bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular mechanism of FGFR activation and resulting differences in the tumor-immune environment of bladder cancer.
Authors: Kawahara Takashi , Kojima Takahiro , Shiga Masanobu , Tanaka Ken , Kandori Shuya , Negoro Hiromitsu , Kawai Koji , Nishiyama Hiroyuki
Published: February 2020

432

Background: Activation of FGFR signals in bladder cancer is frequently observed. Previous study reported that infiltration of tumor immune cells is suppressed in FGFR3 mutated bladder cancer. In this study, we elucidate the relationship between molecular mechanism of FGFR activation and tumor immune environment in bladder cancer. Methods: We analyzed 103 tissues of bladder cancer patients. Detection of somatic mutations were performed by target sequencing and gene expressions were analyzed by RNA-seq. Immunohistochemical staining of CD8 was performed for evaluating tumor-infiltrating lymphocytes. We compared the relationship between molecular mechanism of FGFR activation and tumor immune environment. Results: FGFR3 activated mutation or fusion was found in 37 cases (36%). FGFR1 overexpression was found in 10 cases (10%). FGFR3 activated mutation or fusion and FGFR1 overexpression were mutually exclusive. Tumors harboring FGFR3 mutation showed less infiltration of CD8 positive cells ( p = 0.01) and low PD-L1 expression ( p = 0.08) compared to those without. On the other hand, tumors with FGFR1 overexpression showed more infiltration of CD8 positive cells ( p = 0.06) and high PD-L1 expression ( p = 0.02). Conclusions: Clinicopathological features and intratumor immune environment of bladder cancer is different depending on the molecular mechanism of FGFR activation. These results suggest a possible association between molecular mechanism of FGFR activation and sensitivity of immunotherapy.
Phase II randomized placebo-controlled neoadjuvant trial of nintedanib or placebo with gemcitabine and cisplatin in locally advanced muscle invasive bladder cancer (NEO-BLADE).
Authors: Hussain Syed A. , Lester Jason Francis , Jackson Richard , Gornall Matthew , Elliott Anthony , Crabb Simon J. , Huddart Robert A. , Vasudev Naveen , Birtle Alison Jane , Worlding Jane , James Nicholas D. , Parikh Omi , Vilarino varela Maria , Alonzi Roberto , Linch Mark David , Powles Thomas , Jones Robert J.
Published: February 2020

438

Background: Neo-adjuvant chemotherapy Improves overall survival in patients with MIBC. Nintedanib is an orally available, potent, small molecule, triple kinase inhibitor with the potential to further benefit patient prognosis. Methods: NEO-BLADE was designed as a randomised, placebo controlled phase II study (n=120) to compare the addition of nintedanib (N) (150mg/200mg BD) to a combination of Gemcitabine (G) and Cisplatin (C). The study was powered (80%, alpha=15% [one sided]) to detect an improvement in the histological complete response rate of 20% (OR = 2.37). Results: 120 patients were recruited from 15 sites between 04/Dec/2014 and 03/Sep/2018 (22% Female) with 109 patients evaluable. Complete response (CR) rates ( by ITT) were 22/57 (38.6%) and 25/63 (39.7%) for patients treated with/without N. Pathological CR on ITT was 21/57 (36.8%) and 20/63 (31.74%); For pathological evaluable patients it was 21/41 (51. 22% ) and 20/45 ( 44.44%) respectively. Patients treated with N showed a benefit in terms of PFS and OS with 12 month PFS rates of 89.0% and 74.1% in the Nintedanib and Placebo group respectively. P= 0.038 and HR (CI) 0.479 (0.236, 0.976). OS at 12/24 months N 96.26%/ 88.87% while in Placebo group 82.83%,/69.36%. P=0.022, HR (CI) 0.389 (0.168, 0.902). Toxicity was reported in terms of grade 3 adverse events [12/63 (19%) Placebo, 23/57 (40%) N] and Serious Adverse Events [35/63 (56%) Placebo, 34/57 (53%) N]. In terms of thromboembolic events, this was observed in 16/57 (28%) of patients treated with N and 13/63 (21%) without N (P=0.461). Conclusions: The study failed to reach its primary endpoint in demonstrating an improvement in pathological response rate between N and Placebo when given alongside G and C. The trial met its secondary end point in improvement of progression free survival and over all survival at 12 months and 24 months. Safety data from this placebo -controlled study confirms triplets can be given safely. There are efficacy signals with improvement in PFS and OS and the regimen warrants further investigation in randomised phase III trial. Translational studies to assess bio markers of response are planned. Clinical trial information: 11977.
Who is a bone-predominant patient to maximize clinical benefits of radium-223 dichloride?
Authors: Hashimoto Kohei , Miyoshi Yasuhide , Shindo Tetsuya , Nishiyama Naotaka , Miyamoto Shintaro , Maehana Takeshi , Okada Manabu , Yanase Masahiro , Kato Ryuichi , Hotta Hiroshi , Kunishima Yasuharu , Takahashi Atsushi , Kitamura Hiroshi , Uemura Hiroji , Masumori Naoya , Kobayashi Ko , Tanaka Toshiaki
Published: February 2020

47

Background: Radium-223 dichloride (Ra-223) is used for patients with castration-resistant prostate cancer (CRPC) and bone metastasis (BM). However, some patients often have disease progression of non-BM during Ra-223 and may enable to receive no more other life-prolonging therapies. Thus, diagnostic uncertainty in bone-predominant CRPC yet needs to be determined. To maximize clinical benefits of Ra-223, we clarified how to identify patients with bone-predominant metastatic CRPC. Methods: This was a multi-center retrospective study. The 136 CRPC patients who received Ra-223 between 2012 and 2019 were reviewed. Patients without visceral metastasis and lymph node metastasis of more than 3 cm received Ra-223, 55kBq/kg, every 4 weeks for up to 6 cycles, and were required to continue androgen deprivation therapy alone. All patients were divided into 3 groups by the types of dynamic changes of BM compared to BM at diagnosis: i) only known lesions; ii) new progressive lesions; iii) de novo BM at CRPC. Time from initiation of Ra-223 to failure of subsequent treatment (time to FST), radiographic progression-free survival (rPFS) and overall survival (OS) were evaluated. Results: The median age was 76 years. Of all, 68% received all 6 planned cycles of Ra-223. Overall, PSA responses were observed in 26 (19%). During follow-up of 12 months, the median time of FST, rPFS and OS were 8.3, 10.6 and 16.4 months, respectively. The type of dynamic changes of BM (HR 3.65, p=0.004) and PSA doubling time (PSADT) just before Ra-223 (HR 4.35, p=0.006) were significantly associated with time to FST. The dynamic changes of BM combined with PSADT highlighted an optimal decision of Ra-223. Patients with only known lesions of BM had longer time to FST, better rPFS and OS regardless of PSADT. The same was true for patients with de novo or new progressive lesions of BM and a long PSADT. In contrast, patients with new progressive lesions of BM and PSADT< 3 months were presumably more likely to have the risk of FST and progression of visceral metastasis. Conclusions: Our findings suggest that the risk assessment with the type of dynamic changes of BM and PSADT could determine an ideal patient for Ra-223.
Any regression of tumor (ART) within 12 weeks versus RECIST 1.1 response category as an intermediate endpoint to assess the activity of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC).
Authors: Curran Catherine , Pond Gregory Russell , Nassar Amin , Abou Alaiwi Sarah , McGregor Bradley Alexander , Kilbridge Kerry L. , Sonpavde Guru
Published: February 2020

473

Background: Many ICIs are approved to treat mUC following platinum-based chemo and as 1st-line therapy for selected patients (pts). While RECIST 1.1 responses are generally durable and associated with prolonged survival, the benefit of ICIs extends beyond this group of pts. Stable disease (SD) consists of a heterogeneous population of pts with both increase and decrease in tumor size and is confounded by the impact of pre-ICI disease pace. We hypothesized that in the setting of ICIs, any regression of tumor (ART) within 12 weeks may capture early benefit and correlate with survival more comprehensively than RECIST 1.1. Methods: mUC pts who received an ICI following platinum-based chemo at DFCI were eligible for analysis. Pts were required to have tumor size changes, RECIST 1.1 response by week 12 and survival data available. Demographics and prognostic factors were collected. Descriptive stats were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of ART and RECIST 1.1 with overall survival (OS). Results: 104 pts were evaluable. The median age was 66 (range 34-89). 71% were male. The numbers of pts with ART and RECIST1.1 partial response (PR) were 45 (43.3%) and 32 (30.1%), respectively. Univariable analyses identified an association between ART and RECIST 1.1 response with OS (p<0.001). The 1-year OS (95% CI) for ART vs. no ART was 83.6 % (68.7, 91.8) and 35.9 % (23.1, 48.8), while the 1-year OS (95% CI) for RECIST 1.1 response vs. no response was 81.3% (62.9, 91.1) and 45.6% (32.9, 57.4), respectively. RECIST 1.1 category was not significantly associated with OS (p-value=0.68) after adjusting for ART; however, statistically, ART associated with OS (p=0.002) after adjusting for RECIST 1.1 category. The modest size of this cohort is a limitation. Conclusions: ART within 12 weeks is identified early and is robustly associated with OS in pts with mUC receiving post-platinum ICIs. ART may serve as a more optimal intermediate endpoint for survival compared to RECIST 1.1 in the setting of ICIs. Evaluating this endpoint in other malignancies is warranted.
The multidisciplinary clinic approach for bladder cancer treatment in the neoadjuvant therapy era.
Authors: Smentkowski Katherine E. , Han Timothy M. , Glick Lydia , Lallas Costas D. , Calvaresi Anne , Mann Mark Jonathan , Mark James Ryan , Gomella Leonard G. , Kelly William Kevin , Handley Nathan , Den Robert Benjamin , Hurwitz Mark , Tester William J. , Dicker Adam P. , Chandrasekar Thenappan , Trabulsi Edouard John
Published: February 2020

475

Background: As urologic oncology becomes increasingly complex, the coordination of optimal and efficient care to patients can be challenging. Within our institution, we initiated a multidisciplinary center (MDC) comprised of urology, oncology and radiation oncology in 1996 to help meet these needs. The positive benefits of this approach have been demonstrated in other settings, but outcomes related to bladder cancer remain unclear, especially in the era of neoadjuvant (NA) therapy. Methods: Patients with localized or node positive muscle invasive bladder cancer (MIBC) without prior treatment were obtained from available multidisciplinary appointment records, dating from 7/5/17 to 9/25/19. Charts were then retrospectively reviewed to gather demographic data, treatment data, and pathological outcomes. Results: 66 patients fitting study criteria were identified. Average age was 71.3 years. 45 (68%) patients from this cohort were deemed to be radical cystectomy (RC) candidates, with 37 RC operations completed at time of record review. Of RC-eligible patients, 35/45 (77%) had received NA therapy, either in the form of neoadjuvant chemotherapy (NAC) and/or immunotherapy (NAI). 3 patients declined RC after receiving NAC. 15 patients underwent chemoradiation treatment (23%), while 7 (11%) underwent supportive care without definitive treatment. Downstaging at RC from MIBC (<=T1) was seen in 12/37 patients (32%), with a pT0 rate of 10% (4/37). Conclusions: The coordination of care in bladder cancer remains a challenge for patients and physicians alike. We believe by utilizing a multidisciplinary approach, efficiency and quality of care increases. National database studies have reported overall utilization of neoadjuvant chemotherapy over the past 10 years, with most recent rates ranging from 14.8-20.9%. Our utilization of neoadjuvant therapy is notably higher at 77%, which also includes early adaptation of NAI in patients deemed ineligible for neoadjuvant NAC. Further studies are needed to examine a contemporary control population outside the multidisciplinary setting, however the above outcomes provide a basis for the integration of care and its positive outcomes in quality improvement.
Missed opportunity: An intersectional approach to disparities in long-term survival in bladder cancer.
Authors: Washington Samuel L. , Gregorich Stephen , Song Sikai , Meng Maxwell V. , Suskind Anne , Porten Sima P.
Published: February 2020

476

Background: For individuals with muscle-invasive bladder cancer (MIBC), studies focused on racial disparities have shown black race is associated with 21% lower odds of guideline-based treatment (GBT) and differences in treatment explain 35% of observed black-white differences in survival. To characterize how the interaction between race/ethnicity and receipt of GBT drive within- and between-race differences in survival for black, white, and Latino individuals with MIBC. Methods: We identified a cohort of individuals with cT2-4 MIBC from 2004-2013 in the National Cancer Database. GBT was defined by American Urological Association guidelines. A Cox proportional hazards model of patient mortality estimated effects of patient GBT status, race/ethnicity, and the GBT-by-race/ethnicity interaction, adjusting for covariates. Results: Of 54,910 MIBC individuals with 125,821 person-years of post-treatment observation (max=11 years), 90.1% were white, 6.9% black, and 3.0% Latino. Half (50.2%) received GBT. Averaging across GBT status, Latino individuals had lower hazard of death compared to black (HR 0.81, 95% CI 0.75-0.87) and white individuals (HR 0.92, 0.86-0.98). With GBT, Latino and white individuals had similar outcomes (HR=1.00, 0.91-1.10) and both groups fared significantly better than black individuals (HR=0.88, 0.79-0.99 and HR=0.88, 0.83-0.94, respectively). Without GBT, Latino individuals fared better than white (HR=0.85, 0.77-0.93) and black individuals (HR=0.74, 0.67-0.82) while white individuals fared better than black individuals (HR=0.87, 0.83-0.92). Latino without GBT fared better than black individuals with GBT (H=0.98, 0.88-1.09), although not statistically significant. Conclusions: Our study finds that not only are GBT levels generally low, which is concerning, but there is also an apparent 'under-allocation' of GBT to a patient group who arguably needs it the most-- black individuals. Future efforts to improve the delivery of GBT, a factor directly impacted by urologic care providers, may mitigate the race-based survival differences observed in individuals with MIBC.
Neoadjuvant chemotherapy-induced sarcopenia to predict perioperative complications following radical cystectomy for bladder cancer.
Authors: Haifler Miki , Ventura Yossi , Malsha Kamil , Shpitzer Sagi , Zisman Amnon , Baniel Jack , Amiel Gilad , Hoffman Azik , Golan Shay
Published: February 2020

478

Background: Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is the standard of care for muscle invasive bladder cancer and has a high rate of complications. Malnutrition is common among RC patients and is an established risk factor for peri-operative complications. The association of NAC and nutritional status and its effect on post-operative complications is not fully understood. We hypothesize that NAC hinders nutritional status and thus increases complication rates after RC. Methods: We retrospectively examined the records of NAC/RC patients. We included demographic, clinical and pathologic data and type and cycle number of NAC. Nutritional status was assessed with the smooth muscle area (SMA) of the psoas muscle at the level of L4 vertebrae measured on cross-sectional imaging. Patients with missing imaging data were excluded. SMA was measured pre and post NAC. The difference between the measurements was used as a predictor variable (delta_SMA). The outcomes assessed were ileus, infection, rehospitalization and a composite outcome of any complication. Results: The study included 50 patients, from 3 high volume centers in Israel. Median delta_SMA was -197 (-366, -88) mm2. Demographic, clinical and pathologic parameters were similar in patients with and without complications. delta_SMA was an independent predictor of ileus (OR = 0.98, p=0.003), peri-operative infection (OR = 0.98, p=0.0015) and any complications (OR = 0.98, p = 0.011) on univariable analysis. Delta_SMA remained an independent predictor of ilieus (OR 0.97, p=0.014), peri-operative infections (OR 0.95, p=0.023) and any complications (OR 0.98, p=0.01) on multivariable regression analysis. Delta_SMA was not a significant predictor of rehospitalization. Conclusions: In patients undergoing RC, NAC causes a measurable nutritional insult. The change in SMA predicts significant peri-operative complications. Future studies should examine the role of nutritional intervention during NAC in the framework of a clinical trial.
Perioperative chemotherapy for upper tract urothelial carcinoma: A microsimulation Markov model.
Authors: Magee Diana E. , Hird Amanda Elizabeth , Cheung Douglas , Sander Beate , Nam Robert , Sridhar Srikala S. , Kulkarni Girish S.
Published: February 2020

508

Background: Upper tract urothelial carcinoma (UTUC) accounts for less than 5% of all urothelial cancers. As a result, this disease is clinically understudied and there are no definitive recommendations regarding use and timing of peri-operative chemotherapy. The objective of this study was to create a decision model comparing three treatment pathways in UTUC: nephroureterectomy (NU) alone, neoadjuvant chemotherapy (NAC), and adjuvant chemotherapy (AC). Methods: A Markov microsimulation model was constructed using TreeAge Pro to compare treatment strategies for patients with newly diagnosed UTUC. Our primary outcome was quality adjusted life expectancy (QALE). Secondary outcomes included rates of adverse chemotherapy events, bladder cancer diagnoses, and crude survival. Markov cycle length was 3 months to mimic the follow up interval used in clinical practice for patients with UTUC. A systematic literature review was used to generate probabilities to populate the model. The base case was a 70-year-old patient with a radiographically localized upper tract tumor. Patients could have evidence of nodal disease, but no distant metastasis. Results: A total of 100,000 microsimulations were generated. NAC was preferred with an estimated QALE of 7.52 years versus 6.80 years with NU alone and 7.20 years with AC. Overall, 39.6% of patients in the AC group with invasive pathology received and were able to complete chemotherapy. A total of 37.5% of patients in the NAC group experienced an adverse chemotherapy event compared to 15.1% of patients in the AC group. Bladder cancer recurrence rates were 64.9%, 66.0%, and 67.1% over the patient’s lifetime in the NU, NAC, and AC groups, respectively. Conclusions: This study provides evidence to support the increased use of NAC in UTUC until robust randomized trials can be completed. While the use of NAC in this population appears favourable, the ultimate choice rests with the clinician and should be based on patient and tumor factors.
Optimal timing of radical cystectomy after neoadjuvant chemotherapy in muscle invasive bladder cancer (MIBC).
Authors: Parasramka Saurabh , Sekkath Veedu Janeesh , Chen Quan , Huang Bin , Wang Peng , Myint Zin
Published: February 2020

509

Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with bilateral pelvic lymph node dissection is the current standard of care for MIBC. Pathologic downstaging with NAC is an important surrogate endpoint and associated with overall survival benefit. There have been questions about the impact of delay in definitive surgery because of NAC. The optimal timing of surgery from the start of NAC is uncertain. We studied this question using National Cancer Database (2004-2015). Methods: We identified patients with MIBC (cT2-T4aN0M0 & cT1-T4aN1M0) who received NAC within 6 months of diagnosis and underwent surgery between 10 weeks and 9 months of the start day of NAC. We excluded patients who died within 30 days of surgery. Time period was stratified into three cohorts; 11-16, 17-24, and ≥25 weeks from the start day of NAC. Descriptive analysis, Kaplan-Meier plots, Log-Rank tests for univariate and proportional hazards models for multivariate survival analyses were performed. Results: 3709 patients were identified; 75% were males, 77% cases were cT2 and 73% had charlson-deyo score (CS) of '0'. Median time for surgery 10 weeks after start of NAC was 118 days. Forty-two (42%) had surgery in 11-16, 47% in 17-24 and 9.9% in ≥25 weeks. Majority (60%) were treated at academic and 24% at comprehensive community. Only 29% achieved complete pathological complete response rate (Tis or T0). On univariate analysis receiving NAC within 3 months of diagnosis was significantly associated with survival benefit (p < 0.001). Cox-regression results showed that patients who underwent surgery in 11-16 and 17-24 week time period had significantly better survival than > 25 week group with HR of 0.84 (0.71- 0.98) and 0.82 (0.70-0.97) respectively. In addition patients with CS of '0' had better survival with HR 0.78 (0.62-0.90) and > 75 years of age was associated with worse survival HR 1.73 (1.35-2.22). Conclusions: Our study indicates that appropriate patients with MIBC benefit from receiving surgery within 24 weeks of starting NAC. However, randomized prospective study is warranted to further explore the role of delay of surgery from NAC.
The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle invasive bladder cancer: A single-arm prospective study.
Authors: Matsumoto Hiroaki , Nagao Kazuhiro , Ozawa Sho , Samoto Masahiro , Mori Junichi , Inoue Ryo , Yamamoto Yoshiaki , Yano Seiji , Hirata Hiroshi , Shimabukuro Tomoyuki , Matsuyama Hideyasu
Published: February 2020

516

Background: Radical cystectomy is still the standard treatment for muscle-invasive bladder cancer (MIBC), while the patients with MIBC are not always appropriate candidates due to multiple comorbidities. We establish novel treatment strategy by trimodal treatment. Methods: The regimen was gemcitabine 300 mg/m2, and cisplatin 30mg/m2 in day 1 and concomitant irradiation 2Gy/Fr, 5 fraction per week. Irradiation was administered to whole pelvis up to 30Gy, then boost to true pelvis until total 48Gy to 54Gy. Extensive transurethral resection (TURBT) was performed and we confirmed pathological stage ≥T2. TURBT was also performed after chemoradiotherapy to evaluate the pathological response to treatment. This study was approved in our institutional review board (ID: H23-89) and the information was opened on UMIN (ID: UMIN000006363). We analyzed their treatment efficacy and survival. Results: The patients were 29 men and 9 women, median age was 76.5 y.o. and median follow up was 23 months (1 - 112). Clinical stage T2, T3, T4, N1 and N2 were 23, 10, 5, 4, 2 cases, respectively. The 2- and 5-year metastatic-free survival (MFS), bladder-recurrence free survival (bRFS), cancer-specific survival (CSS), and overall survival (OS) rates after treatment were 91.7 and 84.0%, 59.7 and 42.6%, 87.3 and 87.3%, and 87.3 and 81.8%, respectively. Salvage cystectomy was performed 3 patients and they were still alive. CR rate was 78.9% and overall response rate was 92.1%. cT stage and valiant histology was not associated with treatment response. The patients achieved CR had significant good prognosis in CSS (p=0.0149) and OS (p=0.0149) compared with non-responders. In cox hazard model, CR achievement was significant prognostic factors for OS (p =0.0015, HR 6.804e+26, 95% CI 56.94-1.631e+86). Patients were able to receive 3 to 5 cycle GC radiation and any grade 3 or more adverse event was 7 (18.4%) cases. no treatment related death was recorded. Conclusions: In selected patients, GC radiation for MIBC may provide good oncological outcomes as bladder preservation strategy.
Neoadjuvant cisplatin-based chemotherapy in patients with ureteral obstruction secondary to muscle invasive bladder cancer.
Authors: Strother Marshall , Kutikov Alexander , Lewis Bianca , Deng Mengying , Handorf Elizabeth A. , Epstein Matthew , Ghatalia Pooja , Greenberg Richard E. , Chen David , Viterbo Rosalia , Anari Fern , Smaldone Marc C. , Zibelman Matthew R. , Uzzo Robert Guy , Plimack Elizabeth R. , Geynisman Daniel M.
Published: February 2020

523

Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for muscle-invasive urothelial bladder cancer (MIBC). 15-35% of MIBC patients present with ureteral obstruction. Poor renal function increases cisplatin toxicity. It is unknown whether patients with ureteral obstruction which has been relieved (whether by nephrostomy tube or nephroureteral stent) have the same risk of toxicity as patients without ureteral obstruction. Methods: We retrospectively reviewed an institutional database of all patients undergoing NAC for MIBC with either dose dense MVAC (ddMVAC) or gemcitabine and cisplatin (GC) from January 2004 through May 2017. Patients without ureteral obstruction prior to initiation of NAC (Group A) were compared to those who had ureteral obstruction which was relieved prior to undergoing NAC (Group B). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Fisher’s exact test. The primary outcome was premature discontinuation of NAC, which was defined as failure to complete all planned cycles. Logistic regression was used to test for differences between the groups in this outcome adjusting for age, ECOG performance status, and baseline glomerular filtration rate (GFR). Results: 160 patients in Group A and 59 patients in Group B were identified. Baseline age, Charlson Comorbidity Index, race, smoking status, and ECOG performance status were similar. Patients in Group B had lower GFR (99.2% vs 78.8% p <0.001) and were more likely to be female (21.9% vs 27.3% p <0.025) and to receive ddMVAC (65.0% vs. 83.1% p =0.012). There was no significant difference between groups in rates of premature NAC discontinuation (15.8% vs 22.0% p = 0.284) or grade ≥3 adverse events (23.4% vs 30.5% p = 0.285). Adjusted analysis showed no significant difference between the groups in frequency of premature NAC discontinuation (OR 1.96, 95% CI 0.84-4.57 p=0.12). Conclusions: We detected no difference in frequency of premature discontinuation of NAC in patients with relieved malignant ureteral obstruction relative to patients without obstruction. NAC for MIBC is likely safe in this population.
Utility of a general molecular screening program in patients with GU malignancies: The ProfiLER trial experience.
Authors: Vinceneux Armelle , Moriceau Guillaume , Lorcet Marianne , Carbonnaux Mélodie , Cassier Philippe Alexandre , Terret Catherine , Baudet Christian , Attignon Valéry , Pissaloux Daniel , Chabaud Sylvie , Wang Qing , Pérol David , Tredan Olivier , Blay Jean-Yves , Negrier Sylvie , Boyle Helen Jane , Flechon Aude
Published: February 2020

528

Background: Advances in comprehensive tumor molecular pathology in genito-urinary (GU) tumors have driven development of targeted agents since ten years and changed the landscape of GU tumors treatment. We describe our experience with the institutional molecular trial ProfiLER. Methods: Retrospective review of patients with advanced genitourinary malignancies included in the prospective molecular profiling trial ProfiLER (NCT01774409) Tumor samples were analyzed by sequencing a 69 gene panel by next generation sequencing (NGS, Ion torrent PGM system) and whole genome array comparative genomic hybridization (Agilent platform). Clinical data were collected retrospectively. Cases were presented in a molecular board to drive prescription of molecular targeted therapy (MTT) according to the molecular abnormalities observed. Results: Between February 2013 and December 2018 156 adult patients were included, 42 had kidney cancer (including 32 clear cell carcinoma, 5 papillary type 2); 38 prostate cancer, 52 urothelial carcinoma including (16 upper tract), 12 cisplatin-refractory testicular germ cell tumor, 4 penile cancer, 3 adenocarcinoma of the urachus, 2 urethral carcinoma and 3 Leydig cell tumor. Median age at inclusion was 62 years (range 19, 80). Overall NGS and CGH failed in 11.5% of cases, and in 24% of prostate cancer cases.28.8% patients had at least one actionable target (n=45) with a recommended MTT. Only 17.8 % (n=8) patients actually received MTT corresponding to 5.1% of the total screened population. Only one patient had a clinical benefit from MTT. The most frequently initiated MTT were PIK3/AKT/mTOR pathway inhibitors (44,4%), FGRF/EGFR pathway inhibitors (13.3%) PARP inhibitors (8.7%) or cyclin kinase inhibitors (8.7%). The most frequent reasons for lack of MTT initiation were early death, ineligibility for clinical trials due to general condition. Conclusions: Non tumor-specific molecular profiling is feasible in GU cancers. However the use of targeted sequencing with a tumor type specific panel and at an earlier clinical stage may improve the proportion of MTT recommendations.
Comparative response of bladder cancer models to interferon alpha: Recombinant protein versus adenoviral delivery.
Authors: Green Jennifer , Osterhout Robin , McDonnell Scott , Klova Amy , Kamal Adeela
Published: February 2020

531

Background: Adenoviral delivery of the IFNα2b gene to the bladder urothelium enables prolonged exposure to high levels of IFNα2b protein, relative to intravesically-instilled IFNα protein treatments where short bladder dwell time limits exposure. As such, adenoviral-delivered IFNα2b has demonstrated clinical efficacy in patients with BCG-unresponsive NMIBC. The pleiotropic anti-tumor effects of IFNα include both stimulation of the host immune system and direct cytotoxicity of tumor cells. As clinical efficacy of adenoviral-delivered IFNα2b in the context of bladder cancer could be driven by immune-mediated or direct effects, or both, characterizing the cellular and molecular mechanisms of these activities is warranted. Methods: Here, we investigate the molecular mechanisms of tumor-intrinsic resistance to adenoviral-delivered or recombinant IFNα2b in a panel of bladder cancer cell line and patient-derived bladder cancer organoid models. Adenoviral vectors were constructed that express IFNα2b together with a GFP reporter (Ad-IFNα2b) or GFP alone (Ad-GFP), validated, and benchmarked against in vivo data from the literature. Bladder cancer cells and organoids were treated in vitro with rhIFNα2b, Ad-IFNα2b or conditioned media produced by Ad-IFNα2b infected cells, followed by measurements of cytotoxicity and gene expression in response to treatment. Results: Some bladder cancer models exhibited dose-dependent cytotoxicity in response to IFNα2b treatments, while others were resistant to these effects. Genomic and mRNA features associated with IFNα2b sensitivity/resistance are being evaluated and may inform future investigation of the mechanism of anti-tumor activity in patients. Additional studies to evaluate immune-mediated mechanisms are being conducted. Conclusions: Together, these studies will help to define the molecular mechanisms of response and resistance to IFNa2b treatment in bladder cancer patients.
Impact of histology and toxicities on outcomes of patients with muscle invasive bladder cancer receiving neoadjuvant chemotherapy.
Authors: Curran Catherine , Pond Gregory Russell , Acosta Andres , Nassar Amin , Abou Alaiwi Sarah , Ingham Matthew D. , Preston Mark A. , Steele Graeme S. , Kilbridge Kerry L. , McGregor Bradley Alexander , Mossanen Matthew , Sonpavde Guru
Published: February 2020

540

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) extends survival in muscle invasive bladder cancer (MIBC) patients (pts). Pathologic complete response (pCR) is associated with survival. We conducted a retrospective study to examine the prognostic impact of other variables including histologic subtype, location, multifocality, margins, size of tumor and toxicities. Methods: Pts who underwent RC at Dana-Farber for MIBC stage T2-T4N0-1 were studied. Data were collected for demographics, clinical and pathologic variables. Descriptive stats were reported, and Cox proportional hazards regression analyses were conducted to examine the association with recurrence-free survival (RFS) and overall survival (OS). Results: From 2002 to 2018, 150 patients were available. The median age was 66 (range 36-89) and 102 (68%) were male. MVAC/dose dense MVAC, GC and other non-standard regimens were given in 42 (28%), 85 (56.7%) and 23 (15.3%) pts, respectively. The 2-yr RFS was 63.6%, the 5-yr OS was 68.7% and pCR occurred in 38 pts (25.3%). Multivariable analysis identified pure urothelial carcinoma in the residual tumor and absence of pathologic response to be associated with poor RFS and OS. Positive margins were associated with poor RFS, while grade ≥3 toxicities were associated with poor OS. Conclusions: Pure urothelial carcinoma histology was associated with worse RFS and OS following RC after NAC for MIBC, suggesting molecular studies may be useful in these cases. The association of severe toxicities with poor OS suggests that optimal pt selection for NAC and early recognition of toxicities is important.[Table: see text]
MHCI and FOXP3 predicting outcome to neoadjuvant atezolizumab in sequential urothelial cancer tissue.
Authors: Szabados Bernadett , Kockx Mark , Van Dam Pieter-Jan , Rodriguez-Vida Alejo , Duran Ignacio , Crabb Simon J. , Van Der Heijden Michiel Simon , Font Albert , Gravis Gwenaelle , Prendergast Aaron , Perdicchio Maurizio , Stanoeva Diana , Daelemans Sofie , Mariathasan Sanjeev , Tea Joy S. , Mousa Kelly , Banchereau Romain , Castellano Daniel , Powles Thomas
Published: February 2020

541

Background: Biomarker analysis predicting outcome with neoadjuvant atezolizumab in muscle invasive bladder cancer (MIBC) was performed. This includes previously unreported findings with FOXP3 and MHC1. Methods: Sequential tissue obtained from 95 patients in the ABACUSstudy (NCT02662309) which investigated two cycles of atezolizumab prior to cystectomy in MIBC patients. Multiplex immunohistochemistry staining, Foundation One analysis and RNA sequencing was performed on paired pre- and post- treatment samples. CD8+ T cells, fibroblast activation protein (FAP), granzyme – B (GZMB), FOXP3, MHC1, PD-L1 expressions were analyzed and correlated with outcome. Results: After a median follow up of 13.1 months, 31% had a pathological complete response (pCR) and 18% have relapsed. 40% were PD-L1 positive at baseline and 73%, 19% and 8%had inflamed, excluded and desert phenotype respectively. CD8/GZMB and CD8/MHC1 expression prior to therapy was significantly associated with response in inflamed tumors. CD8, PDL1, GZMB and MHC1 expression all increased with treatment in this group of patients. Immune desert phenotype at baseline, showed low and static expression of immune biomarker. TGFb correlated with relapse in excluded phenotypes. Treatment was associated with increase in cell cycle genes and FAP, both of which were associated with relapse. FOXP3 expression correlated with CD8 and increased with therapy in responding tumors. Combining FAP (high) to CD8 (low) and MHC1 (low) increased the positive predictive value for relapse. TMB did not correlate with outcome or increase with therapy. FGF DNA alterations were associated with response. Conclusions: MIBCs have high T effector immune expression, which may account for high pCR rates. Biomarkers at baseline and after treatment can predict outcome. Assessment of multiple biomarker within algorithms improves accuracy in predicting outcome. FOXP3 expression correlates with activated T cell expression, potentially accounting for the counterintuitive findings. Clinical trial information: NCT02662309.
Molecular characterization of neuroendocrine bladder cancer.
Authors: Choi Woonyoung , Hoffman-Censits Jean H. , Fong Megan , Hahn Noah M. , Comperat Eva , McConkey David James
Published: February 2020

561

Background: Neuroendocrine bladder cancer (NEBC) is a rare and aggressive variant that is associated with poor survival outcomes. Because NEBC is rare, the molecular features of NEBC remain poorly characterized. Therefore, we characterized NEBC at the molecular level to understand the underlying biology and identify novel therapeutic targets. Methods: Whole transcriptome RNAseq was performed on FFPE cores from 24 NEBCs and 51 conventional muscle-invasive bladder cancers (MIBCs) from Tenon Hospital in Paris. Results: Unsupervised cluster analysis of 75 tumors generated 2 distinct clusters that separated NEBCs from MIBCs. The NEBC tumors were strongly enriched with biomarkers for the characteristic of neuroendocrine or small cell malignancies, including DLL3, SOX2, and EZH2. In addition, E2F1 pathway is significantly enriched due to the impair of RB/p53 pathways. Further, the NEBCs were enriched with the TCGA’s neuronal differentiation genes that were associated with high response rates in patients treated in atezolizumab (anti-PDL1) within the context of the ImVigor 210 trial. Nevertheless, the NEBCs were characterized by suppressed immune pathway gene expression signatures, such as the Th1 pathway, effector T cell lymphocyte, and IFNg that are usually highly enriched in tumors that are sensitive to immune checkpoint blockade. Of candidate mechanisms, the suppressed TGFbpathway activity observed in the NEBCs was the most obvious explanation for sensitivity to checkpoint blockade. Conclusions: NEBCs are distinct from conventional MIBCs by gene expression signature. They are also characterized by overexpression of canonical neuroendocrine markers and inhibition of TGFb pathway activity.
Health care team and treatment decision-making experiences among prostate cancer patients.
Authors: Nicksic Nicole E. , Miller Melissa F. , Clark Kelly , Zaleta Alexandra Katherine
Published: February 2020

57

Background: Treatment by a multidisciplinary healthcare team can improve patient outcomes, but not all prostate cancer (PC) patients may access multiple providers. This study explored whether differences in healthcare team at treatment were associated with PC treatment type and decision-making. Methods: Of 311 PC patients enrolled in the Cancer Support Community’s Cancer Experience Registry online, 160 (32% ever metastatic, 28% had recurrence, median 3 years since diagnosis) indicated which specialists comprised their healthcare team during treatment (urologist versus a specialist team including 2-5 doctors, 70% of which included urologists). We examined PC treatment decision-making using chi-square tests, independent sample t-tests, and linear regression. Results: The majority were not experiencing symptoms of PC at diagnosis (69%); 58% were diagnosed after a routine check-up. More PC patients with advanced disease at diagnosis had a team of specialists, whereas those diagnosed at stages 1 or 2 typically only saw a urologist ( p<0.01). Most first received care at a private urology practice (44%) compared to 27% for current treatment. Treatment discussions varied by treatment for urologist-only (28%) versus a team of specialists (72%): chemotherapy (16% vs 36%, p=.01), surgery (89% vs 65%, p<.01), radiation (82% vs 80%, p=.75), hormones (36% vs 75%, p<.001), and active surveillance (51% vs 23%, p<.001). More patients who had seen only a urologist had surgery (95% vs 43%, p<.001); those seeing a specialty team tended to undergo other treatments, such as chemotherapy (4% vs 30%, p=.001), radiation (12% vs 83%, p<.001), and hormones (27% vs 77%, p<.001). After controlling for stage at diagnosis, those treated only by a urologist had lower treatment regret ( β=0.22, p<.01). Conclusions: Advanced PC patients more often treated by a specialist team and discuss different treatment options vs. those followed by a urologist only. While effects were small, care provider type was associated with treatment regret and confidence. Healthcare teams could improve the patient experience by increasing communication surrounding navigating myriad treatment options. Clinical trial information: NCT02333604.
Long-term outcomes of patients with locally advanced bladder cancer that underwent intra-arterial chemotherapy with/without radiotherapy for organ preservation.
Authors: Matsuo Tomohiro , Miyata Yasuyoshi , Mitsunari Kensuke , Ohba Kojiro , Sakai Hideki
Published: February 2020

574

Background: We previously reported efficacy and safety of intra-arterial chemotherapy with/without radiotherapy in patients with locally advanced bladder cancer. However, there was no data on long-term outcomes, such as organ preservation, subsequently metastasis, and survival of such therapy. In this study, we investigated outcomes of intra-arterial chemotherapy with/without radiotherapy in these patients for long term periods. Methods: In this study, we investigated 129 patients who treated with intra-vesical chemotherapy (n = 50) and intra-arterial chemotherapy and radiotherapy (n = 79). There was no significant difference on age at diagnosis, gender, grade, and T stage between these two groups. Mean/median follow up periods in intra-vesical chemotherapy (n = 50) and intra-arterial chemotherapy with radiotherapy was 86.5/101 and 107.7/122 months. Results: Rates of bladder preservation in intra-arterial therapy and intra-arterial therapy with radiotherapy are 66.0 and 82.3%, respectively (P = 0.035), and Kaplan-Meier survival curves showed that intra-arterial therapy with radiotherapy had better than intra-arterial therapy (P = 0.007). On the other hand, subsequently metastasis-free survival rates in intra-arterial therapy with radiotherapy was significantly better than those with intra-arterial therapy (P = 0.037). Regrading cause-specific survival, the survival period in intra-arterial therapy with radiotherapy was significantly better than that in intra-arterial therapy (P < 0.001). In addition, even if radical cystectomy was performed, the survival rates after the operation in intra-arterial therapy with radiotherapy was significantly better than that in intra-arterial therapy (P = 0.002). There was no sever complication at late phase (over 5 years). Conclusions: Our results showed that intra-arterial therapy with radiotherapy showed better outcomes of bladder preservation, subsequently metastasis, and survival. In addition, in patients locally advanced bladder cancer received radical cystectomy, intra-arterial therapy with radiotherapy had better prognosis compared to intra-arterial therapy.
A novel clinical decision aid to support personalized treatment selection for patients with CT1 renal cortical masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity.
Authors: Psutka Sarah P. , Gulati Roman , Jewett Michael A.S. , Fadaak Kamel , Finelli Antonio , Morgan Todd Matthew , Pierorazio Phillip M. , Allaf Mohamad E. , Herrin Jeph , Lohse Christine M. , Thompson R. Houston , Boorjian Stephen A. , Atwell Thomas D. , Schmit Grant , Costello Brian Addis , Legere Laura , Shah Nilay , Leibovich Bradley C.
Published: February 2020

610

Background: Personalized treatment for clinical T1 renal cortical masses (RCMs) should account for competing risks related to tumor and patient characteristics. Using a contemporary multi-institutional cohort, we developed treatment-specific prediction models for cancer-specific mortality (CSM), other-cause mortality (OCM), and 90-day complication rates for patients managed with surgery, thermal ablation (TA), and active surveillance (AS). Methods: Preoperative clinical and radiological features were collected for eligible patients aged 18-91 years treated at four academic centers from 2000-2016. Prediction models used competing risks regressions for CSM and OCM and logistic regressions for 90-day Clavien >3 complications, adjusting for tumor size as well as patient age, sex, ECOG performance status (PS), and Charlson comorbidity index (CCI). Predictions accounted for missing data using multiple imputation. Results: After excluding 25 patients with no follow-up, the cohort included 4995 patients treated with radical nephrectomy (RN, n=1270), partial nephrectomy (PN, n=2842), thermal ablation (n=479), or active surveillance (n=404). Median follow-up was 5.1 years (IQR 2.5-8.5). Predictions from the fitted model are shown in an online calculator ( https://rgulati.shinyapps.io/rcc-risk-calculator ). To illustrate the use of this calculator for a specific patient, a 70-year-old female with a 5.5 cm RCM, PS of 2, and CCI of 3 has a predicted 5-year CSM of 4-7% across treatments, 5-year OCM of 34-49%, and 90-day risk of Clavien ≥3 complications of 4%, 10%, and 6% for RN, PN, and TA respectively. Conclusions: Personalized treatment selection for cT1 RCM is challenging. We present a competing risk calculator that incorporates pretreatment features to quantify competing causes of mortality and treatment-associated complications. Pending validation, this tool may be used in clinical practice to provide patients with estimated individualized treatment-specific probabilities of competing causes of death and complication risks to facilitate shared decision-making.
Real-world utilization and safety of ipilimumab plus nivolumab (I+N) in metastatic renal cell carcinoma (mRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Thana Myuran , Basappa Naveen S. , Ghosh Sunita , Kollmannsberger Christian K. , Heng Daniel Yick Chin , Graham Jeffrey , Soulieres Denis , Hansen Aaron Richard , Lalani Aly-Khan A. , Castonguay Vincent , Reaume M. Neil , Bjarnason Georg A. , Breau Rodney H. , Pouliot Frederic , Kapoor Anil , Wood Lori
Published: February 2020

633

Background: I+N is now standard of care for first line treatment of intermediate/poor risk mRCC patients (pts). Real world data is vital to understand drug usage, toxicity and outcomes in non-trial pts. This project describes the amount and tolerability of treatment delivered including discontinuation rates, reasons for discontinuation and outcomes from the CKCis database. Methods: Pts in CKCis, a prospective Canadian database from 15 academic centers, who received first line I+N were included. The number of doses of I+N, number of pts who received single-agent nivolumab (N) and duration of single agent N were determined. Reasons for treatment discontinuation, including the rate, type, and grade of toxicities were identified. Efficacy outcomes included time to failure (TTF – time to progression, death, or second line therapy), overall response rate (ORR) and overall survival (OS). Results: The cohort consists of 182 pts. Median age was 63 yrs, 71% had clear cell histology, 11% were on a clinical trial, the IMDC risk distribution was 5% good, 63% intermediate, 32% poor. Median follow up was 8.8 m. All 4 I+N doses were received by 30% of pts of which 78% went on to receive single-agent N. Less than 4 doses of I+N were received by 70% of pts of which 28% went on to receive single-agent N. The median time on single agent N was 5.7 m. In the entire cohort, 21% of patients discontinued therapy due to toxicity. The most common toxicity events were colitis (56% of all events), pneumonitis (19%), and hepatitis (8%). There were no toxicity-related deaths. Median OS has not been reached (22 events to date). Median TTF was 12.4 m. ORR was 32% (5% complete responses). 26% of pts received second line treatment, the most common being sunitinib in 79%. Conclusions: In this real world cohort, the majority of mRCC pts did not receive all 4 doses of I+N, contrasting with clinical trial reporting, yet many of these pts went on to receive single agent N. Discontinuation rates due to toxicity were similar to those reported in CheckMate 214. Further follow up is ongoing and efficacy outcomes analyzed on the basis of treatment quantity/duration will be presented.