bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Cancer-related fatigue in carcinoma urinary bladder patients receiving chemotherapy: A single institutional study from northern India.
Authors: Talwar Vineet , Goel Varun , DASH Prasanta
Published: March 2019

361

Background: Fatigue is one of the most disabling phenomenon among patients receiving anti cancer treatment, which has profound effect on their Quality of life (QOL). Although clinicians across the globe acknowledge the importance of regular assessment of fatigue, however it is seldom being assessed and documented in clinical practice in India and very few studies have reported Cancer Related Fatigue among Indian population. Methods: For this study an exploratory design was adopted, using a purposive sampling method. Patients (N=206,) undergoing chemotherapy at Rajiv Gandhi Cancer Hospital and Research Center, Delhi, India; aged 18-83 years were included. The level of fatigue was assessed using 16- item Multidimensional assessment of Fatigue (MAF) scale and a semi structured in depth interview schedule. These interviews were recorded, transcribed and analyzed. Results: Irrespective of age, and education, 81% patients experience clinically significant fatigue. Extreme level of fatigue was reported by 29% patients requiring immediate clinical intervention while 52% patients reported moderate level of clinically significant fatigue. Top four psychosocial issues reported were: apprehension of CT side effects (23.5%), fear of pain (19%), Loss of appetite (17.5%) and anxiety during CT (13.5 %), followed by financial issues (11%). Among all patients, (49.5%) were aware of their diagnosis of which 8% were either fully aware or partially aware about the prognosis (23%). Conclusions: Fatigue remains one of the most important clinical parameters among majority of Carcinoma Urinary Bladder patients receiving chemotherapy, and is neither assessed by clinicians nor reported by majority of the patients. While almost one fourth of the patients report fear of chemotherapy as their pressing psychosocial concern, others report fear of pain, loss of appetite, manifest anxiety symptoms or report financial and logistics issue during CT. Various exercise, educational material and psychotherapeutic interventions should be developed to prepare and support them during their treatment for better preparedness of side effects and their management, reduced symptoms and better quality of life.
Decreasing ureteral stent duration following radical cystectomy decreases readmissions and urinary infectious complications.
Authors: Beano Hamza Mustafa , He Jiaxian , Hensel Caitlin , Worrilow William Mills , Gaston Kris E , Clark Peter E , Riggs Stephen Boyd
Published: March 2019

366

Background: Readmission following Radical Cystectomy with Urinary Diversion (RCUD) is often related to Urinary Tract Infection (UTI). We hypothesized that decreasing the duration of ureteral stenting postoperatively would decrease UTI-related complications without affecting ureteroenteric stenosis (UES) rates. Methods: We analyzed a prospectively and retrospectively collected dataset for cystectomy patients at our tertiary center. Adult patient who underwent RCUD for malignancy from January 2013-January 2018 were included. Patients with a history of abdominal/pelvic radiation and continent diversions were excluded. The patient population was divided to Late stent removal group (LSR- POD 14) and early stent removal group (ESR- POD 4). Statistical methods included t-test, chi-square test and multivariate logistic regression. Results: 177 patients were included in the final analysis after inclusion/exclusion criteria were applied. The LSR (n=75) and ESR (n=102) groups were similar in preoperative characteristics except higher intracorporeal ileal conduit formation in ESR. The LSR had higher 90-day overall readmission rates (OR=2.26, 95% CI;1.13,4.51, p-value=0.021), UTI-related readmissions (OR=3.05, 95% CI:1.32,7.04, p-value=0.010) and UAE (OR=3.02, 95%CI;1.47,6.18, p-value=0.003). Conclusions: Shorter ureteral stent duration following RCUD is associated with decreased readmissions and urinary infections complications without concurrent increase in UES. Strong consideration should be directed towards early stent removal. [Table: see text]
Hyperprogressive disease (HPD) in genitourinary (GU) cancer patients treated with PD-1/PD-L1 inhibitors.
Authors: Hwang Inhwan , Park Inkeun , Yoon Shin-Kyo , Lee Jae-Lyun
Published: March 2019

369

Background: Post immunotherapy response and disease progression pattern are still under investigation. In terms of progression, rapid progression pattern called HPD has been observed during the early cycles of PD-1/PD-L1 inhibitors therapy in patients with various cancers. Data of HPD in patients with GU cancer are limited. Methods: This study included 203 patients with GU cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as greater than 50% increase in tumor burden compared with before-treatment computed tomography (CT) scan and greater than 2-fold increase in tumor growth rate (TGR) compared with previous TGR. Development of extensive new lesions were also regarded as HPD. Response was evaluated by RECIST v1.1 on at least two consecutive CT scan before the initiation of PD-1/PD-L1 inhibitors and one CT scan within 2 months after initiation of PD-1/PD-L1 inhibitors. Results: 102 patients with renal cell carcinoma (RCC) and 101 patients with urothelial cell carcinoma (UCC) were included. Median age was 64 years (range 56-71) and 141 patients (70%) were male. The most common metastatic site was lymph node (66%), followed by lung (51%) and bone (34%). HPD was observed in 13 out of 230 patients (5.7%; 95% CI, 5.0-6.3). Median OS for patients with progressive disease and HPD were 7.3 months and 3.5 months, respectively ( p=0.09). HPD was more frequently found in patients with UCC than RCC (11% vs. 0.9%, p=0.01). In multivariate analysis, patients of UCC ( p <0.001), presence of liver metastasis ( p=0.002), elevated LDH level (> upper normal limit, p=0.01), and hypoalbumimemia (< 3.5 gm/dL, p<0.001) were independent predictive factors for HPD. Conclusions: The incidence of HPD in GU cancer patients seems to be low compared to previous studies (9-10%). The majority of HPD developed in UCC and the incidence in RCC is negligible. Cares should be taken when treating patients with PD-1/PD-L1 inhibitors, especially when patients have UCC and liver metastases, elevated LDH and hypoalbuminemia.
Distinct genomic hallmarks exist between metastatic upper and lower tract urothelial carcinoma.
Authors: Winters Brian , De Sarkar Navonil , Arora Sonali , Bolouri Hamid , Vakar-Lopez, MD Funda , Cheng Heather H. , Yu Evan Y. , Kollath Lori , Grivas Petros , McFerrin Lisa , Montgomery Robert B. , Wright Jonathan , Lam Hung-Ming , Hsieh Andrew Caleb
Published: March 2019

371

Background: Although the genomic landscape of LTUC is well studied, less is known about UTUC, including in the metastatic sites. We compared genomic features of metastatic UTUC and LTUC. Methods: We performed whole exome sequencing on 7 rapid autopsy patients with metastatic UC, with matched primary and metastatic tumor samples (N = 37). Single nucleotide variants (SNV) were identified using Mutect and Strelka. Focused analyses were performed on mutations with known significance in UC as well as mutations predicted to have functional impact using 11 mutation assessors. Genome scale copy number aberrations (CNA) were estimated using Sequenza (normalized for ploidy) to derive gene definition restricted copy number estimation outcomes. Multi-dimensional scaling (MDS) was used to visualize how copy number and mutation-derived genomic distances differed between LTUC and UTUC. Results: Three pts with UTUC (3 primary samples, 13 metastases) and four pts with LTUC (4 primary samples, 17 metastases) were examined. The majority of patients were male (5) and received cisplatin-based therapy (5). We found that SNV burden (mean mutation per megabase) was significantly higher in LTUC vs. UTUC overall (6.6 vs. 3.8, p = 0.001) and when stratified by primaries (6.1 vs. 2.9, p = 0.047); or metastases (6.7 vs. 4.1, p = 0.001). Mutational signature analysis revealed higher proportion of APOBEC signature in all LTUC vs. UTUC tumors. Both inter- and intra-individual genomic distances between primary and metastatic tissues were substantially larger in UTUC than LTUC, suggesting a wider spectrum of mutations at the level of individual nucleotides and chromosomal structure. Interestingly, Gene definition-restricted CNA analysis revealed MDM2 amplification exclusively in UTUC tumors which was associated with shallow p53 deletion. Conclusions: Metastatic UTUC appears to have a lower overall mutational burden but greater genomic variability compared to LTUC. Our relatively small dataset suggests that metastatic UTUC displays a greater spectrum of mutational divergence from LTUC which may partially explain differences in clinical behavior.
Risk for vascular thromboembolic events (VaTEs) in patients (pts) with advanced urinary tract cancer (aUTC) treated with chemotherapy.
Authors: Bamias Aristotelis , Tsironis George , Dimitriadis Ioannis , Tzanis Kimon , Tsiara Anna , Xirokosta Aikaterini , Kaparelou Maria , Kyriazoglou Anastasios , Cohen Abis , Barbarousi Despoina , Koutsoukos Konstantinos , Liontos Michael , Zakopoulou Roubini , Kostouros Euthymios , Pagoni Stamatina , Matsouka Charis , Dimopoulos Meletios A.
Published: March 2019

383

Background: Venous thromboembolism (VTE) is a frequent complication of cancer or its treatment. Khorana (KRS) and Compass scores are two Risk Assessment Models for VTE. However, aUTC was not adequately represented and arterial events were not included, in these models. Methods: Data from pts with aUTC treated with at least one line of chemotherapy in our institution were analyzed. VaTE definition included: DVT and PE defined as venous events and peripheral arterial thrombosis or embolus, ischemic stroke and coronary events, grouped as arterial events. The association of baseline and treatment-related factors with the development of VaTE was assessed using competing-risk regressions. According to the results of our multivariate analysis we stratified patients according to the number of the identified risk factors. Results: 354 aUTC pts treated between 4/1995 and 9/2015 entered our study. 53% of pts had received cisplatin and 42% carboplatin-based regimens. 44 pts (12.4%) suffered 45 VaTEs (13 arterial, 32 venous) within a median time of 3.3 months. The cumulative and 6-month incidence was 14.8% (95% CI: 10.9-19.4) and 9.7% (95% CI: 6.8-13.1), [venous 10.5% (95% CI: 7.3-14.3)/7.5% (95% CI: 5-10.7); arterial 5.3% (95% CI: 2.8-9)/2.7% (95% CI: 1.3-5), respectively]. No association of the KRS and the COMPASS score with the incidence of VaTEs was observed. In the univariate and multivariate analysis, cumulative VaTE incidence was significantly increased in pts with “peripheral arterial disease (PAD) or history of VΤE” (adjusted SHR: 3.29; 95% CI: 1.65-6.55; p=0.001) and pts with other solid tumor (SHR: 2.20; 95% CI: 1.05-4.62; p=0.038). There was a strong correlation between the number of risk factors and the risk for VaTE development (p<0.001). Patients with 1 or 2, vs 0 factors had a 3-fold increased risk [cumulative incidence was 10.9% (95% CI: 7.4.-15.2) and 30.2% (95% CI: 18.4-42.8), respectively; SHR: 3.01 95% CI: 1.65-5.51]. Conclusions: Development of tumor-specific algorithms for the risk of vascular events is supported by our results. Pts with aUTC and a history of VTE, PAD and other solid tumor have a very high risk for VaTE. The role of prophylaxis should be prospectively studied.
Long-term follow-up after radiotherapy for prostate cancer with and without rectal hydrogel spacer: A pooled prospective evaluation of quality of life.
Authors: Seymour Zachary A , Daignault Stephanie , Bosch Walter , Gay Hiram Alberto , Michalski Jeff M. , Hamstra Daniel A. , Pinkawa Michael
Published: March 2019

39

Background: Hydrogel spacers are a tool to improve dosimetry and overall quality of life with limited follow-up in men receiving radiotherapy for prostate cancer. This present study is a pooled analysis of a prospective cohorts with long-term follow-up quality of life (QOL) data with or without hydrogel spacers to minimize dose adjacent organs at risk. Methods: QOL was examined using the Expanded Prostate Cancer Index Composite (EPIC) to compare mean changes from baseline. A total of 215 patients from a randomized multi-institutional trial of radiation with or without hydrogel spacer with a QOL end-point were pooled with 165 non-randomized patients from a single institution with prospective QOL collection in both patients with or without hydrogel spacer. The proportions of men with minimally important differences (MIDs) relative to pre-treatment baseline in each domain were tested using repeated measures logistic models with pre-specified thresholds for clinically significant decline. Results: A total of 380 men were evaluated (64% with spacer and 36% without) with QOL data being available for 199 men beyond 24 months of follow-up (median: 39.5 months, range: 31-71.4 mo). Treatment with spacer was associated with less decline in average long-term bowel QOL (89.4 for control and 94.7 for experimental) with differences at > 2 years meeting the threshold of MID difference between cohorts (Bowel Score Difference from baseline: control = -5.1 spacer = 0.3 Diff = -5.4 p = 0.0003). When evaluated over time men without spacer were more likely to have 1xMID (5 points) declines in bowel QOL (p = 0.01). At long-term follow-up 1xMID was 36% without spacer vs 14% with spacer (p = 0.0006 OR = 3.5) while 2x MID was seen in 19% vs 6% (p = 0.008 OR = 3.6). The use of spacer was associated with improved bowel frequency (p = 0.002), reduced bleeding (p = 0.005) and less overall bowel problems (p = 0.007). Conclusions: In this pooled analysis of QOL after prostate radiotherapy with up to 5-years of follow-up utilization of a hydrogel spacer was associated with preservation of bowel QOL. This QOL benefit was preserved with long-term follow-up.
Real-world trends in first-line checkpoint inhibitor use (CPI) in advanced urothelial cell carcinoma (aUC).
Authors: Parikh Ravi Bharat , Galsky Matt D. , Baxi Shrujal S. , Adamson Blythe J.S. , Cohen Aaron Benjamin , Feld Emily , Christodouleas John Paul , Boursi Shimon Ben , Meropol Neal J. , Mamtani Ronac
Published: March 2019

392

Background: Standard first-line treatment of aUC is cisplatin-based chemotherapy, with carboplatin-based chemotherapy or CPI reserved for cisplatin-ineligible individuals. However, given their favorable toxicity profile, there may be an indication drift of first-line CPI into cisplatin-eligible patients, despite no approved indication in this population. Methods: Using the Flatiron Health Database, a nationally representative electronic medical record-based dataset, we examined real-world prescribing patterns of first-line systemic therapies among 2090 patients with aUC diagnosed between the first quarter (q) of 2015 and 2018q1. Our analysis of cisplatin-eligible individuals excluded patients with pre-treatment (1) Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, (2) creatinine ≥ 1.5 mg/dL, or (3) diagnostic codes for chronic renal failure, congestive heart failure, hearing loss, or peripheral neuropathy. We used nonparametric tests of trend to describe first-line CPI and chemotherapy use over time. Results: Between 2015 and 2018, the quarterly proportion of patients who received first-line CPI increased from 1.4% to 43%, while the proportion who received platinum-based chemotherapy decreased from 89% to 56% (ptrend< 0.001) Similarly, among cisplatin-eligible patients (n = 1181), the proportion of first-line CPI users increased from 1.0% in 2015q4 to 42% in 2018q1 (ptrend= 0.001), while the proportion of first-line cisplatin users fell from 53% in 2015q4 to 33% in 2018q1 (ptrend= 0.018). First-line CPI initiators were older (median age 76 vs 71) and had worse performance status (PS ≥ 2 17.8% vs 11.4%) relative to platinum initiators (Table). Conclusions: Our analysis suggests a dramatic rise in first-line CPI use, even in patients who may be cisplatin-eligible, for whom first-line CPI is not evidence-based. [Table: see text]
Identification of novel targets in non-muscle invasive bladder cancer: A systems biology approach.
Authors: Osterhout Robin , Kamal Adeela , Spigelman Samuel
Published: March 2019

396

Background: Most bladder cancers are diagnosed as non-muscle invasive bladder cancer (NMIBC). Because of the high rate of recurrence and limited treatment options for recurrent disease, there is an urgent need to identify new treatment options. In this study, a network-based drug discovery approach was applied to identify novel targets in NMIBC. Methods: A computational systems-biology framework integrating genomic, transcriptomic, protein-protein, and protein-drug interactions was applied to identify and prioritize potential NMIBC targets and pathways. First, a NMIBC disease network module was constructed from genetic associations augmented with known protein-protein interactions. Independent NMIBC case/control expression data sets were leveraged to develop a phenotypic network module comprising genes differentially expressed in NMIBC. Proteins and pathways linking the disease model with the phenotypic module were identified, ranked, and benchmarked against known NMIBC pathways and drug targets from the literature. Results: NMIBC seed genes cluster significantly within the human interactome, reflecting an underlying disease module. The expanded disease module comprises 103 genes that show functional and literature-based enrichment. Genes differentially expressed in NMIBC were significantly connected to disease module genes compared with random expectation (z = 23.3), and are enriched in several biologically relevant pathways. Based on similarity to disease biology and network topology, 11 NMIBC pathways were identified as bridging genetic predisposition for and phenotypic expression of NMIBC. Within these overlapping pathways, known and novel drug targets were identified. Of these in silico targets, 19 are currently under development for treatment of bladder cancer, validating the approach. To further validate the approach, we observed overlap between in silico targets and hits from a chemogenomic library phenotypic screen. Conclusions: A network-driven systems biology approach identified both known NMIBC targets and novel proteins/pathways that are potential targets for the treatment of NMIBC. Further target validation is required.
Non-urothelial bladder cancer: Genomic alterations and patient outcomes.
Authors: Anari Fern , Miron Benjamin , Henson Donald , Arguello David , Plimack Elizabeth R. , Zibelman Matthew R. , Ramamurthy Chethan , Ghatalia Pooja , Heath Elisabeth I. , Burgess Earle Frederick , Dawson Nancy Ann , Vaena Daniel A. , Somer Bradley G. , Hogan Thomas F. , Hauke Ralph J. , Aragon-Ching Jeanny B. , Geynisman Daniel M.
Published: March 2019

399

Background: Adenocarcinoma (ADA) and squamous cell carcinoma (SCC) are rare, aggressive subtypes of bladder cancer, for which no clear standard of care exists. We report on survival of pts with ADA and SCC and identify potential therapeutic targets using molecular profiling via next generation sequencing (NGS). Methods: Survival trends, demographics, pt characteristics were obtained from the Surveillance, Epidemiology, and End Results (SEER) Database. In a separate cohort, NGS results from 72 specimens (50% metastatic) were also analyzed, using either a hotspot 47 gene panel or a 592 gene assay (Caris Life Sciences, Phoenix, AZ). Results: In SEER, 235,537 cases of bladder cancer were extracted from 1988-2008, of which 3096 were SCC and 671 were ADA. 90% of pts were white, although more African-American patients (15%) were seen in those with ADA. Among all stages, median overall survival (mOS) and 5-yr survival rates were 17.9 mos and 58% for ADA and 15 mos and 37% for SCC. Via NGS testing, 43 patients (28 ADA, 15 SCC) were tested with a 47 gene panel and 29 (21 ADA, 8 SCC) with a 592 gene panel. In the 47 gene panel, among ADA pts, the highest mutation rates were TP53 (57.1%), KRAS (21.4%), SMAD4 (14.8%), PIK3CA (10.7%) and BRCA2 (7.7%). Among SCC pts, the highest mutation rates were TP53 (66.7%), PIK3CA (33.3%), HRAS (14.3%), FBXW7 (6.7%) and AKT1 (6.7%). In the 592 gene assay, the genes with the highest mutation rates in pts with ADA were TP53 (81%), SMAD4 (33.3%), KRAS (23.8%), KMT2C (11.8%), ARID1A (11.1%), BRAF (9.5%), CTNNB1 (9.5%), KMT2D (9.5%), TSC1 (9.5%), KDM6A (5.9%), CDKN2A (5%). Among SCC pts, the highest mutation rates were TP53 (75%), CDKN2A (42.9%), FGFR3 (25%), PIK3CA (25%), CIC (14.3%), KDM6A (14.3%), BRAF (12.5%), BRCA1 (12.5%), FH (12.5%), HRAS (12.5%) and KMT2D (12.5%). Only 1 pt had high TMB. Conclusions: Genomic profiling identifies differences in underlying tumor biology of bladder ADA and SCC, which on a population level are rare with poor survival. Overall, the alterations in the PIK3CA/ AKT/ mTOR and TP53 pathways are similar to what has been reported in UC. Future analyses of these malignancies should investigate the emerging actionable targets, such as TSC1, FGFR3, BRCA1/2 and BRAF.
Time to PSA nadir and the risk of death from prostate cancer following radiation and androgen deprivation therapy.
Authors: Pike Luke Roy George , Wu Jing , Chen Ming-Hui , Loffredo Marian , Renshaw Andrew A. , Pfail John , Kantoff Philip W. , D'Amico Anthony Victor
Published: March 2019

4

Background: Whether the time to PSA nadir (TTN) has differential prognostic value in men who reach an undetectable versus detectable PSA nadir remains unknown. Methods: Two-hundred and four men from a prospective randomized controlled trial (RCT) involving radiation therapy with or without 6 months of androgen deprivation therapy (ADT) in unfavorable risk CaP at academic or community based centers in Massachusetts, enrolled between 1995 and 2001. Adjusted hazard ratios (AHR) of the risk of CaP-specific mortality (PCSM) calculated using Fine and Gray competing risk regression. Results: After a median follow-up of 18.17 years, 160 men died; 30 (18.75%) of CaP. Amongst men with a PSA nadir ≥ 0.2 ng/ml, a TTN < median (12 months) was significantly associated with an increased PCSM-risk versus the median or more (AHR 5.07, 95% CI 2.10-12.23, p<0.001); whereas this association was not observed among men with a PSA nadir of <0.2 ng/ml, (AHR 9.9, 95% CI 0.23-433.8, p=0.23). Conclusions: Men with both a short TTN and detectable PSA nadir could be considered for entry on RCTs at a novel entry point prior to PSA failure at the time of PSA nadir to complete planned conventional ADT versus that plus agent(s) shown to improve outcomes in men with or at high risk of having castrate-resistant CaP.
Clinical impact of gemcitabine mono-maintenance versus best supportive care after first-line gemcitabine with platinum in patients with metastatic urothelial carcinoma.
Authors: Lee Seung-Hwan , Ha U-Syn , Hong Sung-Hoo , Lee Ji Youl , Kim In-Ho
Published: March 2019

404

Background: To evaluate the clinical impact of gemcitabine (GEM) monotherapy after 1st line GEM with platinum in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 113 patients who showed with radiological response or stabilization after 4-6 cycles of GEM with platinum.61 patients received maintenance of GEM-mono (GEM group) as 1000 mg/m2 on day 1 and 8 every three weeks until progression or development of unacceptable toxicity. And 52 patients received best supportive care (BSC) with regular radiologic evaluation (BSC group). Progression free survival (PFS) and overall survival (OS) from start date of GEM-mono or BSC was examined. Results: After a median follow-up of all population of 8.21 months, 43 (70%) patients had progressed and 32 (52%) died in the GEM-mono arm, compared to 45 (86%) and 39 (76%) in the BSC arm, respectively. Maintenance of GEM-mono was for a median 6 cycles (2-19). Median PFS was 7–12 months (range 1.5-13.0) in the GEM-mono arm and 4–8 months (range 1.4-8.6) in the BSC arm (Hazard Ratio 0.580, 95%CI 0.38-0.95, p=0.032). Most common grade 3/4 adverse events in the GEM arm were neutropenia (n=11; 18%) and fatigue (n=13; 21%). After progression, 42 (68%) patients received treatment at the GEM and 30 (58%) at the BSC arm. Conclusions: Our data suggest that maintenance of GEM-mono therapy in patients who responded to 1st line GEM with platinum provides a significant prolongation of PFS, and with a manageable toxicity profile.
Digital holography can differentiate between bladder cancer grades.
Authors: Haifler Miki , Yogev Almog , Goldstein Ofer , Zisman Amnon , Shaked Natan T
Published: March 2019

413

Background: Treatment of high grade non-muscle invasive bladder cancer (HG NMIBC) is controversial with BCG instillation and early cystectomy as viable options. However, accurate predictive markers for HG NMIBC are lacking. Refractive index (RI) is an optical feature of tissues and has been shown to be correlated with various oncologic outcomes in prostate and breast cancers. The role of RI in NMIBC has not been explored yet. The aim of this study is to measure and compare RI values of benign and malignant low and high grade NMIBC. Methods: After IRB approval, tissue samples were obtained from high and low grade NMIBC patients. Measurements were performed on non-stained slides using digital holography. Areas of benign and malignant tissues were marked by a fellowship trained GU pathologist. The average RI (RIavg) and RI variance (RIvar) over malignant and benign cell nuclei were measured. Comparison between benign and malignant tissue and between low and high grade tumors was performed with the Student's t-test. Results: Multiple nuclei of LG and HG patients were measured . Mean difference of RIavg between malignant and benign cells was 0.03 in HG patients (p < 0.001). Mean difference of RIvar between malignant and benign tissues was 0.016 in HG patients (p < 0.001). In LG tissues, there was no significant difference in RIavg or RIvar between benign and malignant cells. Finally, there was a significant difference in RIavg between HG and LG cells (p < 0.001). Conclusions: For the first time, RI was measured in bladder cancer tissue by digital holography. The RI values and variance were different between malignant and benign cells in HG tissues. Furtheremore, we found a significant difference in RI values between HG and LG cells. This technology may assist in the future in tissue diagnosis and classification of bladder tumor.