bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline DNA copy number polymorphism to predict the efficacy of BCG therapy for non-muscle invasive bladder cancer.
Authors: Yamamoto Yoshiaki , Ozawa Sho , Samoto Masahiro , Mori Junichi , Inoue Ryo , Yano Seiji , Hirata Hiroshi , Matsumoto Hiroaki , Matsuyama Hideyasu 
Published: February 2020

431 Background: Bacillus Calmette-Guerin (BCG) intravesical instillation is the most effective immunotherapy for non-muscle-invasive bladder cancer (NMIBC), however there are few reliable markers to elucidate the efficacy of BCG therapy. Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in NMIBC treated with BCG therapy remains unclear. FAM81A located on 15q22.2 was reported as one of tumor-associated ETS shared target genes in prostate cancer. PCSK6 located on 15q26.3 was reported to regulate proliferation and tumor progression in several cancers. The purpose of this study is to determine the prognostic value of CNPs for NMIBC treated with BCG therapy. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the efficacy of immunotherapy. Methods: Array comparative genomic hybridization (CGH) was performed to search for candidate whole genome-wide CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate the effect of BCG therapy for 57 Japanese patients with NMIBC treated with BCG intravesical instillation. Results: Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with disease progression in NMIBC treated with BCG. The means of the relative copy numbers of patients with CNP and those without it were 1.58 and 2.10 for FAM81A ( P < 0.0001), and 1.06 and 1.80 for PCSK6 ( P < 0.0001), respectively. Univariate Cox proportional hazards regression analysis showed that FAM81A ( P = 0.0022), and PCSK6 ( P = 0.0147) copy number had a significant effect on progression-free survival. In multivariate analyses, FAM81A copy number was an independent prognostic factor for progression-free survival ( P = 0.0419, RR = 7.59, 95% CI, 1.07–153.42). The combination of FAM81A or PCSK6 CNP was the most significant prognostic biomarker to predict the efficacy of BCG therapy for NMIBC ( P = 0.0002). Conclusions: Germline DNA CNPs may be a potential new biomarker for estimating the efficacy of BCG therapy in Japanese patients with NMIBC.
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.