bluuebunny/crossref_metadata_2025 huggingface dataset:
Population-based analysis of treatment toxicity among men with castration-resistant prostate cancer.
Authors: Nam Robert , Wallis Christopher J.D. , Saskin Refik , Bansal Symron , Emmenegger Urban , Satkunasivam Raj
Published: March 2017

252

Background: There is little phase 4 data regarding the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments. We examined hospital admissions and emergency room (ER) visits and survival among patients in the Province of Ontario treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC. Methods: We performed a population-based, retrospective cohort study of 2439 men over the age of 65 treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC from 2003-2015 in Ontario, Canada. Outcomes were toxicity (hospitalizations and ER visits) and overall survival. We used multivariable Cox proportional hazards models with time-varying exposures to calculate hazard ratios (HR). Results: Among 2439 patients, cumulative exposure was greatest for docetaxel (n = 1886 (77.3%); 11,436 person-months), followed by abiraterone (n = 893 (36.6%); 5143 person-months), enzalutamide (n = 52 (2.1%); 351 person-months) and cabazitaxel (n = 18 (0.7%); 61 person-months). Abiraterone exposure was not significantly associated with any-cause (HR 0.88, 95% CI 0.72-1.07) or treatment-related (HR 1.09, 95% CI 0.87-1.37) hospitalizations or ER visits. Enzalutamide was not significantly associated with any-cause (HR 1.20, 95% CI 0.69-2.07) or treatment-related (HR 0.85, 95% CI 0.43-1.68) toxicity. Docetaxel exposure was associated with a significantly increased risk of any-cause (HR 1.29, 95% CI 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicity. Cabazitaxel exposure was also associated with treatment-related (HR 5.94, 95% CI 1.87-18.92) but not any-cause (HR 2.37, 95% CI 0.59-9.63) toxicity. Patients who began CRPC treatment after the introduction of oral therapies had improved overall survival compared with those treated prior to their introduction (aHR 0.70, 95% CI 0.64-0.77). Conclusions: Among patients with metastatic CRPC, treatment with chemotherapy (docetaxel or cabazitaxel) is associated with an increased risk of hospitalizations and emergency room visits. We failed to show a significantly increased risk for patients treated with oral agents (abiraterone or enzalutamide).
Survival outcomes for de novo versus primary progressive metastatic prostate cancer.
Authors: Gupta Kanika , Finianos Antoine Nafez , Clark Brandon , Simmens Samuel J. , Aragon-Ching Jeanny B.
Published: March 2017

258

Background: We reported initial findings on the phenotypic differences between de novo versus primary progressive metastatic prostate cancer (Finianos et al., ASCO GU; abstr 285). We sought to determine the differences in the phenotypic characteristics of these 2 cohorts of patients and update the data with overall survival and patterns of response to androgen deprivation therapy (ADT) in patients presenting with de novo versus primary progressive prostate cancer. Methods: A retrospective chart review in a single-institution center for a period of 2 years was undertaken. Phenotypic characteristics included age at diagnosis, race, overall survival, treatment patterns, and response to ADT. Analysis was by t-test, Mann-Whitney U test, and Fisher’s Exact test. Results: A total of 90 patients were included in this cohort with de novo, dn (n = 38) and primary progressive, pp (n = 52) patients. There were no significant differences between the 2 cohorts with regard to the median age at diagnosis (dn = 66, pp = 61, p = 0.11), alkaline phosphatase level (dn = 135.5, pp = 86, p = 0.27), BMI (dn = 28.47, pp = 27, p = 0.78), creatinine (dn = 1.02, pp = 0.99, p = 0.34), LDH (dn = 188, pp = 166, p = 0.34), and testosterone on metastasis (dn = 276, pp = 31, p = 0.16). However, de novo cancers were diagnosed with higher mean gleason scores (dn = 8.36, pp = 7.7, p = 0.004), had higher median PSA upon diagnosis (dn = 63.1, pp = 8.8, p < .0001) and higher PSA on metastasis (dn = 61.7, pp = 12.5, p = .0002), and had a statistically significant decreased duration of hormone sensitivity (dn = 642 days, pp = 1783 days, p = < .0001). Patients with d e novo cancers also had a shorter median survival than primary progressive cancers (dn = 2257 days, pp = 4217 days, p = 0.02). Conclusions: Patients who present with de novo metastatic prostate cancer appear to develop early castration resistance and have worse overall survival than those who present with primary progressive disease. We are exploring the molecular differences in terms of androgen receptor expression as a potential etiology for development of early castration resistance.
Efficacy of eplerenone (Epe) in the management of mineralocorticoid excess (MCE) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (AA) without prednisone (P).
Authors: Gill David Michael , Gaston David , Hahn Andrew W. , Bailey Erin B. , Buckley Tyler Howard , Johnson Eric , Batten Julia A. , Alex Anitha , Boucher Kenneth M. , Stenehjem David D. , Agarwal Neeraj
Published: March 2017

261

Background: AA is approved for Mcrpc with co-administration with P to prevent MCE toxicity such as hypertension, hypokalemia and edema. However, use of P is often not desirable by the relatively asymptomatic patients because of potential for detrimental effects of long term corticosteroid therapy. Epe is a non-steroidal mineralocorticoid antagonist demonstrated to abrogate MCE. Here we report real world experience of use of Epe with AA in men with mCRPC who wished to avoid concomitant P. Methods: Incidence and grade (CTCAE v4) of MCE, along with baseline demographics, disease characteristics, and progression free survival (PFS) in men with mCRPC treated with AA (1000 mg daily), not willing to be treated with P (and thus received treatment with Epe 50 mg daily) were collected retrospectively, and compared with those treated with AA + P (10 mg daily) during the same time period (Table). Continuous variables were assessed by Wilcoxon rank sum or student t-test, and categorical variables were assessed by Fischer’s Exact test or chi-square as appropriate. PFS was compared by Kaplan-Meier. Results: Baseline and disease characteristics, median PFS, and toxicities of all grades were similar in both cohorts (Table). Conclusions: In real world population of men with mCRPC treated with AA, corticosteroids may be avoided by concomitant treatment with Epe. Data need further validation in a larger cohort. [Table: see text]
Impact of use of phosphodiesterase type 5 inhibitors (PDE5-I) after radical prostatectomy (RP) on biochemical recurrence-free (BCRF) and overall survival (OS): A retrospective study from the Northwestern University SPORE in prostate cancer.
Authors: Roston Arden B. , Helenowski Irene B. , Catalona William , Leikin Robin , Gurley Michael , Trapp Luke , Jovanovic Borko , Kuzel Timothy M
Published: March 2017

27

Background: The correlation between PDE5-I use to improve erectile function post RP and BCRF and OS on prostate cancer (PCa) patients (pts) has yielded conflicting results among prior retrospective cohort studies (Michl, 2015). Recent data suggests that these drugs may have an impact on immunity that may explain possible benefits. This study’s purpose was to determine whether PDE5-I use affects BCRF and OS for pts treated with RP for PCa. Methods: This is an IRB approved retrospective cohort study analyzing a subset of pts consented to the SPORE in PCa at Northwestern University’s Lurie Cancer Center. Inclusion criteria included men diagnosed with PCa and treated with RP with curative intent between 2003-2015. Study population (n = 2,410) showed 834 (34.6%) received a PDE5-I post-RP, while 1,576 (65.4%) did not. Pts were grouped based on PDE5-I use and no PDE5-I use after RP. A PDE5-I user must have filled at least 2 prescriptions or completed at least 2 inpatient administrations of a PDE5-I. Continuous variables were summarized by descriptive statistics and differences between groups were assessed via the Wilcoxon rank sum test. Categorical variables were reported by frequencies and percentages and compared via Fisher’s exact test. OS and BCRF survival were summarized for 10-yr rates using Kaplan-Meier estimates. The difference in BCRF and OS between groups was evaluated via log-rank test. Results: Mean age at RP was 60, and 90.95 % were Caucasian. Except for pairwise comparisons for significance of Gleason 3+3 vs. 3+4 histology with higher prevalence of 3+4 in the PDE5-I group (p = 0.0004) and a higher percent of clinical stage T2b-c than T2a in the no PDE5-I group (p = 0.01), no differences were noted in demographics. The 10-yr BCRF survival among PDE5-I users was 92.53% compared to 79.63% among non-users after RP (p < 0.0001). The 10-yr OS rate among PDE5-I users was 97.22% compared to 92.69% among non-users (p = 0.008). Conclusions: This retrospective analysis suggests that PDE5-I use improves biochemical recurrence free survival and overall survival in pts treated with RP for PCa.
The usefullness of low-molecular-weight protein tyrosine phosphatase as a prognostic factor in metastatic hormone-sensitive prostate cancer.
Authors: Ohtaka Mari , Kawahara Takashi , Yasui Masato , Uemura Kouichi , Yoneyama Shuko , Mochizuki Taku , Hattori Yusuke , Teranishi Jun-ichi , Yumura Yasushi , Yokomizo Yumiko , Uemura Hiroji , Miyamoto Hiroshi , Yao Masahiro , Miyoshi Yasuhide
Published: March 2017

277

Background: Protein tyrosine phosphorylation is an important event that is associated with the processes of cellular metabolism. The control of protein tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTP). Thus, these proteins can control diverse processes like cell proliferation, adhesion, and migration. Recent studies revealed the importance of PTP in the oncogenic process, especially, the significance of low-molecular-weight protein tyrosine phosphatase (LMW-PTP) as a prognostic factor in early prostate cancer. In this study, we evaluated the significance of expression of LMW-PTP in metastatic hormone-sensitive prostate cancer (mHSPC) as a prognostic biomarker. Methods: We identified consecutive 48 men with mHSPC. The prostate cancer tissues obtained by needle biopsies were immunohistochemically stained for LMW-PTP. A pathologist blindly evaluated the expression of LMW-PTP and intensity of staining was classified into two groups, high (diffusely strongly positive) and low (at least focally weak-negative). The correlations between clinicopathological characteristics including age, initial PSA levels, Gleason scores, T stage, N stage, extend of disease on bone scan (EOD), and expression of LMW-PTP and overall survival (OS) were analyzed by multivariate analysis using cox proportional hazards regression model. Results: Median age was 70.0 years and median initial PSA level was 85.4 ng/mL. Gleason scores were 6-7 in 16 patients (33.4%) and 8-10 in 32 patients (66.6%). Clinical T stages were T2-3 disease in 34 patients (70.8%) and T4 in 14 patients (29.2%). Clinical N stages were N0 disease in 21 patients (43.7%) and N1 in 27 patients (56.3%). EOD grades were 0 in 13 patients (27.0%), 1 in 12 patients (25.0%), 2 in 14 patients (29.2%), 3 in 8 patients (16.7%), and 4 in 1 patient (2.1%). Multivariate analysis revealed that Gleason score (≥ 8 vs ≤ 7; HR: 5.795, 95%CI: 1.266-26.520, p = 0.024) and LMW-PTP expression (high vs low; HR: 2.736, 95%CI: 1.035-7.232, p = 0.042) were independent prognostic factors for OS. Conclusions: LMW-PTP might be a potential biomarker to predict overall survival for men with mHSPC.
Muscle-invasive bladder cancer: Molecular subtypes and response to neoadjuvant chemotherapy.
Authors: Seiler Roland , Winters Brian , Douglas James , van Rhijn Bas W.G. , Sjödahl Gottfrid , Lerner Seth P. , Hoadley Katherine A. , North Scott A. , McConkey David James , Choi Woonyoung , Kim William Y. , van Kessel Kim E.M , Thalmann George N. , Davicioni Elai , Crabb Simon J. , Boormans Joost L , Dall'Era Marc , Wright Jonathan Lawrence , Van Der Heijden Michiel Simon , Black Peter C.
Published: March 2017

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Background: Molecular subtypes of muscle-invasive bladder cancers (MIBC) have recently been discovered based on gene expression. We investigated the impact of different subtyping methods on response to neoadjuvant cisplatin-based chemotherapy (NAC) and developed a single sample model for subtyping. Methods: Transcriptome-wide microarray analysis was conducted on pre-NAC transurethral resection (TUR) specimens of 223 patients with MIBC who received NAC followed by cystectomy at 5 centers. The specimens were classified according to four published methods for molecular subtype (UNC, MDA, TCGA, Lund). Overall survival (OS) for each subtype was compared between NAC patients in this study and non-NAC patients from the provisional TCGA. A genomic classifier (GSC) was trained to predict subtype in a single sample model and validated in independent NAC (2 centers) and non-NAC datasets. Results: The models generated subtype calls similar to previously published ratios. Concordance of a given subtype between the different methods was high. Luminal tumors had the best OS independent of NAC. Patients with tumors classified as UNC basal, MDA basal and TCGA cluster III experienced the greatest improvement in OS after NAC compared to surgery alone. Tumors assigned as UNC claudin-low had the worst OS irrespective of treatment regimen (p=0.005). GSC accurately predicted four classes (luminal, luminal-infiltrated, basal, claudin-low) and the differential impact of a basal subtype on patient OS in NAC (3-yr survival of 75.2%; p=0.001) and non-NAC (3-yr survival of 42.4%; p=0.014) cohorts could be validated. Conclusions: The benefit of NAC varies between molecular subtypes. The good prognosis of luminal/cluster I tumors could not be improved with NAC, which suggests these patients may be managed best with surgery alone. The prognosis of patients with basal tumors improved the most when treated with NAC compared to surgery alone. Poor OS of claudin-low tumors even after NAC implies that these tumors are resistant to cisplatin-based chemotherapy, and these patients should be included in protocols investigating alternative treatment options like immunotherapy. Further validation prior to clinical implementation is needed.
Borealis-2: A randomized phase II study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial cancer (mUC) (Hoosier Cancer Research Network GU12-160).
Authors: Choueiri Toni K. , Hahn Noah M. , Werner Lillian , Regan Meredith M. , Rosenberg Jonathan E. ,   BOREALIS-02 investigators
Published: March 2017

289

Background: OGX-427 (apatorsen; A) is an antisense oligonucleotide that binds Heat shock protein 27 (Hsp27) mRNA with synergistic effect with chemotherapy. Borealis-2 is a randomized multicenter phase 2 study of A in combination with docetaxel (D) vs. D alone in advanced UC patients (pts) after at least 1 prior platinum-based therapy. Methods: The primary objective was to determine whether D+A prolonged overall survival (OS) vs D. Patients were stratified (time from prior systemic chemotherapy; Bellmunt criteria) and randomized in a 1:1 ratio. D was administered for up to 10 cycles in both arms. OGX-427 maintenance continued in pts with no disease progression. Secondary objectives included safety, objective response, and serum levels of Hsp27. The trial design provided 90% power to detect a 33% decrease in OS hazard (hazard ratio [HR] = 0.667), with one-sided α = 0.10 after 162 deaths, and one interim futility analysis; a p-value < 0.1 would result in a positive study for the primary endpoint. Results: 200 pts were randomized between 8/2013 and 9/2015. 72.5% had 1-3 Bellmunt risk factors and 43.5% were < 3mos from prior chemotherapy. 163 pts had died (77 A+D; 86 D) at final analysis. The A+D group had a statistically-significant reduction in hazard for death vs. D (HR = 0.80; 80% CI, 0.65 to 0.98; one-sided P = 0.08). For A+D, median OS was 6.4 mos (95%CI 4.6-9.2) and 12-mo OS was 34.4% (95% CI 25.1-43.9). For D, median OS was 5.9 mos (95%CI 4.8-7.3) and 12-mo OS was 25.0% (95%CI 17.0-33.8). All causality grade 3 or higher toxicities were similar between A+D group (82%; 95%CI 73%-89%) and the D group (75%; 95%CI 65%-83%). The treatment effect of pts with baseline serum Hsp27 < 5.7ng/mL (median) vs. Hsp27 ≥ 5.7ng/mL was not different (2-sided p = 0.87 for interaction). Conclusions: In this platinum-pretreated population of advanced UC, adding OGX-427 to D provided a statistically significant improvement in OS and is worthy of further investigation in previously treated metastatic UC pts. Clinical trial information: NCT01780545.
Atezolizumab (atezo) in patients with metastatic urothelial carcinoma (mUC): A 2-year clinical update from a phase Ia study.
Authors: Petrylak Daniel Peter , Powles Thomas , Bellmunt Joaquim , Braiteh Fadi S. , Loriot Yohann , Morales Rafael , Burris Howard A. , Kim Joseph W. , Ding Beiying , Chang Dannis , Fasso Marcella , O'Hear Carol , Vogelzang Nicholas J.
Published: March 2017

290

Background: Atezo (anti–PD-L1) has demonstrated safety and efficacy in a broad range of cancers and is approved in the United States for mUC previously treated with platinum-based chemotherapy. Here we report long-term results in mUC from Phase Ia study NCT01375842 (PCD4989g). Methods: Previously treated mUC patients received atezo 15 mg/kg or 1200 mg IV q3w. Enrollment in this Phase Ia expansion cohort initially required PD-L1–selected status and later opened to patients regardless of PD-L1 expression on tumor-infiltrating immune cells. The primary endpoint was safety/tolerability. Secondary endpoints included investigator-assessed RECIST v1.1 ORR (confirmed), DOR and OS. Results: 95 patients were safety evaluable (Table). Median age was 66 years, 76% were male and 80% had primary bladder tumors. 61% had ECOG PS 1. 52% received ≥ 3 prior systemic therapies for mUC (70% platinum). Median treatment duration was 3 months (range: 0-32 months); 24% were treated for ≥ 1 year. Treatment-related AEs occurred in 66% (all Grade) and 8% (Grade 3-4) of patients. No treatment-related deaths were reported. In 94 objective response–evaluable patients (follow-up ≥ 12 weeks), the ORR was 27% (95% CI: 18, 37%), and the CR rate was 10%; the SD rate was 19%. mDOR was 22.1 months (95% CI: 12.1, NE months) in all patients; 56% of responses (7/9 CRs and 7/16 PRs) were ongoing at the December 15, 2015 data cutoff. With a 24-month median follow-up duration (range: 1+ to 32 months), the 1-year OS rate was 47% (95% CI: 36, 58%), and the 2-year rate was 29% (19, 40%); mOS is in the Table. Updated clinical data with further follow-up and analyses by PD-L1 status will be presented. Conclusions: Long-term treatment with atezo was well tolerated, without new safety signals in heavily pre-treated mUC patients. The durability of responses, including CRs, along with extended OS, confirm atezo as a new standard for previously treated mUC patients. Clinical trial information: NCT01375842. [Table: see text]
Targeted DNA and RNA sequencing of paired urothelial and squamous bladder cancers to reveal discordant genomic and transcriptomic events and unique therapeutic opportunities.
Authors: Hovelson Daniel H. , Lazo De La Vega Lorena , McDaniel Andrew , Udager Aaron , Mehra Rohit , Palapattu Ganesh S. , Weizer Alon Z. , Morgan Todd Matthew , Montgomery Jeffrey Scott , Tomlins Scott A.
Published: March 2017

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Background: Expression-based molecular subtypes thought to be intrinsic in bladder cancer have been widely reported, carrying important potential clinical treatment implications. Histologically, bladder cancers are also heterogeneous diseases, with a large portion of urothelial carcinomas exhibiting divergent differentiation. Previous subtyping efforts have been carried out using predominantly fresh frozen tissue samples, potentially obscuring this known differentiation heterogeneity. Methods: Here we performed targeted multiplexed, amplicon-based DNA and RNA sequencing on 100 formalin-fixed paraffin-embedded (FFPE) bladder cancer samples (including 12 paired urothelial / squamous lesions). High-confidence somatic point mutations, short insertions/deletions (indels), and copy number alterations were detected using the DNA component of the Oncomine Comprehensive Assay (OCP). Targeted RNA sequencing was carried out using a custom Ampliseq panel comprised of 8 housekeeping genes and 103 target genes assessing major transcriptional programs as identified from publically available data. Results: By DNA analysis, we observe frequent TP53 (35%) and activating hotspot PIK3CA (23%) somatic mutations across the cohort, as well as targetable high-level (log-2 copy number ratio > = 1.5) focal amplifications of ERBB2 (3%) or EGFR (3%) in a subset of samples. We report a novel approach for detecting sub-gene copy-number alterations, and confirm several detectable multi-exon losses using whole transcriptome RNA sequencing. Pairing targeted RNA expression analysis with DNA-based alterations, we show high level expression of EGFR and ERBB2 in focally-amplified samples. Most importantly, we show that despite identical prioritized somatic genomic alterations, we observe divergent expression-based profiles in 3 of 12 (25%) paired urothelial and squamous samples. Conclusions: Taken together, these results highlight the importance of molecular heterogeneity in bladder cancer and suggest important considerations for using existing expression-based clustering approaches to guide clinical treatment decisions.
Clinical destiny of indeterminate pulmonary nodules in patients undergoing radical cystectomy for urothelial carcinoma of the bladder.
Authors: Cahn David B. , McGreen Brian , Lee Albert , Plimack Elizabeth R. , Geynisman Daniel M. , Zibelman Matthew R. , Ristau Benjamin T. , Smaldone Marc C. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Uzzo Robert G. , Kutikov Alexander
Published: March 2017

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Background: Perioperative risks and significant quality of life concerns following radical cystectomy (RC) render accurate pre-operative staging paramount, since metastatic patients are unlikely to benefit from extirpation. Yet, incidental indeterminate pulmonary nodules (IPNs) are a common pre-operative finding in clinical practice, thus representing a significant management challenge. As such, we sought to evaluate the natural history of IPNs in a large institutional cohort that underwent RC. Methods: We reviewed our institutional database for patients who underwent RC from 2000 through 2014 for urothelial carcinoma (UCC) of the bladder and had at least 1 identifiable pulmonary lesion on preoperative staging imaging measuring <2cm in any axis. Patients who were M1 at surgery, had gynecologic, colorectal, or missing pathology, or non-urothelial histology were excluded. We sought to determine the natural history of these pulmonary lesions and evaluated predictors of metastatic etiology. Results: During the study period, 681 RC were performed at our institution. We identified 73 patients with an identifiable preoperative IPN who met inclusion criteria and underwent RC. In this subset, 23.3% were female, 21.9% were active smokers, and 54.8% former smokers. The median age at surgery was 70±8.6 years. Nearly half (49.3%) received neoadjuvant chemotherapy. 61.6% of RC were performed using the traditional open approach, while 38.4% were performed robotically. Final pathologic staging included 16.4% pT0N0Mx, 19.2% pTa/Tis/T1N0Mx, 42.5% pT2-4N0Mx, and 21.9% pTanyN+Mx. Median IPN size was 0.7±0.3cm. At median follow up of 23.5±21.9 months, 93% (68/73) of IPNs in our cohort were clinically benign, with metastatic urothelial cancer confirmed in only 4 patients, and a primary lung malignancy diagnosed in 1 patient. Conclusions: The majority of IPNs in patients who proceeded to RC for UCC of the bladder were stable upon follow-up and rarely represented malignancy. As such, in appropriately screened UCC patients, IPNs should not be a barrier to proceeding with extirpative surgical therapy.
Changes in multiparametric prostate MRI and immune subsets in patients (Pts) receiving neoadjuvant immunotherapy and androgen deprivation therapy (ADT) prior to radiation.
Authors: Madan Ravi Amrit , Turkbey Baris , Lepone Lauren Marissa , Donahue Renee Nicole , Grenga Italia , Borofsky Samuel , Pinto Peter A. , Citrin Deborah E. , Kaushal Aradhana , Krauze Andra V. , McMahon Sheri , Rauchhorst Myrna , Couvillon Anna , Falk Martin H. , Eggleton Peter , Choyke Peter L. , Dahut William L. , Schlom Jeffrey , Gulley James
Published: March 2017

30

Background: Endorectal(er) MRI is an emerging tool in assessing intraprostatic tumors. Immunotherapy development in prostate cancer has been limited due to the lack of intermediate (bio)markers of response. Methods: Untreatedpts with high-risk prostate cancer were randomized in a trial (NCT01496131) of standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25). Pts had erMRI at baseline and after 2 months of ADT+/- biweekly immunotherapy. Low dose (300 mg/m2, maximum 600 mg) cyclophosphamide for regulatory T-cell depletion preceded first immunotherapy. Multiparametric MRI included evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments utilized flow cytometry to evaluate immune cell subsets. This analysis focuses on the 2 month neoadjuvant period of ADT+/-immunotherapy before radiation. Results: 28 pts (n = 14/arm) with high risk prostate cancer (Gleason 8-10, PSA > 20, or stage T3) were enrolled. PSA declined in all pts 2 months after ADT. erMRI findings at 2 months indicated greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI suggests improvements in intratumoral diffusion and has been associated with decreased tumor density. This relative improvement between the groups occurred both per patient (p = 0.16) and per lesion (p = 0.031). Relative to baseline, pts receiving immunotherapy+ADT had increases in CTLA4+ CD8+ T-cells consistent with immune activation (p = 0.0134) and decreases in myeloid derived suppressor cells (MDSCs; p = 0.0353) during the neoadjuvant period corresponding to the erMRI changes. These immune findings were not seen in the ADT alone group. Conclusions: Pts who received immunotherapy+ADT for 2 months had greater improvements in ADC values on erMRI, consistent with decreased tumor density, relative to pts receiving ADT alone. Corresponding increases in activated CD8+ T-cells and decreases in MDSCs were seen in pts receiving vaccine+ADT. These preliminary findings suggest that ADC on MRI may be useful in assessing immunologic impact. Further study is warranted. Clinical trial information: NCT01496131.
Second primary lung cancer in the United States: 1992–2008.
Authors: Donin Nicholas , Kwan Lorna , Lenis Andrew T. , Alexandra Drakaki , Litwin Mark S. , Chamie Karim
Published: March 2017

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Background: Tobacco smoke is a known risk factor for both bladder and lung cancer. We hypothesized that bladder cancer survivors are at high risk for second primary lung cancers (SPLC), and sought to describe the incidence and mortality attributable to SPLC among survivors of bladder cancer as well as other common cancers in the United States. Methods: We identified adult patients diagnosed with a localized primary malignancy from 8 of the most common non-pulmonary cancer sites in Surveillance, Epidemiology, and End Results (SEER) data from 1992–2008. We explored factors associated with the incidence and mortality from SPLC using bivariable and multivariable models. Finally, we compared standardized incidence rates (SIRs) for SPLC in our cohort with the control arm of the National Lung Screening Trial (NLST), a large lung cancer screening trial in patients at high risk for lung cancer. Results: We identified 1,431,809 survivors of common non-pulmonary cancers, of whom 24,477 (1.7%) developed SPLC at a mean (SD) follow-up of 5.7 (3.6) years. Bladder cancer survivors developed SPLC at twice the rate of other cancer survivors, with 10% developing SPLC in the 20 years following their bladder cancer diagnosis. Increasing age and male gender were independent risk factors for SPLC, irrespective of the primary cancer type. Of patients who developed SPLC, 19,059 (78%) died during follow-up. Lung cancer was responsible for 73% of these deaths, such that over half (57%) of the cancer survivors who develop SPLC ultimately died of lung cancer. Bladder cancer survivors demonstrated a SIR of 512 cases/100,000 person-years, which approaches the rate (572 cases/100,000 person-years) seen in the control arm of the NLST. Conclusions: Over half of patients who develop SPLC died of their disease. Almost 10% of bladder cancer survivors develop SPLC in the 20-years following their diagnosis. This rate approaches that seen in the control arm of the NLST, suggesting that the incidence in bladder cancer survivors could justify lung cancer screening in this population. Further efforts to better define the potential risks and benefits of lung cancer screening in bladder cancer survivors is warranted.
Does liposomal bupivacaine use intraoperatively decrease postoperative narcotic use in radical cystectomy patients?
Authors: Kukreja Janet Baack , Chang Courtney M , Seif Mohamed , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul
Published: March 2017

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Background: Bupivacaine liposome injectable suspension (LB) can be used to help control postoperative pain. It slowly releases bupivacaine for up to 96 hours after injection. This study sought to determine if the use of LB intraoperatively for radical cystectomy (RC) patients decreases postoperative narcotic use. Methods: A retrospective cohort study was performed. 281 patients underwent RC between November 2013 and May 2016, 203 received LB. LB was administered after fascial closure but before skin closure by performing suprafascial and subfascial injection with 20ml of LB. Patient demographics, BMI, renal function, operative characteristics, and the total postoperative intravenous morphine equivalents were reviewed. Where appropriate chi-squared, Mann-Whitney and t-tests were used for statical analysis. Multivariable analysis and linear regression models were performed. Because enhanced recovery principles were used simultaneously, enhanced recovery status was also used to adjust for predictors of post-operative opioid use. Results: There was no difference in baseline demographics, BMI, renal function or baseline opioid use between the LB and non-LB group. The operative time was longer in those who had LB administered and there were more open RCs performed in the LB group. Total morphine equivalents averaged to 8.0 mgs for the LB group and 50.7 mgs for the non-LB group, p-value <0.001. More patients had epidurals and IV PCA pumps in the non-LB group, (p=0.001 and <0.001, respectively). There were 42 patients whom did not require any IV morphine equivalents in the LB group compared to only 4 in the non-LB group (p=0.002). After adjusting for modality, and operative time, the linear regression model was predictive of less IV morphine equivalents in those with LB, p=0.044. Conclusions: The addition of LB to enhanced recovery principles increases the number of patients with zero narcotic use postoperatively. Irrespective of open or robotic modality and operative time, LB use decreases opioid use after RC.
Effect of green tea polyphenol on changes in cancer-related factors in a mouse model of bladder cancer.
Authors: Matsuo Tomohiro , Miyata Yasuyoshi , Nakamura Yuichiro , Takuji Yasuda , Asai Akihiro , Ohba Kojiro , Sakai Hideki
Published: March 2017

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Background: Many studies have demonstrated the anti-cancer effects of green tea polyphenol (GTP) in a variety of malignancies including bladder cancer, and epidemiologic studies have shown that green tea consumption reduces cancer risk. New cancer treatment strategies in combination with GTP intake have been recommended for several types of cancer. Thus, GTP is thought to be useful not only for cancer prevention but also for treatment. However, the mechanistic basis of these effects is not well understood. Hence, The aims of this study is to clarify the molecular mechanisms of GTP-induced anti-cancer effects, we used a mouse model of chemically induced bladder cancer. Methods: C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14–24 weeks. Mice in the BBN + GTP group (n = 47) were also treated with 0.5% GTP solution over the same period. Tumor cell proliferation, and microvessel density were evaluated along with immunohistochemical analysis of human antigen R (HuR), vascular endothelial growth factor (VEGF)-A, cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Results: Cytoplasmic HuR expression in cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. A multivariate analysis of GTP intake and cytoplasmic HuR expression revealed that GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of VEGF-A and HO-1 was associated with angiogenesis. In regard to nuclear HuR, its expression was not associated with any parameters, such as carcinogenesis, muscle invasion, and GTP intake. Conclusions: Our results supported the opinion that GTP intake can suppress tumor progression and malignant behavior in animal model of bladder cancer. In addition, we speculate that GTP directly and indirectly suppresses tumor cell proliferation and angiogenesis via HuR-related pathways in bladder cancer tissue.
Circulating tumor (ct)-DNA alterations in advanced urothelial carcinoma: Association with outcomes and evolution with therapy.
Authors: Grivas Petros , Nagy Rebecca J , Pond Gregory Russell , Gupta Sumati , Wang Jue , Vaishampayan Ulka N. , Pal Sumanta K. , Bilen Mehmet Asim , Naik Gurudatta , Ghatalia Pooja , Gopalakrishnan Dharmesh , Barata Pedro , Lanman Richard B. , Talasaz AmirAli , Sonpavde Guru
Published: March 2017

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Background: Cell-free ctDNA may be potentially actionable, prognostic for outcomes and evolve after therapy. We conducted a retrospective study to evaluate these issues and shed light on UC biology. Methods: Patients (pts) with advanced UC who underwent ctDNA analysis for potentially actionable alterations using Guardant360 were identified. Data were requested for prognostic factors, current and prior therapies, TTF (time to treatment failure) and overall survival (OS). A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 cancer genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of non-synonymous potentially functional alterations with outcomes and prior therapy was examined. Results: There were 217 pts with 238 samples. ctDNA was detectable in 212 (89%) samples. Median age was 62 (range 39-91). The most common recurrent somatic mutations were in TP53 (n = 122, 57%) ARID1A (n = 47, 22%), NF1 (n = 35, 16%), FGFR2, FGFR3, and BRCA1 (n = 30, 14% each), MET (n = 27, 13%), ERBB2 (n = 25, 12%), PIK3CA (n = 24, 11%), and EGFR (n = 22, 10%). Most common genes with increased copy numbers were ERBB2 (n = 19, 9%) and RAF1 (n = 18, 8%). Clinical data were available for 64 pts, of whom 38 (59%) had prior chemotherapy. FGFR1 alterations noted in 3 of those pts (5%, 2 functional, 1 amplification) were associated with shorter OS (HR 2.95, p = 0.05). Pts with prior chemotherapy showed trend towards frequent alterations in DNA repair genes (45% vs. 23%, p = 0.11). Serial ctDNA profiling of 21 pts receiving therapy revealed the clonal evolution of mutations in BRCA2, NF1 and GATA3. Conclusions: ctDNA was very frequently detected in pts with advanced UC, and alterations were similar to those previously seen in muscle-invasive UC tumor tissue. FGFR1 alterations predicted for unfavorable outcome and DNA repair gene alterations evolved commonly after chemotherapy. Drugs exploiting these targets such as FGFR1 and PARP inhibitors may warrant exploration as salvage therapy in selected pts.
Phase I/Ib study of enzalutamide and gemcitabine and cisplatin in bladder cancer.
Authors: Gupta Shilpa , Fishman Mayer N. , Dhillon Jasreman , Magliocco Anthony Martin , Puskas John , Caceres Gisela , Al-Toubah Taymeyah E , Konety Badrinath R. , Lindemam Matthew , Jha Gautam Gopalji , Zhang Jingsong
Published: March 2017

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Background: Metastatic bladder cancer (mBC) is a fatal disease and novel therapies are urgently needed. Preclinical evidence suggests role of AR in BC progression. Enzalutamide (ENZ) is a novel AR antagonist that inhibits nuclear translocation of AR, DNA binding, and co activator recruitment. Our ongoing phase 1 trial is is assessing safety and tolerability of ENZ in combination with gemcitabine and cisplatin (GC) in mBC and explore novel correlatives in tumor tissues and CTCs. Methods: The study has 2 phases, dose escalation phase and dose expansion phase. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 mg and 160 mg respectively with GC (gemcitabine 10000 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 on day 1 every 21 days). The dose escalation phase allowed both AR + and AR - mBC pts. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and CT scans to assess response. Primary objective is safety and tolerability of ENZ and GC. Secondary objectives are objective tumor response, time to progression, and overall survival. Exploratory objectives include qualitative and quantitative evaluation of AR and pAKT expression with AQUA in tumor tissues and correlation with outcomes. CTCs are being evaluated at baseline and cycle 3, including AR expression in CTCs and correlation will be done with tumor AR expression and clinical outcomes. Key eligibility criteria are ECOG PS of 0-1, and no contraindications to study drugs. Results: In the dose expamnsion phase, 3 patients were enrolled in each cohort of 80 mg and 160 mg of ENZ respectively with GC and there were no DLTs or significant AEs related to the combination; the MTD of ENZ is 160 mg. Enrollment on dose expansion phase is ongoing. detectable CTCs were seen in 4/6 BC patients with 2 patients showing AR + CTCs at baseline. Further CTC analysis, including AR expression and tissue analysis for AR and pAKT analysis in tissues is ongoing. (Trial identifier: NCT02300610). Conclusions: This is a first of its kind clinical trial exploring the role of AR signaling in BC and targeting it with ENZ along with GC. The data gathered form this study will help us understand the clinical relevance of targeting AR in BC. Clinical trial information: NCT02300610.
Thrombo-embolic events (TEE) during neoadjuvant chemotherapy for muscle invasive bladder cancer.
Authors: Hussain Syed A. , Gomberg Simon , Probert Cairine , Hickerton Bethan , Jackson Richard , Weston Robin
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Background: Patients with muscle invasive bladder cancer receiving neo-adjuvant chemotherapy (NAC) prior to radical cystectomy or organ preservation treatment are at higher risk of thrombo-embolic events (TEE). Methods: Retrospective data were collected on patients undergoing NAC prior to radical treatment who had surveillance CT scan chest abdomen pelvis following NAC to assess for response or underwent scan following clinical presentation during NAC requiring imaging. The aim of this study was to document the incidence and characteristics of TEE during NAC prior to radical treatment. Results: Data were collected on 94 patients between January 2012 and December 2015. Median patient age was 67 (IQR: 63, 72) with 28 (30%) females. Chemotherapy received was Cisplatin and Gemcitabine in 90% of cases, Gemcitabine and Carboplatin (9%), and Cisplatin and Etoposide (1%). Performance status was 0 in 59% of cases. G3 disease was recorded in 87%, T2 or T3 in 80% and TCC in 91% of cases. 28 TEE (29.8%, 95 % CI: 20.5%, 39%) were recorded of which 22 (79%) were subclinical TEE and 6 (21%) were clinical TEE. 23 (82%) of TEE were pulmonary emboli, 2 (7%) were concurrent pulmonary emboli and deep vein thombosis, 2 (7%) were abdominal aorta thrombosis, and 1 (4%) was a deep vein thrombosis. Conclusions: Our single centre study demonstrates that the incidence of TEE during NAC prior to radical treatment for bladder cancer is high. Improved imaging techniques lead to reporting of number of sub clinical TEE of uncertain clinical significance. These findings give weight to future prospective clinical trials to investigate the role of anti-coagulation in subclinical TEE and benefit of prophylactic anti-coagulation during NAC.
Difference in toxicity reporting between patients and clinicians during systemic chemotherapy for urothelial carcinoma.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: March 2017

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Background: Symptomatic toxicities associated with anticancer treatments are at high risk of under-reporting by clinicians. However, insufficient evidence is available for urothelial carcinoma. To compare toxicity reporting by patients and clinicians in urothelial carcinoma patients who received systemic chemotherapy. Methods: Between June 2013 and March 2016, 100 urothelial carcinoma patients who received two courses of chemotherapy of gemcitabine plus cisplatin (GCis) or gemcitabine plus carboplatin (GCb) were included in this study. Outcome Measurements and Statistical Analysis: During chemotherapy, patients answered QLQ-C30 quality of life (QOL) questionnaires, which included questions on four toxicity-related symptoms (appetite loss, nausea, constipation, and diarrhea). Clinicians evaluated adverse events using CTCAE v4.0. Differences in toxicity reporting were retrospectively compared between patients and clinicians. Logistic regression analyses were performed to investigate potential factors for under-reporting by clinicians. Results: Toxicity under-reporting was most frequent in diarrhea (44%), followed by appetite loss (39%), constipation (33%), and nausea (22%). In total, toxicity under-reporting was observed in 72% patients. Background-adjusted logistic regression analyses showed that pretreatment QOL items, such as global and symptomatic scores, were selected as potential predictors for toxicity under-reporting by clinicians. Limitations of our study included its retrospective nature and small sample size. Conclusions: Toxicity under-reporting by clinicians is frequent in urothelial carcinoma patients who received systemic chemotherapy. Pretreatment QOL evaluation is essential to identify potential individuals at risk for toxicity under-reporting. Clinical trial information: UMIN000020784.
5-year outcomes from a prospective multi-institutional trial of heterogeneous dosing stereotactic body radiotherapy (SBRT) for low- and intermediate-risk prostate cancer.
Authors: Fuller Donald B. , Kane Brent L. , Medbery Clinton A. , Underhill Kelly , Gray James R. , Peddada Anuj , Chen Ronald C.
Published: March 2017

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Background: SBRT is an emerging treatment for prostate cancer, but long-term reporting remains sparse. We present a prospective Phase II trial with 90% treated in community facilities. Methods: 14 institutions enrolled 259 patients - 112 low-risk; 147 intermediate-risk. The regimen emulated a high-dose rate brachytherapy (HDR) regimen - 38 Gy/4 fractions delivered by robotic SBRT. Androgen deprivation therapy was not allowed. HDR-like heterogeneous prostate dosing was used (Dmax >57 Gy). Toxicities were assessed by CTCAE v3.0 and quality of life assessed by Expanded Prostate Cancer Index Composite (EPIC). Biochemical recurrence was defined by Phoenix criteria. Results: Median follow-up is 5 years. 5-yr Grade 2 GU toxicity was 13.7% and GI toxicity 4.5%, with Grade 3 rates of 3% (GU) and 0% (GI) (one Gd 4 GU event). 5-yr median PSA was 0.1 ng/mL with further subsequent decrease (7 y = 0.035 ng/mL). 5-yr biochemical disease-free survival (bDFS) = 100% for low-risk and 88.5% for int-risk. 6 patients developed distant metastasis and one died of disease. Median EPIC GU obstruction and GI scores were similar at baseline vs. 5 years. 2% of patients had baseline GU incontinence requiring pad use vs 10% at 5 yrs. Of baseline potent men, 46% remained so at 5 yrs (66.7% for those age ≤65 vs. 37.1% age >65 at treatment). Conclusions: This is the first report of 5-year median follow-up outcomes post heterogeneous dosing SBRT for early prostate cancer. This treatment produces a low PSA nadir vs other forms of radiotherapy, with a favorable long-term result that appears reproducible in the community. Clinical trial information: 00643617. [Table: see text]
Comprehensive genomic profiling of relapsed and refractory small cell neuroendocrine carcinoma of the urinary bladder.
Authors: Pal Sumanta K. , Hoffman-Censits Jean H. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Fisher Hugh A.G. , Mian Badar , Nazeer Tipu , Fabrizio David , Frampton Garrett Michael , Stephens Phil , Miller Vincent A. , Gay Laurie M. , Ross Jeffrey S.
Published: March 2017

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Background: Small cell neuroendocrine carcinoma of the bladder (SCCB) is rare but aggressive form of genitourinary cancer that can arise de novo or in conjunction with urothelial carcinoma (UCB). Methods: DNA was extracted from 40 microns of FFPE specimen from 29 cases of relapsed, refractory and metastatic SCCB and 1,113 UCB. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 503X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: 29 SCCB cases were confirmed on routine histology and featured positive IHC staining for chromogranin, synaptophysin or both. Patients had a mean age of 68.1 years (range 49-90 years) and 25 (86%) were male. At the time of CGP, 3 (10%) SCCB were Stage III and 26 (90%) were stage IV. The primary SCCB was used for sequencing in 14 (48%) of cases and a metastasis sample in 15 (52%). The 29 SCCB featured 2.86 GA/case.The genomics of SCCB differed significantly from UCB (Table). The most frequent clinically relevant GA in SCCB were RICTOR amp (21%) and PIK3CA (10%), BRCA1, HGF, FBXW7 and CCND2 SV (7% each). The relatively high TMB in SCCB (7% TMB > 20 mut/Mb and 28% TMB > 10 mut/Mb) is similar to that seen in UCB. No SCCB cases were MSI-high. ERBB2 and FGFR1 GA frequencies (both 3%) in SCCB were lower than in similarly studied UCB. Conclusions: SCCB differs in genomic landscape from UCB in having higher frequencies of TP53 and RB1 GA and lower frequencies of FGFR3 and ERBB2 GA. However, like UCB, SCCB shares the presence of multiple GA associated with potential responses to targeted therapies and high TMB associated with response to immune checkpoint inhibitor therapy. [Table: see text]