bluuebunny/crossref_metadata_2025 huggingface dataset:
Radium-223 in metastatic castration resistant prostate cancer: Progression free survival and pain scores—Real-world single-institution experience.
Authors: Challapalli Amarnath , Hilman Serena , Cowley Sue , Masson Susan , Grifiths Dorothy , Persad Rajendra , Mitchell Kathryn , Huckett Rebecca , Greenwood Rosemary , Compton Eleanor , Bahl Amit
Published: February 2017

250

Background: Radium-223 (Ra223) is a novel alpha-emitting radiopharmaceutical agent approved for use in patients with metastatic castration resistant prostate cancer (mCRPC) and bone metastases based on ALSYMPCA results. We report our early experience in this setting. Methods: 36 patients were treated with Ra223 from Feb 2014 - Aug 2015. The patients were planned to receive 6 injections at a dose of 50 kBq/kg every 4 weekly. The pain was assessed using the visual analogue score (VAS). The effect of 6 cycles of Ra223 on blood counts, serum alkaline phosphatase (SAP), PSA, VAS and progression free survival (PFS) were evaluated. Results: At baseline (BL) median age was 79years; 66% of patients were ECOG 0-1; median VAS was 6. 53% had received prior docetaxel. 18 patients (50%) received all the scheduled 6 cycles of Ra223. In these patients there was a significant reduction in the pain scores both after the first cycle and after 6 cycles compared to the BL score (p < 0.05 & p < 0.001, respectively). A 30% reduction in the SAP levels was seen (p = 0.03). The reduction in pain scores was independent of the PSA response. The treatment was well tolerated with no grade 3,4 toxicity. Discontinuation rate was 50% (18/36) and was due to disease progression. Prior docetaxel use was associated with a higher discontinuation rate (12/18), as was albumin level < 34g/dL (60% vs. 43%). 7 (19%) required blood transfusions during the course. The median PFS was 6.1 months. It was significantly longer in those who completed 6 cycles of treatment and in patients with SAP < 220 U/L (10.97vs.5.2 & 10.33vs.6.4 months, respectively: p < 0.0001). There was a non-significant trend towards longer PFS in patients who had no prior docetaxel (10.33vs.6.5m; p = 0.05) and in patients with Albumin > 34 (8.9vs.6.4m; p = 0.06). Conclusions: Ra223 is a safe and effective treatment for mCRPC with bone metastases. Completion of 6 cycles is associated with a significantly better PFS, reduction in pain scores and in SAP levels. Prior docetaxel use and lower albumin levels were associated with a higher discontinuation rate and this should be considered in the decision process for optimising therapy sequencing.
The relationship of B7H3 expression to androgen and prostate cancer outcomes in a large natural history cohort of men undergoing prostatectomy.
Authors: Ross Ashley , Benzon Benjamin , Zhao Shuang , Takhar Mandeep , Haffner Michael , Erho Nicholas , Hurley Paula , Tosoian Jeffrey J. , Alshalalfa Mohammed , Glavaris Stephanie , Simons Brian , Tran Phuoc T. , Davicioni Elai , Karnes Jeffrey , Schaeffer Edward M. , Drake Charles G. , Feng Felix Yi-Chung
Published: February 2017

256

Background: B7-H3 (CD276), part of the B7 superfamily, has been shown to play an immunomodulatory role, however its regulation, receptor and mechanism of action remain unclear. Protein levels of B7-H3 have been previously shown to relate to prostate cancer outcomes and currently, humanized monoclonal antibodies are being developed for clinical use (MGA271, Macrogenics). Here we use genomic expression data to examine the relationship of B7-H3 to prostate cancer outcomes and molecular subtypes. Methods: Prostatectomy tissue from 905 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Kruskal-Wallis tests were used to identify significant associations of B7-H3 expression with clinico-pathologic variables, and survival analysis were used to evaluate the prognostic value of B7-H3. Pearson’s correlation analyses were also performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy of promoter regions was derived in silico from chromosomal immune-precipitation (ChIP) data. Results: B7-H3 expression was positively associated with Gleason score (p < 0.01) and tumor stage (p < 0.01). High B7-H3 expression also correlated with the development of metastasis and prostate cancer specific mortality (HR of 3.4 and 2.4 respectively, p < 0.05 for both), but this was not significant on multi-variable analysis. B7-H3 was positively associated with ERG+ disease (n = 670, r = 0.85, p < 0.05) and AR expression (n = 670, r = 0.46, p < 0.001). B7-H3 was found to be one of the most correlated genes with AR (95th percentile) and ChIP analysis revealed AR binding upstream of B7-H3, suggesting potential androgen dependent regulation. Conclusions: B7-H3 expression correlates with high Gleason grade and advanced prostate cancer stage with higher quartiles of expression portending poor oncologic outcomes in two independent prostatectomy cohorts. B7-H3 expression appears to relate to the androgen receptor.
Chemotherapy in metastatic hormone-naïve prostate cancer: Pooled analysis of randomized clinical trials.
Authors: Fabbri Paolo , Stocchi Lucia , Nicoletti Stefania , Drudi Fabrizio , Tamburini Emiliano , Nicolini Mario , Gianni Lorenzo , Pasini Giuseppe , Montanari Francesco , Tassinari Davide
Published: February 2017

259

Background: To assess the role of chemotherapy in metastatic, hormone-naïve prostate cancer, we presents the preliminary data of a pooled analysis comparing the outcome of patients with metastatic hormone-naïve prostate cancer. Methods: A pooled analysis of the outcome of randomized clinical trials approaching the role of docetaxel in metastatic hormone-naïve prostate cancer was performed using a random effect model. The final outcome of all the patients enrolled into the trials was the primary end point of our analysis. The pooled final result was reported as pooled Hazard Ratio and 95% Confidence Interval. The between-the trials heterogeneity was assessed using the I2 test. An α-error of 5% was identified as index of statistical significance. Overall survival of the entire population enrolled into the trials was the outcome of the preliminary analysis, while no subgroup analysis was performed in this preliminary phase of a multi-steps analysis. Results: Three trials (the CHAARTED, the STAMPEDE and the GETUG-AFU 15 trial) were considered eligible and included into the analysis. A pooled Hazard Ratio of 0.76 (95% Confidence Interval of 0.59-0.98, p = 0.037) was detected for overall survival, with an I2 of 67.8. The pooled datum was obtained observed the outcome of 951 patients treated with docetaxel plus androgen blockade and 1338 with androgen blockade alone. Conclusions: Although the between-the-trials heterogeneity seems to suggest caution in the final interpretation of the results, a significant reduction of the risk of death can be obtained with docetaxel in the treatment of metastatic hormone-naïve prostate cancer. Our preliminary analysis, including all the patients with metastatic hormone-naïve prostate cancer, seems to suggest a role of docetaxel in all the patients with metastatic disease; further data are probably needed to detect its role in some different subclasses of patients (patients with high burden of the disease, fit or unfit patients, elderly patients).
Quality of life (QOL) analysis from E3805, chemohormonal androgen ablation randomized trial (CHAARTED) in prostate cancer (PrCa).
Authors: Patrick-Miller Linda J. , Chen Yu-Hui , Carducci Michael Anthony , Cella David , DiPaola Robert S. , Gartrell Benjamin Adam , Jarrard David Frazier , Liu Glenn , Morgans Alicia Katherine , Wong Yu-Ning , Sweeney Christopher
Published: February 2017

286

Background: Docetaxel concurrent with androgen deprivation (ADT) for metastatic hormone sensitive prostate cancer (mHSPC) improves overall survival over ADT alone. However, docetaxel as a cytotoxic has an adverse event profile that can diminish QOL. Methods: Patients were randomized to ADT plus 6 cycles of docetaxel every 3 weeks (Arm A, N = 397) or ADT alone (Arm B, N = 393). Validated QOL instruments for PrCa and docetaxel including Functional Assessment of Cancer Therapy (FACT)–Prostate were administered at baseline and 3, 6, 9 and 12 months (mos.) after randomization. Paired t-tests were used to examine QOL changes over time. A mixed effect model compared QOL between arms at each time point (Table). Results: 790 patients were randomized and QOL completed for Arm A and B (91% and 88%, baseline; 87% and 80%, 3 mos.; and 70% and 67%, 12 mos.). Patients in Arm A (ADT + docetaxel) reported -2.7 [Standard Error (SE) 0.9] decline in FACT-P at 3 mos. (p = 0.003), but did not differ significantly from baseline at 12 mos. (-0.7, SE 1.1). In contrast, patients in Arm B (ADT alone), did not differ significantly at 3 mos. [-1.1 (SE: 1.0)], but reported a significant decline [-4.2 (SE: 1.1); p = 0.0001] from baseline to 12 mos. FACT-P scores differed significantly between Arm A and B at 3 mos. (p = 0.02) and 12 mos. (0.04), with Arm A lower at 3 mos. and higher at 12 mos. Conclusions: Docetaxel is associated with decreased QOL on treatment (at 3 mos.) not seen with ADT alone. However, 12 mos. QOL was better for the patients who had docetaxel versus ADT alone, returning to baseline. This suggests that docetaxel + ADT does not confer long-term negative impact on QOL for mHSPC. Clinical trial information: NCT00309985. [Table: see text]
Frequency of BRCA mutations and co-occurring alterations in prostate cancer.
Authors: Myers Charles E. , Feldman Rebecca , Abbott Brian L. , Reddy Sandeep K. , Castro Michael
Published: February 2017

289

Background: Evidence is building for the utility of PARP (oral poly (ADP-ribose) polymerase) inhibitors in BRCA-mutated patients, across solid tumors. We examined the presence of somatic BRCA mutations (detected in tumor), in a population of prostate cancer patients. Comparisons between BRCA-mutated and BRCA-wildtype patients were made to determine potential combination strategies. Methods: 85 advanced prostate cancer patients were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Average age of BRCA-mutated patients was 58, compared to 62 in the non-BRCA-mutated cohort. Metastatic (Stage IV) disease was present in 67% in both cohorts (8/12; 49/73). BRCA2 mutations were more frequent (12%; 10/85) than BRCA1 (2%; 2/85). Of the BRCA-mutated patients, 5 variants are classified as having pathogenic effect; the rest consisted of variants of unknown clinical significance. Concurrent mutations in BRCA1 and BRCA2 were found in 17% (2/12) of patients. One patient harbored multiple BRCA mutations (n = 4, c.7977-1G > C, I2068fs, K2077Q, T2337I). Regarding co-occurring alterations, 36% (4/11) and 0% (0/11) exhibited PD1 + TILs and PD-L1+ tumor expression. Amongst theranostic markers tested by IHC, TOPO1 and TUBB3 were differentially expressed in BRCA-mutated vs. BRCA-wildtype groups: 91% (10/11) vs. 59% (41/69); p = 0.04 and 64% (7/11) and 23% (16/70); p = 0.0099. Co-occurring variants detected by NGS, included high rates of TP53: 42% (5/12) compared to BRCA- wildtype (30% 21/71), not significant. Of 3 patients that included expanded NGS analysis (600 genes), each harbored ≥ 39 mutations. Conclusions: The frequency of somatic BRCA mutations observed in prostate cancer, together, with preliminary clinical evidence for the efficacy of targeted therapies for these patients; highlight the potential role of a new class of agents for advanced prostate cancer.
Does androgen deprivation therapy impair renal function in patients with prostate cancer?
Authors: Mitsuzuka Koji , Kyan Atsushi , Sato Tomonori , Orikasa Kazuhiko , Miyazato Minoru , Kakoi Narihiko , Narita Shintaro , Koie Takuya , Habuchi Tomonori , Ohyama Chikara , Arai Yoichi ,   Tohoku Evidence-Based Medicine Study Group and Michinoku Urological Cancer Study Group
Published: February 2017

323

Background: While the adverse effects of androgen deprivation therapy (ADT) in patients with prostate cancer are generally well-known among physicians, it is not clear whether ADT affects renal function. Therefore, the goal of the present study was to assess changes in renal function in response to ADT for 1 year. Methods: Patients with prostate cancer who were hormone-naïve and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight and blood testing, including lipid and glucose metabolism and renal function, were recorded every 3 months during 1 year of ADT. Estimated glomerular filtration rate (eGFR) was calculated based on baseline age throughout ADT. Computed tomography (CT) was performed to measure psoas muscle area before and after 1 year of ADT to evaluate the influence of a decrease in lean mass on renal function. ADT was limited to a luteinizing hormone-releasing hormone agonist with or without bicalutamide. Patients who had severe renal dysfunction (eGFR < 30 mL/min/m2) or who had disease progression during 1 year of ADT were excluded from analyses. Results: Of 217 registered patients, renal function data were available from 170 patients who completed 1 year of ADT. Mean changes in serum creatinine and eGFR were 1.3% and 0.2%, respectively. Prostate specific antigen, clinical stage, body mass index, total testosterone, hemoglobin A1c, creatinine, eGFR, and comorbidities (e.g., hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease) at baseline were not associated with a change in renal function. Age < 70 years at baseline was associated with an increase in eGFR in univariate and multivariate analyses (univariate: P = 0.01, multivariate: 95% confidence interval 1.13-4.87, P = 0.03). CT was performed in 72 patients before and after 1 year of ADT. The mean decrease in psoas muscle area was -8.4%. Decrease in psoas muscle area and increase of eGFR were more frequent in patients of age < 70 years than in those of age ≥ 70 years (psoas muscle: -10.2% vs. -7.5%, P = 0.05; eGFR: 6.4% vs. 0.2%, P = 0.03). Conclusions: ADT did not impair renal function in patients with prostate cancer. eGFR was more likely to increase in younger patients, but this increase may be due to a decrease in lean mass. Clinical trial information: UMIN000004709.
Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma.
Authors: Sonpavde Guru , Nagy Rebecca J , Apolo Andrea B. , Agarwal Neeraj , Pal Sumanta K. , Grivas Petros , Vaishampayan Ulka N. , Lanman Richard Burnham , Talasaz AmirAli
Published: February 2017

358

Background: Urothelial carcinoma (UC) exhibits one of the highest somatic mutation burdens. Circulating cell-free DNA (cfDNA) is obtained non-invasively from peripheral blood and appears detectable in most patients (pts) with advanced UC. We report cfDNA profiling of patients with advanced UC using biopsy-free cfDNA sequencing. Methods: Twenty-nine patients with advanced UC that underwent cfDNA analysis using Guardant360 were identified. A 68-gene cfDNA next generation sequencing (NGS) panel from a CLIA-licensed, CAP-accredited laboratory (Guardant360) offers complete sequencing for all exons in 29 cancer associated genes, as well as the critical exons in 39 other genes, and copy number amplifications (16), fusions (4) and indels (1) in selected genes, harvested from 20 mL of peripheral blood. The mutant allele fraction (MAF) is defined as the number of mutated cfDNA molecules divided by the number wild type cfDNA molecules at a given nucleotide position. Results: Of 29 patients with advanced UC, cfDNA was detectable in 25 patients (86.2%). Twenty-nine patients were available with bladder primary in 27 pts (93.1%), and the median age was 75 years (range 52-91). The most common recurrent somatic mutations in the 25 patients with ≥ 1 alteration were in TP53 (n = 17), BRCA1/2 (n = 6), FGFR2 (n = 5), EGFR (n = 5), PIK3CA (n = 4), APC (n = 4), KRAS (n = 4), RAF1/BRAF (n = 4), and FGFR3, ALK, PDGFRA, NF1, CDKN2A and ARID1A were observed in 3 patients each. The most common genes with ≥ 2 copy numbers in the 25 evaluable patients were ERBB2 (n = 2) and PIK3CA, EGFR, RAF1, and FGFR1 in one patient each. Analysis of additional patients is ongoing in this expanding dataset. MAF data will be presented. Conclusions: cfDNA is frequently detected in patients with advanced UC, and alterations appear similar to those previously reported from UC tumor tissue. The correlation of cfDNA profiling with tumor tissue profiling within patients and ability to predict response requires study. Given that cfDNA offers a non-invasive means of profiling tumor DNA and MAF, further development of this promising modality is warranted to guide therapy with biologic agents and immunotherapy, and serial monitoring may provide insights regarding tumor biology.
Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy.
Authors: Koie Takuya , Ohyama Chikara , Hatakeyama Shingo , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro
Published: February 2017

373

Background: Butyrylcholinesterase (BChE) is an alpha-glycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, inflammation, injury, infection, malnutrition, and malignant disease. In this study, we analyzed the potential prognostic significance of preoperative BChE levels in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Methods: We retrospectively evaluated 327 patients with MIBC who underwent RC from 1996 to 2013 at a single institution. Serum BChE was routinely measured before operation in all patients. Covariates included age, gender, preoperative laboratory data (anemia, BChE, lactate dehydrogenase, C-reactive protein), clinical T (cT) and N stage (cN), tumor grade, and RC with/without neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall (OS) and disease-free survival (DFS). Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model. Results: The median BChE level was 187 U/L (normal range, 168–470 U/L). The median age of the enrolled patients was 69 years, and the median follow-up period was 51 months. The 5-year OS and DFS rates were 69.6% and 69.3%, respectively. The 5-year OS rates were 90.1% and 51.3% in the BChE ≥ 168 and < 168 U/L groups, respectively (P < 0.001). The 5-year DFS rates were 83.5% and 55.4% in the BChE ≥ 168 and ≤ 167 U/L groups, respectively (P < 0.001). In the univariate analysis, BChE, cT, cN, and RC with/without neoadjuvant chemotherapy were significantly associated with both OS and DFS. Multivariate analysis revealed that BChE was the factor most significantly associated with OS, and BChE, cT, and cN were significantly associated with DFS. Conclusions: This study validated preoperative serum BChE levels as an independent prognostic factor for MIBC after RC.
Incidence, characteristics, and implications of thrombo-embolic events in patients with urothelial carcinoma of the bladder undergoing neoadjuvant chemotherapy.
Authors: Duivenvoorden Wilhelmina CM , Daneshmand Siamak , Canter Daniel J. , Lotan Yair , Black Peter C. , Abdi Hamidreza , Van Rhijn Bas W.G. , Fransen van de Putte Elisabeth E. , Bostrom Peter J. , Koskinen Ilmari , Zareba Piotr , Baack Kukreja Janet E. , Kassouf Wassim , Traboulsi Samer , Pinthus Jehonathan H
Published: February 2017

393

Background: Neoadjuvant chemotherapy (NAC), in combination with radical cystectomy (RC), is associated with a significant survival advantage for patients with muscle-invasive bladder cancer. Chemotherapy as well as pelvic surgery are significant risk factors for thrombo-embolic events (TEE). The objectives of this study were to investigate the incidence and characteristics of TEE during and after NAC and subsequent RC for urothelial bladder cancer patients. Methods: A retrospective study was carried out on 827 consecutive patients who underwent NAC and cystectomy for urothelial bladder carcinoma from 2002 to 2014 at ten different tertiary centers across North America and Europe. The median time of follow-up from bladder cancer diagnosis was 13 months (range 1-119 months). The incidence (venous, arterial, port-site or deep vein thrombosis, thrombosis, clinical or incidentally detected pulmonary embolism) and timing of TEE (before or after ( < or > 30 days) RC) and Khorana score (based on baseline hemoglobin, platelet and leukocyte counts, BMI and tumor site, which was established for cancer patients treated with chemotherapy) was determined for all patients. Multivariate analysis was performed on 827 patients. Kaplan Meier survival curves and log rank test were used to compare survival between patients who developed TEE and those who did not. Results: The Khorana criteria indicated intermediate TEE risk in most patients. Khorana risk score was 1 or 2 in 88% of patients. Nevertheless, the incidence of TEE in patients undergoing NAC was 15%. 59 TEE were detected pre-operatively (7.1%), 21 early within 30 days of RC (2.5%) and 36 late post-operatively (4.3%). 32% of the TEE events were detected incidentally by imaging, 68% were detected clinically. Median overall survival of patients who developed TEE was 28 months compared to 71 months for those who did not develop TEE (p = 0.012). Conclusions: This multi-centre retrospective study suggests that TEE are very common in bladder cancer patients undergoing NAC followed by RC and is associated with poorer survival. Further investigation with a prospective prevention trial is warranted.
Single arm phase II study of docetaxel and lapatinib in metastatic urothelial cancer: USC trial 4B-10-4.
Authors: Tang Sujie , Dorff Tanya B. , Tsao-Wei Denice D , Massopust Kristy , Ketchens Charlean , Hu James , Goldkorn Amir , Sadeghi Sarmad , Pinski Jacek K. , Averia Monica , Groshen Susan G. , Press Michael F. , Schuckman Anne K. , Quinn David I.
Published: February 2017

424

Background: Advanced urothelial cancer progressing after first line systemic therapy is fatal. No agent in the second line or later setting has demonstrated improved survival although taxanes, pemetrexed, gemcitabine & vinflunine have activity & are used as palliative therapy. The Her2 pathway is up-regulated in some urothelial cancers and Her2 targeted therapy has enhanced chemotherapy effect in other cancers. We tested docetaxel with lapatinib, a Her1/Her2 TKI in urothelial cancer patients. Methods: Pts with measurable or evaluable urothelial cancerentered a single arm 2-stage phase II clinical trial, with PFS rate at 12 weeks as the primary endpoint in a Simon 2-stage design of 14+26 patients. The goal was a 12 week non progression rate of 60% - seen as promising compared to a rate of < 40% seen as not. In a 2-stage design if ≥ 6 of 14 patients had not progressed by 12 weeks the trial would continue to 40 pts. Secondary endpts: ORR, safety & OS. First 6 patients were given lapatinib 1250mg PO daily & docetaxel 60mg/m2 IV q3wk; docetaxel dose then increased to 75mg/m2 q3wk. Tumor tissue & circulating microenvironment were evaluated. Results: From July 2011 to July 2013, 15 pts were accrued. Median age 65 y, male 80%, ECOG 0 73%, Caucasian 73%, Mets: Liver 20%, Lung 20%, Bone 20%. PFS at 12 weeks 40%+/-13% - the trial was terminated after first stage. Reason off therapy: PD 10 (67%), toxicity 4 (27%). RECIST 1.1 best response: CR 1 (8%), SD 4 (31%), PD 8 (62%). Median OS: 6.3 (2.2, 12.7), PFS 2.0 (1.3, 6.6) months; 2 pts alive, follow up at 6.9 & 8.1 months. Common toxicities: diarrhea 80% (gr3 33%), vomiting 40% (gr3 26.7%), nausea 67% (gr3 26.7%) & fatigue 73.3% (gr3 6.7%). Conclusions: This phase II study of docetaxel with lapatinib in advanced urothelial cancer patients failed to provide sufficient efficacy for us to complete full accrual. One patient had a complete response and molecular correlatives may shed light on what may have predisposed to this. Intercurrently, another trial of maintenance lapatinib or placebo after chemotherapy in Her2+ patients reports no benefit (Powles ASCO 2015). Lapatinib alone or in combination is not recommended as therapy in urothelial cancer patients unless new tractable markers of response are developed. Clinical trial information: NCT01382706.
GBAS as a novel regulator for targeting centrosome amplification and malignant behavior in bladder cancer.
Authors: Matsumoto Hiroaki , Fujii Nakanori , Kobayashi Keita , Inoue Ryo , Yamamoto Yoshiaki , Nagao Kazuhiro , Matsuyama Hideyasu
Published: February 2017

429

Background: It has been reported that centrosome amplification (CA) facilitate to enhance the malignant potential and poor prognosis in bladder cancer. Besides Aurora A kinase drives CA, many studies suggest that inhibition of Aurora A is promising approach to concur invasive bladder cancer. We assess the novel molecule that is potential regulator of CA in bladder cancer. Methods: From 2000 to 2008, 57 bladder cancer patients treated in our hospital were included in this study. We obtained tumor sample by TUR or radical cystectomy with informed consent. We evaluated status of CA by fluorescent immuno-cytochemistry using anti pericentrin antibody. Then we performed array CGH to clarify hyper amplification gene in CA patients. By another approach, we identified candidate micro RNAs targeting Aurora A by miRNA tip array using CA+ or CA- bladder cancer cell lines. We performed pathway analysis to investigate potential target for CA regulated genes by both strategy. Finally, we found GBAS gene as a potential regulator for CA. Then, we assessed the function of GBAS gene by repressing or overexpressing in vitro and the status of GBAS expression by immunohistochemistry in tumor sample. Results: In CA- cell lines, GBAS overexpression increased CA rate compared with mock cells. Contrary, GBAS knock down reduced CA rate in CA+ cells. Also, in WST-1 assay, GBAS knock down repressed CA+ cell proliferation. While, GBAS overexpression facilitated migration and invasion in CA- cells. By western blot analysis, GBAS overexpression increased Aurora A expression, while GBAS suppression decreased that expression. GBAS knock down also repressed p53 expression in J82 cells. In immunohistochemistry, the patients with high GBAS expression were significant worse cancer specific survival compared with those of low expression (p < 0.0001). Conclusions: These results suggest that GBAS gene could be a potential regulator of centrosome duplication via Aurora A expression in bladder cancer. Regulation of GBAS is providing pre-clinical proof-of-principle as promising approach for invasive bladder cancer.
Effect of diet on bladder cancer survivors.
Authors: Longo Thomas Andrew , Gopalakrishna Ajay , Fantony Joseph J , Inman Brant Allen
Published: February 2017

437

Background: Diet has been shown to affect cancer recurrence, progression, and overall survival. A reduction in overall mortality is associated with high intake of vegetables and whole grains, but little is known about the role of other macronutrients. Further, the role of macronutrients in bladder cancer survivors as they move beyond the treatment period is unknown. Methods: After IRB approval, an institutional database was used to identify a large cohort of bladder cancer patients. They were mailed a survey that included the Diet History Questionnaire II (DHQ II). This validated instrument is recommended by the American Cancer Society and National Cancer Institute. It involves 151 questions covering portion size over 134 food items and 8 supplements, and takes a patient roughly an hour to complete. Our cross-sectional survey used the results from the DHQ II to assess compliance with the US Dietary Guidelines for Americans. Results: Out of 962 subjects, 461 completed the survey (48%). Mean age was 73, 80% were male, and 87% were white. The recommended protein intake was met or exceeded 98% of respondents and 66.8% were able to meet the fruit and vegetable recommendations. Similarly, 62.9% met carbohydrate recommendations. Unfortunately, only 44.5% met fat recommendations, and 0.9% met the whole grain recommendations. Recommended sodium intake was exceeded by 62% of subjects. Conclusions: Bladder cancer survivors exhibit poor adherence to standard dietary recommendations, but they represent a unique metabolic state. It is unknown what constitutes a healthy diet in a bladder cancer survivor, but a healthy diet has potential to be a component of survivorship intervention and not merely sustenance. Cancer survivors are an important target population for health promotion efforts and we plan further investigation of diet and its impact on quality of life amongst other lifestyle factors.
Contemporary utilization trends of systemic chemotherapy for upper tract urothelial carcinoma (UTUC).
Authors: Haseebuddin Mohammed , Handorf Elizabeth , Jones Joshua , Kutikov Alexander , Waingankar Nikhil , Ristau Benjamin T. , Haifler Miki , Wong Yu-Ning , Viterbo Rosalia , Greenberg Richard Evan , Uzzo Robert G. , Chen David Y. T. , Smaldone Marc C.
Published: February 2017

441

Background: There is currently no consensus regarding the use of systemic therapy (ST) for surgically-treated patients with invasive UTUC. Using a large national cancer registry, our objective was to assess temporal trends in utilization of ST for stage II-IV UTUC undergoing definitive resection. Methods: The National Cancer Database (NCDB) was queried for all patients surgically treated (nephroureterectomy, segmental resection) for stage II-IV UTUC from 1998-2012. Temporal trends in receipt of ST [neoadjuvant (NAT), adjuvant (AT), or unknown timing (UKT)] were assessed using chi square analyses. After exclusion of patients receiving NAT or UKT, adjusting for patient and clinicopathologic characteristics, multivariable logistic models were used to examine the association between clinicopathologic characteristics and receipt of ST within 9 months of resection. Kaplan Meier analyses and stratified log-rank tests were performed comparing overall survival (OS) between patients receiving ST < 9 months and those who did not. Results: Of 7,629 patients identified over the study period, 24.1% of patients surgically treated for stage II-IV UTUC received any ST (NAT: 1.44%, AT: 19.11%, UKT: 3.51%). Utilization of any ST significantly increased from 1998-2012 (20.2% vs. 28.7%, p < 0.0001). Following adjustment, patients of increased age (61-70 years: OR 0.62 [CI 0.42-0.91], 71+ years: OR 0.26 [CI 0.17-0.38]) were less likely to receive ST, and patients with high grade (OR 2.46 [CI 1.95-3.09]), Stage III (OR 4.75 [CI 3.89-5.79]), and Stage IV (OR 9.37 [CI 7.49-11.74]) disease were more likely to be treated with ST. When restricted to stage III-IV disease, receipt of ST < 9 months was significantly associated with improved OS after adjustment for age, grade, and charlson index (p < 0.002). Conclusions: In hospitals reporting to the NCDB, while utilization has significantly increased from 1998-2012, less than one third of patients surgically treated for stage II-IV UTUC receive ST. In addition to unmeasured characteristics (decline of renal function following surgery), the lack of explicit guidelines and prospective evidence may contribute to limited use of systemic treatment.
Phase Ib trial of ALT-803, an IL-15 superagonist, plus Bacillus Calmette Guerin (BCG) for the treatment of patients with BCG-naïve non-muscle-invasive bladder cancer (NMIBC).
Authors: Rosser Charles Joel , Nix Jeffrey , Hernandez Liza , Rhode Peter R. , Wong Hing C.
Published: February 2017

470

Background: Novel agents are necessary to treat NMIBC to avoid recurrence and progression. This phase Ib clinical trial evaluated the safety and toleraibility of ALT-803, an IL-15 superagonist, plus BCG in patients with BCG-naïve NMIBC. Methods: This is a Phase Ib trial using the 3+3 design to evaluate intravesical ALT-803 plus BCG 50 mg in BCG-naïve NMIBC patients, who would normally be eligible for intravesical BCG alone. The initial dose of ALT-803 was 100 μg/instillation with 2 dose-escalations allowed (200 μg/instillation and 400 μg/instillation) if dose limiting toxicities (DLTs) were not evident. Patients received intravesical ALT-803 in conjunction with BCG weekly for 6 consecutive weeks (Induction Phase). Patients then had routine follow-up with cystoscopy and voided urinary cytology (VUC) every 3 months for 2 years equating to confirmatory response assessment. Negative cystoscopy, VUC and/or biopsy yielded a complete response (CR). When appropriate for high-risk patients, physicians and patients were encouraged to receive maintenance BCG alone as per common practice patterns. Results: No patient in 100 μg/instillation of ALT-803/BCG and 200 μg/instillation of ALT-803/BCG reported an AE. One patient in 400 μg/instillation/BCG cohort developed a urinary tract infection requiring delay of intravesical treatment by 1 week. No grade 3/4 toxicities were noted. All patients have completed therapy without DLTs. To date, 4 patients have 12 month follow-up and are CR. The remaining 5 patients have no evidence of disease. However, follow-ups are currently approximately 3 months. Corollary immune studies are still pending. Conclusions: Intravesical ALT-803 plus BCG was safe and tolerable in patients with BCG-naive NMIBC. Further evaluation in expansion cohorts in a phase II trial is currently underway. Clinical trial information: NCT02138734.
An open-label, single-group, phase 2 study of brentuximab vedotin as salvage therapy for males with relapsed germ-cell tumors (GCT): Results at the end of first stage (FM12GCT01).
Authors: Necchi Andrea , Magazzu Domenico , Anichini Andrea , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Colecchia Maurizio , Paolini Biagio , Coradeschi Elisa , Tassi Elena , Grazia Giulia , Mortarini Roberta , Calareso Giuseppina , Togliardi Elena , Crippa Flavio , Salvioni Roberto , Gianni Alessandro M. , Valagussa Pinuccia
Published: February 2017

480

Background: Prognosis of patients (pts) failing multiple chemotherapy (CT) regimens is quite dismal. CD30 is expressed and prognostic in embryonal carcinoma, hence it is a rational target for treatment. Brentuximab Vedotin (BV) is an antibody-drug conjugate consisting of the chimeric anti-CD30 antibody SGN-30 conjugated to an antitubulin synthetic analog (MMAE). A phase 2 trial is ongoing in GCT (NCT01851200). Methods: 24 pts with biopsy-proven CD30+ GCT will receive BV 1.8 mg/Kg IV q3 weeks until disease progression or onset of unacceptable toxicity. Eligibility will include failure of 2 or 3 platinum-based CT (including HDCT). All pts will undergo measurement of serum tumor markers (STM), a computed tomography and a PET scan q6 weeks. An optimal Simon’s 2-stage design will be applied. The primary endpoint is the objective response-rate (ORR; H0: ≤ 5%, H1: ≥ 25%, α and β = 10%). In stage 1, 9 evaluable patients will be accrued. Sequential peripheral blood samples are being collected for immune profiling by flow cytometry of immune cell subsets. Results: From 07/13 to 04/15, 9 pts have been treated, 3 in third-line, and 6 beyond the third-line. 5 had received HDCT. STM decline was obtained in 7 pts (77.8%) after the first dose and in 4 pts (44.4%) after 2 doses (with normalized [1] or still positive [3] STM). ORR was 22.2% (1 CR+1 PR) according to RECIST v1.1, and there were 3 metabolic PR. 3-month PFS was 11.1% (95%CI: 0.6-38.8), 6-month OS was 85.7% (95%CI: 33.4-97.9). 1 case of reversible G3 hyperglycemia was recorded. No BV discontinuation due to toxicity occurred. In 7 evaluable pts, a trend to increasing expression of activation (HLA-DR), proliferation (Ki67), and functional differentiation (Granzyme B) markers in CD4 and CD8 T cells was observed during BV. In CR patient, an increased frequency of naive and central memory T cells was observed after the first cycle of BV, as well as a reduction in the fraction of PD1+/CD8+ T cells. Conclusions: Brentuximab is endowed with potent antitumor activity and meaningful immunomodulatory effects in GCT. The rapid development of resistance is a concern. ORR is pending confirmation in the whole sample size. Clinical trial information: NCT01851200.
Systemic immune-inflammation index to predict the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.
Authors: Lolli Cristian , Maruzzo Marco , Derosa Lisa , Sava Teodoro , Santoni Matteo , Massari Francesco , Wheater Matthew James , Aieta Michele , Scarpi Emanuela , La Russa Francesca , Crabb Simon J. , Cascinu Stefano , Galli Luca , Basso Umberto , De Giorgi Ugo
Published: February 2017

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Background: A systemic immune-inflammatory index (SII) based on lymphocyte (L), neutrophil (N), and platelet (P) counts has been recently developed. In this retrospective analysis, we explored its prognostic and predictive value at baseline and changes at week 6 during first-line sunitinib in patients (pts) with metastatic renal cell cancer (mRCC). Methods: We included 335 consecutive pts mRCC treated with first-line sunitinib for which P,N, and L data were available at start of therapy, and 6 weeks thereafter. The SII was defined as follows: SII = P x N/L. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the baseline data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion on PFS and OS was evaluated by Cox regression analyses. Results: An optimal cutoff point for the SII of 730 x 109stratified these pts into high (≥ 730) and low SII (<730) groups. Median age was 63 years (range, 27 to 88); histotype clear cell carcinoma was reported in 94% of cases; 29.6%, 59.4% and 11% were classified in the favorable, intermediate and poor Motzer prognostic groups, respectively. The median PFS was 6.2 months (mo) (95% CI=5.5-9.5) in pts with baseline SII ≥730 and 17.7 mo (14.3-21.8) in those with SII <730, P<0.0001. The median OS was 13.7 mo (95% CI=9.6-20.3) in pts with baseline SII ≥730 and 41.8 mo (95% CI=34.5-51.8) in those with baseline SII <730, P<0.0001. Data for SII at baseline and change in SII by week 6 using a cut-off of 730 are shown in the table. Conclusions: The SII is a powerful prognostic and predictive indicator of poor outcome in pts with mRCC. A validation study from prospective data is warranted. [Table: see text]
Correlation between findings from comprehensive genomic profiling and targeted therapy response in metastatic renal cell carcinoma.
Authors: Ho Thai Huu , Choueiri Toni K. , Wang Kai , Karam Jose A. , Chalmers Zachary Rockow , Frampton Garrett Michael , Elvin Julia Andrea , Johnson Adrienne , Liu Xueli , Lin Yulan , Joseph Richard Wayne , Stanton Melissa L. , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S. , Ali Siraj Mahamed , Pal Sumanta K.
Published: February 2017

570

Background: Vascular endothelial growth factor- (VEGF-) and mammalian target of rapamycin- (mTOR-) directed therapies represent a standard of care in metastatic renal cell carcinoma (mRCC). However, these agents are not employed based on an assessment of predictive biomarkers such as genomic alterations (GA). We sought to determine if an association exists between GA detected by comprehensive genomic profiling (CGP) and the response to VEGFR and mTOR pathway targeted therapies in a cohort of mRCC treated in a clinical practice setting. Methods: The results of CGP performed in the course of clinical care on 31 consecutive mRCC obtained from patients who had received VEGFR- and/or mTOR-inhibitors were reviewed. Duration of treatment (DOT), extent and duration of clinical response was obtained from review of medical records. All classes of genomic alterations - base substitutions, short insertions, deletions, gene fusions, rearrangements and copy number - were assessed via CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. Results: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%) and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT > 21 months) were more frequent amongst patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1. Conclusions: Multiple GAs are more prevalent in exceptional responders to VEGF-directed therapy. Prospective validation of these findings may lead to use of CGP to optimize therapeutic selection.
Sunitinib to upregulate IFNg-STAT1 signaling and to increase indoleamine 2,3-dioxygenase (IDO) expression in renal cell carcinoma (RCC).
Authors: Jonasch Eric , Hoang Anh , Sun Mianen , Zhou Lijun , Ding Zhiyong , Zhang Xuesong , Bai Shanshan , Tannir Nizar M. , Liu Xiande
Published: February 2017

614

Background: Recently we reported that antiangiogenic therapy-treated primary RCC demonstrated increased infiltration of CD4 and CD8 T cells and higher expression of the immune checkpoint ligand PD-L1, all of which were associated with therapy resistance. IFNg-STAT1 signaling pathway drives the expression of both immunosuppressive and immunostimulatory molecules that are involved in lymphocyte trafficking, antigen presentation and immune checkpoints. The purpose of this study was to assess the impact of antiangiogenic therapy on IFNg signaling and on a broader tumor specific immune profile. Methods: We performed immunohistochemical staining of tissue microarrays (TMAs) generated from 40 sunitinib treated primary RCC from patients treated on clinical trial and compared stains to untreated control tumors. We used Vectra imaging to spectrally unmix antibody signal and to quantitate expression levels. We used immunoblot and real-time PCR to investigate the changes in protein and mRNA, respectively. We assessed for statistical significance using an unpaired Student t test. Results: We found that sunitinib treated RCC tissues demonstrated STAT1 phosphorylation (1.2% vs. 4.8%; P<0.001) or nuclear localization (7.4% vs. 15.6%; P=0.005), which was inversely related to patient survival. Furthermore, sunitinib treatment magnified IFNg-induced STAT1 activity by increasing the activity of janus kinase 2 (JAK2) and decreasing the protein levels of inhibitors PIAS and SOCS. On the one hand, sunitinib increased the transcription of VCAM1, CCL4, HLA-B and CD80, which facilitate T cell infiltration or antigen presentation; on the other hand, sunitinib increased transcription of the T cell negative regulator IDO1 (1 vs. 3.2, P<0.001) and CTLA4 (1 vs. 3.1, P=0.01). Conclusions: These results indicate that sunitinib both positively and negatively regulates the tumor immune microenvironment via modulation of STAT1 mediated signaling. IDO upregulation is a key driver of T-cell nutrient deprivation and can be targeted therapeutically. These findings will help us devise precise interventions to overcome tumor cell specific immunosuppressive signaling.
Enhancing cancer survivorship through improved provider communication, care coordination, and professional education.
Authors: Daly John M. , Howald Alan G. , Filchner Kelly Ann , Miller Bonnie J. , Lyons Leanne , Denlinger Crystal Shereen , O'Brien Patrick , Schlueter Amanda , Gonzalez Evelyn , Seggev Jennifer
Published: February 2017

104

Background: Care coordination among oncology and primary care physicians (PCPs) is an essential element of survivorship care. Providers at an NCI-designated comprehensive cancer center noted gaps in coordinating care with PCPs. We sought to develop a program that enhances communication and education between provider groups to ensure a seamless continuum of care thereby improving overall survivorship care. Methods: The Fox Chase Cancer Center (FCCC) Care Connect program was created to comprehensively connect PCPs in the regional service area with cancer center providers. Program participation requirements for PCP’s include attendance at 2 of 4 targeted professional education programs and participation in quality measures for breast, cervical, and colon cancer screening. Formalized processes to efficiently move patients between oncologists and PCP’s were established. Communication gaps were addressed by providing electronic access via a secure physician portal, access to FCCC disease navigation services, and establishment of designated referral navigators to coordinate clinical needs between provider groups. Results: FCCC initiated the Care Connect program with 5 PCP practices. During a 3 month pilot phase, FCCC directed 19 patients to Care Connect PCP’s to manage ongoing clinical needs and implement survivorship plans. Eight-six percent of referrals were classified as non-urgent. Median time from referral to PCP appointment was 16 days, 24% below regional average. One CME education program was conducted during the pilot phase. Of the attendees, 91% reported an intent to change current practice by implementing a new procedure, discussing new information or seek additional information. Attendees identified potential care barriers which will be included in future program development. Post-education, one practice referred 3 patients to the lung cancer screening program. Conclusions: A formal program that aligns PCPs and oncologists is an effective initiative to improve communication and awareness of cancer patient survivorship needs in oncology and primary care settings.
Reduction of paclitaxel neuropathy with cryotherapy.
Authors: Wilkinson Mary , Cocilovo Costanza , Vargas Hernan I. , Cohen Robert Alan , Bruce Sara , Edmiston Kirsten H. , Franco Claudia Yvette , Agra Maria Gracia , Bayer Suzanne , Khan Afifah , Le Lamvy , Saifollahi Parisa , Steimer Mary , Szeremeta Christopher , Deeken John F.
Published: February 2017

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Background: Chemotherapy induced peripheral neuropathy (CIPN) is a common and potentially debilitating side effect of taxanes. Prior studies indicate weekly paclitaxel results in grade 2 or higher neuropathy in 25% of patients. Patients may experience persistent pain that impacts quality of life. Currently, there is little data that exists on effective therapies for prevention of paclitaxel neuropathy. This study investigates the efficacy and safety of cryotherapy for the prevention of paclitaxel-induced peripheral neuropathy. Methods: This is a single arm, phase II study of the effects of cryotherapy for breast cancer patients undergoing 12 cycles of weekly paclitaxel. Cryotherapy was administered by hypothermia mitts and slippers to patients’ hands and feet during, and 15 minutes before and after paclitaxel treatments. Neurologic assessments and neuropathy questionnaires were evaluated at baseline, every 4 cycles during treatment, and every 6 months follow up for two years. The primary objective is to assess if cryotherapy can decrease the rate of peripheral neuropathy. The primary efficacy endpoint is the rate of neuropathy in patients undergoing weekly paclitaxel treatments. Results: Between November 2014 and June 2015, 41 patients were enrolled in the study. Of 39 evaluable patients, 19 (48.7%) were without neurologic toxicity. 19 (48.7%) had grade 1 toxicity, paresthesia but without pain. Only one patient (2.6%) had grade 2 toxicity. Cryotherapy treatment was well tolerated; one patient could not participate due to cold intolerance. Conclusions: Cryotherapy reduced the incidence of pain and grade 2 or higher sensory neuropathy in patients receiving weekly paclitaxel. Clinical trial information: NCT02230319. [Table: see text]