathogenic BLM mutations in prostate cancer. Methods: Prostate cancer patients with heterozygous BLM mutations were assembled from Tulane Cancer Center (TCC), Johns Hopkins Hospital (JHH) and University of Washington (UW). BLM germline mutations were identified either through commercial germline testing (Invitae), the UW-BROCA panel, or whole-exome sequencing. Corresponding tumor tissue was analyzed by DNA sequencing for somatic alterations. Population level control data were obtained from the Genome Aggregation Database (gnomAD). Results: 6 BLM germline carriers were identified among 985 advanced prostate cancer case; 2/295 TCC patients, 2/172 JHH patients, and 2/518 UW patients. Overall, pathogenic BLM mutations were detected in 0.609% (6/985) of prostate cancer cases. All mutations were loss-of-function truncating lesions (splicing or nonsense alterations). No Ashkenazi BLM mutations were observed. The population frequency of pathogenic or likely pathogenic BLM alterations detected in gnomAD was 0.025% (31/124,589). Compared to gnomAD controls, the relative risk of BLM mutations in prostate cancer patients was 24.3 (95% CI 10.2 to 58.2; P < 0.0001). One family had a pathogenic splice variant in BLM that cosegregated with disease in three of three cases with lethal/high risk prostate cancer. Tumor DNA sequencing was possible in 5 of 6 BLM carriers; no case demonstrated LOH or additional somatic BLM mutations. Interestingly, 2/5 cases on tumor sequencing also had bi-allelic BRCA2 inactivation. Conclusions: Germline BLM mutations may play a role in prostate cancer risk. Given the role of BLM in chromosomal stability and evidence of concurrent BRCA2 inactivation in a subset of cases, larger cohorts and functional analyses will be critical for better understanding the role of BLM in prostate cancer.
Prostatectomy in men with clinically positive lymph nodes.
Authors: Ghali Fady , Ryan Stephen , Hansen Moritz , Hayn Matthew , Sammon Jesse , Sarkar Reith , Murphy James Don , Kader A. Karim , Rose Brent 
Published: March 2019

327 Background: A prostate cancer (PCa) patient with non-metastatic but clinical positive lymph nodes (cN+) represents a difficult clinical scenario. We compared OS after RP in cN- (High Risk), cN+/pN- (Discordant), and cN+/pN+ (Concordant). Methods: The National Cancer Database was queried for all PCa patients from 2004-2013. Inclusion criteria were known age and PSA at diagnosis, biopsy Gleason score, TNM staging (cT1-3B, cN0/1, M0/X), margin, nodal status and primary treatment modality. cN+ was separated into two cohorts: pN- (Discordant) and pN+ (Concordant). RPs for High Risk PCa (cT3a/b or GS ≥ 8 or PSA > 20) with cN- was used as a comparison. OS was analyzed with Kaplan Meier (KMA) and Cox proportional hazard model combing demographic, clinical, and pathological factors. Results: 4944 cN+ men were identified (21.7% RP, 27.5% systemic therapy only). 794 RPs had completed records. Discordant and Concordant represented 18.8% and 81.2% with median follow-up 48 and 48.9 months, and 13 and 97 deaths, respectively. KMA pairwise OS of High Risk (n=35, 502) verses Discordant was not significant (p=0.28) but was significant verses Concordant (p < 0.001). There was no difference in OS on KMA between Discordant and Concordant (p=0.11). OS on Cox proportional hazard model, High Risk and Discordant had no observable difference (p=1.22). Concordant pathology had much worsened OS (HR 1.829, p < 0.001), as well as Medicaid/Medicare patients (HR 1.344, p < 0.001), biopsy Gleason score ≥ 8 (HR 1.350, p=0.0019), pathologic T stage (pT3a HR 1.567, pT3b 2.396, p < 0.001), and positive surgical margin (HR 1.257, p < 0.001). Conclusions: In a large cohort of nonmetastatic PCa patients with cN+ disease, > 27% were treated with systemic therapy based on clinical staging, but 18.8% of cN+ RPs were incorrectly staged. There was no difference in OS between cN- High Risk patients and pathologic Discordant (cN+/pN-) men, and the much worse OS in men with pN+. Study is needed for more accurate clinical staging tools to identify the pathologically discordant population.
Gemcitabine-carboplatin (GCb) versus gemcitabine-oxaliplatin (GemOx) in cisplatin un-fit advanced urothelial carcinoma: Randomized phase II study (COACH Study).
Authors: Lee Jae-Lyun , Kim Bong-Seog , Lim Ho Yeong , Kim Hee Jun , Park Inkeun , Lee Hyo Jin , Choi Yoon Ji , Park Kyong Hwa , Lee Kyung Hee , Yoon Shinkyo , Hong Bumsik , Hong Jun Hyuck , Ahn Hanjong 
Published: March 2019

355 Background: More than half of patients (pts) with advanced urothelial cell carcinoma (UCC) are ineligible for cisplatin because of renal dysfunction or poor performance status. We investigated the activity and safety of first-line gemcitabine-oxaliplatin (GemOx) compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible pts with advanced UCC. Methods: Treatment naïve, cisplatin-ineligible pts with advanced UCC were randomly assigned to GemOx (gemcitabine 1000 mg/m2, oxliplatin 100 mg/m2 on D1 Q2W) or GCb (gemcitabine 1000 mg/m2 on D1 and 8, carboplatin AUC 4.5 on D1 Q3W) stratified by ECOG performance status (PS) and visceral metastases. The primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between May 2013 and Mar 2017, 80 pts were enrolled and 79 pts received at least one dose of chemotherapy (39 pts in GCb; 40 pts in GemOx). Median age was 73 years (47-86) and ECOG PS was 2 in 42% of pts and 60% had visceral metastases. Median GFR was 45 ml/min (range 22-108) in GCb and 47 ml/min (range 15-73) in GemOx arm. With median follow-up duration of 37.8 months, all pts were off study treatments. RR were 48.7% and 55.0% in GCb and GemOx, respectively (p = 0.742). Median PFS and OS in GCb and GemOx arm were 5.5 months (95% CI, 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) [HR GemOx/GCb 0.92; p = 0.756] and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0) [HR 0.72; p = 0.194], respectively. The median cycle was 6 (1-10) in GCb and 7 (1-12) in GemOx. Grade 3 leukopenia, neutropenia and fatigue were more common in GCb arm (25.6% vs. 2.5%, p = 0.003; 33.3% vs. 10.0%, p = 0.014; 15.4% vs. 0%, p = 0.012). Dose delay and reduction in GCb and GemOx group were needed in 46.2%, 50.0% and 53.8%, 32.5%, respectively. Salvage chemotherapy after study treatment was offered in 54.3% and 55.9% of patients who experienced PD in GCb and GemOx arm. Conclusions: GemOx has showed comparable efficacy with GCb and favorable hematologic toxicity profile. GemOx may be used as a new option for patients who are not suitable for cisplatin-containing chemotherapy. Clinical trial information: NCT01487915.
Cell-free DNA (cfDNA) whole genome bisulfite sequencing in patients with muscle-invasive bladder cancer patient treated with cystectomy with curative intent.
Authors: Lu Yi-Tsung , Gooden Gerald C , Tew Ben Yi , Buckley David , Siegmund Kimberly , Daneshmand Siamak , Salhia Bodour , Goldkorn Amir 
Published: March 2019

359 Background: Muscle invasive bladder cancer (MIBC) frequently recurs despite radical cystectomy, and new biomarkers are needed to guide treatment. DNA methylation plays a key regulatory role in cancer initiation and progression and has been correlated with prognosis in multiple cancer types. We hypothesized that methylation patterns in cfDNA can predict recurrence after curative cystectomy. Methods: Using a clinically annotated USC bladder cancer tissue archive under an IRB approved protocol, we selected 40 patients whose cancer relapsed within 3 years of radical cystectomy, as well as 46 age-matched and stage-matched patients who did not recur after 3 years of follow-up. cfDNA was extracted from the archival plasma, and samples were pooled for whole genome bisulfite sequencing (WGBS) based on pathologic stages (T2a, T2b, T3a, T3b, and T4/N+) and recurrence status. Results: Extracted cfDNA and sequencing met QC criteria, and differentially methylated regions (DMRs) were called by metlene and filtered based on > 10% methylation difference (recurrence vs. cured) and p value < 0.01. Pooled analysis across stages yielded 729 DMRs, of which 487 (67%) were hypomethylated in the recurrence groups. Unsupervised clustering of these DMRs accurately distinguished the recurrence groups. Stage-specific DMRs were also called and used to generate a list of differentially methylated genes shared across stages. Methylation by stage and pooled across stage in our recurrence groups was directly correlated with methylation in tumor tissue in publically available datasets (Basespace Correlation Engine) and was inversely correlated with TCGA expression datasets. Conclusions: WGBS was successfully performed in MIBC using cfDNA extracted from archival plasma. Methylation patterns were concordant with publically available datasets, and cfDNA hypomethylation pre-cystectomy was associated with cancer recurrence in our cohort. Additional data filtering and annotation is ongoing and will be used to define a methylation signature for validation as a biomarker predictive of recurrence in MIBC.