bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes and tolerability of selective bladder preservation by combined modality therapy for invasive bladder cancer in elderly patients.
Authors: Miyamoto David Tomoaki , Drumm Michael , Clayman Rebecca Helen , Niemierko Andrzej , Heney Niall M. , Kaufman Donald S. , Zietman Anthony L. , Shipley William U. , Efstathiou Jason A. 
Published: March 2017

316 Background: The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the US is 72 years old, and only about half of those over 70 years receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of patients are undertreated. To address this unmet need, we examined the outcomes and tolerability of chemoradiation (chemoRT) in the elderly. Methods: We conducted an analysis of 455 patients with cT2-T4a disease treated at our institution between 1986 and 2013. Patients underwent induction chemoRT (40Gy) after transurethral resection of bladder tumor (TURBT). Patients achieving a complete response (CR) received consolidation chemoRT to a total goal dose of 64-65Gy. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. Elderly was defined as 75 years or older. For comparison with younger patients, propensity score matching was performed based on sex, T-stage, hydronephrosis, completion of TURBT, and decade of treatment. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Results: Median age was 66 years (range 27-94). One hundred and one patients (22%) were 75 years or older. Median follow-up was 7.4 years for surviving patients. In a propensity score matched pair analysis of 84 elderly and 84 younger patients, DSS at 5 and 10 years for the elderly was 64.8% and 51%, compared to 71.7% and 62.0% for younger patients (p = 0.28). Elderly patients, compared to the younger patients, had similar rates of ED visits during treatment (10% vs 12%, p = 0.76), hospital admissions for any cause (17% vs. 14%, p = 0.8), unplanned treatment breaks for any cause (24% vs. 12%, p = 0.16), and discontinuation of therapy due to toxicities (6% vs 7%, p = 1.0). Conclusions: In elderly patients with MIBC, outcomes and tolerability of bladder-sparing chemoRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.
Association of presurgery neutrophil-to-lymphocyte ratio with survival outcomes in patients with urothelial carcinoma treated without neoadjuvant chemotherapy and with radical cystectomy.
Authors: Kukreja Janet Baack , Podolnick Jason M , Wang Xuemei , Chen Hsiang-Chun , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul 
Published: March 2017

324 Background: There is growing interest in finding inexpensive, easily reproducible biomarkers to predict outcomes in patients with urothelial bladder carcinoma (BC). An elevated preoperative neutrophil-to-lymphocyte Ratio (NLR) has been found to be an independent prognostic factor for decreased survival, predictive of upstaging at radical cystectomy (RC), and predictive of recurrence and progression. This study investigated the utility of the preoperative NLR predicting long-term outcomes in chemotherapy naïve patients undergoing RC for BC at a large tertiary care center. Methods: In a retrospective cohort study, 849 RC patients with BC were identified between 2000 and 2011. NLR data for these patients was obtained within 30 days prior to RC. Univariate CART analysis was used to determine an NLR cutoff point that was significantly associated with both overall survival (OS) and disease specific survival (DSS). OS and DSS were estimated using Kaplan-Meier curves. Results: The median follow-up time among survivors was 7.3 years. 597 (70%) patients died and 252 (30%) were alive at last follow. Using CART analysis, a preoperative NLR cutoff point of 3.19 was identified to have the strongest association with both OS and DSS (p < 0.001). 562 (66%) patients had a preoperative NLR < 3.19 and 475 (34%) had a preoperative NLR ≥ 3.19. The median OS and DSS for patients with preoperative NLR < 3.19 was 5.96 years and 15.64 years, respectively. The median OS and DSS for patients with a NLR ≥ 3.19 was 4.44 years (95% CI: 3.18-4.81 years) and 8.23 years (95% CI: 5.15-11.87 years). DSS Kaplan-Meier curve was significant, p < 0.001. Patients with a NLR < 3.19 had a 5-year OS and DSS of 59% and 77%, respectively. RC patients with a NLR ≥ 3.19 had a 5-year OS and DSS of 43% and 56%. Conclusions: A preoperative NLR ≥ 3.19 is significantly associated with decreased OS and DSS in patients treated with RC for UC. This finding further validates NLR as a biomarker in BC prognosis. NLR can help to determine patients with a poor prognosis who may benefit from more aggressive, adjuvant therapy following RC.
External validation and optimization of international consensus clinical target volumes for adjuvant radiation in bladder cancer.
Authors: Reddy Abhinav V. , Christodouleas John Paul , Wu Tianming , Smith Norm D. , Steinberg Gary D. , Liauw Stanley L. 
Published: March 2017

336 Background: International Consensus (IC) clinical target volumes (CTVs) have been proposed to standardize radiation field design in the treatment of patients at high risk for local regional failure (LRF) after radical cystectomy. The purpose of this study was to externally validate the IC CTVs in a cohort of post-surgical patients followed for LRF, and identify revisions that might improve its performance. Methods: Of 334 patients with pT3-4 bladder cancer treated with radical cystectomy, 58 (17%) developed LRF, of which 52 had CTs available for review. Images with LRF were exported into a treatment planning system, and IC CTVs were contoured and evaluated for adequacy of coverage of each LRF, with respect to both the patient and each of six pelvic subsites: common iliac (CI), obturator region (OR), external and internal iliac (EI/II), presacral (PS), cystectomy bed (CB), or other pelvic site. Revisions to the IC contours were proposed based on the findings. Results: Of the 52 patients with documented LRF, 13 (25%) patients had LRFs that were outside of the IC CTV involving 17 pelvic subsites: 5 near the CI CTV, 5 near the OR CTV, 1 near the EI/II, and 6 near the CB. The 5 CI failures were located superior to the CTV and the 5 OR failures were located medial to the CTV. Increasing the superior boundary of the CI to a vessel-based definition of the aortic bifurcation, and increasing the medial extension of the OR by an additional 9 mm, decreased the rate of patients with LRF outside of the IC CTV to 7 (13%) patients. Conclusions: “Modified IC CTVs” inclusive of a slight adjustment superiorly for the common iliac region, and medially for the obturator region, may reduce the risk for pelvic failure in patients treated with adjuvant radiation therapy.
The impact of treatment delay from diagnosis to prostatectomy on the biochemical recurrence rate.
Authors: Isharwal Sudhir , Zabell Joseph , Berglund Ryan Kent , Stephenson Andrew J. 
Published: March 2017

34 Background: In this study, we evaluate the impact of treatment delay on the biochemical recurrence (BCR) rate specifically in patients with NCCN intermediate to high-risk prostate cancer (PCa). Methods: We reviewed our institutional database of patients who underwent radical prostatectomy (RP) between 2004-2014. A validated preoperative nomogram was used to predict the 5-year BCR-free probability. We evaluated the actual risk of BCR (PSA>0.2) stratified by time from diagnosis to treatment controlling for age and preoperative nomogram derived risk of BCR. We did subset analysis in the cohort of NCCN defined intermediate/high-risk categories. Results: A total of 3029 patients met the inclusion criteria. Median age for the entire cohort was 60 years. Median time from diagnosis to treatment was 77 days (IQR 54-110). Median overall follow-up time was 25 months. Group 1 (61.7%) experienced delay of less than 90 days, Group 2 (31.5%) 90-180 days, and Group 3 (6.7%) >180 days. BCR occurred in 9.6%, 9.6%, and 4.9% of patients in Groups 1, 2, and 3 respectively (p=0.08). Out of the entire cohort, 1837 (60.6%) patients had NCCN intermediate or high-risk disease. On cox multivariable analysis, there was no significant difference in risk of BCR stratified by time to RP in the entire cohort as well in the patients with intermediate/high-risk disease (see table). Conclusions: In our cohort of patients, the delay in treatment did not have significant effect on the risk of BCR. While patients with high-risk pathology should receive prompt treatment, our data suggests that patients and urologists have time to obtain genomic or imaging information, seek second opinions or referral for surgery without significantly affecting the BCR. [Table: see text]
Efficacy of mycobacterium phlei cell wall-nucleic acid complex (MCNA) in BCG-unresponsive patients.
Authors: Li Roger , Amrhein John , Cohen Zvi , Champagne Monique , Kamat Ashish M. 
Published: March 2017

342 Background: Previously, we reported the results of a single-armed, multi-institutional study on the efficacy of MCNA in patients who failed intravesical BCG treatment. Since that publication, a new standardized definition for BCG-unresponsiveness has been established. We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition. Methods: Patients with recurring high grade NMIBC after intravesical BCG were enrolled. For this analysis, we focused on the patients satisfying the minimum criterion for adequate BCG treatment (5/6 induction and 2/3 maintenance). Treatment course included 6 weekly intravesical instillations of 8mg MCNA followed by 3 weekly instillations at months 3, 6, 12, 18, and 24. Followup assessments included cystoscopy, urine cytology and biopsy. Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free. Results: Of the 129 patients enrolled, 94 (68 CIS with/without papillary tumors, 26 papillary only tumors) fit the criteria for the new BCG-unresponsive definition. In the group with papillary tumors, DFS measured at months 6, 12, and 24 were 61.2%(38.2-77.8%), 61.2(38.2-77.8%), and 50.1%(27.5-69%). In the CIS-containing group, the corresponding DFS were 44.8%(32.3-56.4%), 26.5%(16.3-37.9%), and 16.6%(8.6-26.9%), respectively. Conclusions: Intravesical MCNA therapy has the potential to offer 26.5% of patients with CIS and 61.2% of patients with papillary tumors a chance to safely preserve their bladder for at least 1 year. The efficacy in BCG-unresponsive patients was higher than that reported with all-comers, suggesting that adequate priming with BCG might be required for further immune-based response.
Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase II study.
Authors: Necchi Andrea , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Calareso Giuseppina , Togliardi Elena , Colecchia Maurizio , Busico Adele , Perrone Federica , Pennati Marzia , Zaffaroni Nadia , Mariani Luigi , Salvioni Roberto 
Published: March 2017

345 Background: Despite cisplatin-based chemotherapy (CT) is recommended in MIUBC, an unmet need is to identify new drugs or combinations to improve the outcomes. SGC combination was evaluated in an open-label, single-arm, phase 2 trial (NCT01222676). Methods: After TURB, pts with T2-T4a N0 MIUBC received 4 cycles of cisplatin 70 mg/m2 d1, gemcitabine 1000 mg/m2d1 and 8, q3 wks. Sorafenib 400 mg q12h was administered daily from day 1 until radical cystectomy. In a Simon’s 2-stage design, the primary endpoint was pathologic complete responses (pT0). Residual carcinoma in situ was considered pT0. ITT analysis was applied. Statistical hypothesis assumed H0: ≤0.20 and H1: ≥0.40 (α and β of 5% and 10%). ERCC1 immunohistochemistry (IHC) and next-generation sequencing (NGS) of TURB tissue, and measurement of baseline circulating VEGF levels, were planned. Results: From 04/2011-06/2016, 45 pts were enrolled. 28 pts (62.2%) had macroscopical residual disease after TURB, 17 (37.8%) presented with clinical stage T3-4. pT0 was obtained in 19 pts (42.2%, 95%CI: 27.6-57.9); pT≤1 in 24 (53.3%, 95%CI: 37.9-68.3). After median follow-up of 35 months, median PFS was not reached (IQR: 29.4-NE), like median OS (IQR: 30.3-NE). Pathological response (pT0 vs pT≤1 vs other) predicted for both PFS (p=0.015) and OS (p=0.046). Hematologic (hem) G3-4 adverse events (AE): platelet 28.9%, neutrophils 15.6%, Hb (4.4%). Extra-hem AEs were seen in 9 pts (20%). 24 (53.3%) pts needed S temporary interruption (5 cases discontinuation). Tumor samples were available from 23 pts for ERCC1-IHC, 24 for NGS: ERCC1 IHC expression was associated with non response (pT≥2, p=0.033). ERBB2/ERBB3 mutations were found only in responders (pT≤1, 20%). PIK3CA/AKTmutations (missense, and newly-identified mutations) were more frequent in pT≥2 pts (35.7% vs 20%). Baseline VEGF levels did not predict for PFS/OS. NGS of the remaining pts of the trial is ongoing. Conclusions: SGC combination was active and effective in MIUBC. Translational analyses are providing information to develop combination of CT with new more potent and selective TKIs, possibly in more selected pts. Clinical trial information: NCT01222676.
Nomogram to assess benefit of new over historical agents as salvage therapy for metastatic urothelial carcinoma (mUC) in non-randomized trials: Effect of atezolizumab on 12-month survival.
Authors: Pond Gregory Russell , Sonpavde Guru , Rosenberg Jonathan E. , Choueiri Toni K. , Bellmunt Joaquim , Regazzi Ashley Marie , Mullane Stephanie Anne , Necchi Andrea , Raggi Daniele , Lee Jae-Lyun , Lee Soonil , Simpson Joe , Derleth Christina Louise , Lin Shih-Wen , Bajorin Dean F. 
Published: March 2017

346 Background: Early surrogate endpoints of benefit in mUC phase 2 salvage therapy trials are necessary to identify promising drugs, particularly for checkpoint inhibitors where response and progression-free survival are inadequate. We developed a nomogram using prognostic variables from phase 2 trials of historical agents to estimate 12 month survival to which observed survival in single arm trials could be compared. Methods: Data were obtained from phase II trials of salvage therapy for mUC for survival and 5 prognostic factors: hemoglobin, performance status, liver metastasis, treatment-free interval and albumin. Patients (pts) were randomly allotted to discovery:validation (DIS:VAL) datasets in a 2:1 ratio. A nomogram was developed for estimating 12-month survival. Calibration plots were constructed in the VAL dataset by plotting estimated vs. observed 12-mo survival and data bootstrapped to assess performance. The nomogram was applied to external nonrandomized salvage therapy data: 1) retrospective pemetrexed data or 2) trials of atezolizumab: PCD4989g and IMvigor210. Results: Data were available from 340 pts receiving sunitinib (n = 77), everolimus (n = 45), docetaxel + vandetanib or placebo (n = 109), pazopanib (n = 42), paclitaxel (n = 36) and docetaxel (n = 31). Calibration and prognostic ability of the model was acceptable (c-index = 0.634, 95% CI = 0.596-0.652). Observed 12-month survival for pts on pemetrexed (n = 127, 23.5% [95% CI: 16.2%-31.7%]) were similar to nomogram-predicted survival (19% [95% CI: 16.5-21.5], P> 0.05), while observed result with atezolizumab (n = 403, 39.0% [95% CI: 34.1-43.9]) exceeded predicted result (24.6% [95% CI: 23.4-25.8], P< 0.001). Conclusions: Atezolizumab was associated with a significantly longer 12-mo survival compared to nomogram-predicted survival while pemetrexed was not. This nomogram incorporates baseline prognostic factors to provide expected 12-mo survival of phase 2 patient cohorts with which to compare observed survival, thereby providing a useful tool to quantify benefit in phase II studies while controlling for the impact of clinical variables.
Cell-free tumor DNA and TERT promoter mutations in bladder cancer.
Authors: Huang Franklin W. , Rinne Mikael L. , Lundgren Kevin T. , Mullane Stephanie Anne , Moreno Irene , Reed Sarah , Gydush Greg , Adalsteinsson Viktor , Novak Jesse , Hahn William C. , Signoretti Sabina , Choueiri Toni K. , Garraway Levi A. , Bellmunt Joaquim 
Published: March 2017

353 Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.
Evaluation of monocytic myeloid-derived suppressor cell (M-MDSC) frequency in patients with metastatic urothelial carcinoma (mUC).
Authors: Funt Samuel , Mu Zhenyu , Cipolla Catharine Kline , Kania Brooke Elizabeth , Zheng Junting , Boyd Mariel Elena , Snyder Charen Alexandra , Callahan Margaret K. , Autio Karen A. , Regazzi Ashley Marie , Moran Meredith Maisie , Ostrovnaya Irina , Iyer Gopa , Wong Phillip , Lesokhin Alexander M. , Rosenberg Jonathan E. , Bajorin Dean F. 
Published: March 2017

356 Background: M-MDSCs promote tumor progression through complex mechanisms, including immunosuppression and the production of mediators of angiogenesis and invasion. M-MDSCs are associated with poor outcomes in a number of malignancies. We conducted an exploratory analysis enumerating M-MDSCs (Lin-CD14+/HLA-DRlow/-) in the blood of pts with mUC and assessed for assay variability and correlation with clinical outcomes. Methods: Whole blood was collected at a single time point for each pt and stabilized in Cyto-Chex tubes. M-MDSC% was calculated by flow cytometric analysis of HLA-DR expression on CD14+ monocytes using an MSKCC developed computational algorithm-based approach (Kitano et al. 2014). Individual samples were run in quadruplicate at MSKCC. The mean MDSC% was used in subsequent analyses and the replicate standard deviation (SD) was considered a reflection of intra-assay variability. Clinical variables were collected and pts followed for OS, which was calculated from time of sample collection. Results: 21 pts with mUC who progressed after prior chemotherapy were included. At the time of collection, pts were on clinical trials with immune checkpoint blockade (n=13) or targeted therapy (n=1), receiving salvage chemotherapy (n=2), or awaiting treatment on clinical trials with immune checkpoint blockade (n=4) or targeted therapy (n=1). The median follow up from the time of collection in surviving patients (n=15) was 11.1 months (range: 10.5-11.5). Median OS was not reached. Mean (SD) M-MDSC% was 29.2 (4.92). The range of replicate SD was 0.13-1.05. M-MDSC% was not higher in pts with visceral mets (p=0.109). Pts with above median M-MDSC% had worse OS (p=0.01; 6 patients died during follow up, all with above median M-MDSC%). Conclusions: In a heterogeneous cohort of pts with mUC, the enumeration of M-MDSCs in stabilized whole blood was feasible and demonstrated marked inter-patient but not intra-assay variability. Pts with higher M-MDSC% values had worse OS. Additional characterization of M-MDSCs in larger cohorts and in pts receiving immunotherapy is ongoing and may have important prognostic and therapeutic implications in mUC.
Clinical and pathological outcomes for patients with T1HG bladder cancer managed with upfront cystectomy with or without neoadjuvant chemotherapy and the impact of the MDACC high-risk features.
Authors: Metcalfe Michael J. , Ferguson James Edward , Li Roger , Xiao Lianchun , Dinney Colin P.N. , Navai Neema , Shah Jay Bakul , Kamat Ashish M. 
Published: March 2017

366 Background: In muscle invasive bladder cancer there is an increased risk for systemic disease identified for patients with certain high risk features (HRF): pre-operative hydronephrosis (POH), lymphovascular invasion (LVI), abnormal exam under anesthesia (AbnEUA), and the presence of variant histology (VH). We sought to identify the effect of these high risk features in the T1HG population. Methods: With IRB approval, a single center retrospective review was performed on all patients at MDACC from 1995-2013 who underwent radical cystectomy (RC) for T1HG urothelial cancer. Patients were stratified according to the presence or absence of HRF defined by the presence of LVI, POH, VH, AbnEUA, prostatic ductal involvement (PDI), and the delivery of neoadjuvant chemotherapy (NAC). Primary outcome included pathologic T (pT) upstage and presence of lymph node positive disease (LN+) at time of RC, as well as survival outcomes. Results: 372 T1HG patients underwent RC, of these 196 (53%) have HRF including: VH (n=98, 25%), LVI (n=44, 12%), PDI (n=31, 8%), POH (n=38, 10%) and/or AbnEUA (n=34, 9%). pT upstage occurred in 43/176 (24.4%) of patients without HRF, in 45/151 (30%) of patients with 1 HRF, and in 38% (17/45) of patients with > 2 HRF (p=0.088). LN+ occurred in 18/176 (10.2%) of patients without HRF, 7.8% (15/151) of patients with 1 HRF and in 17.8% (8/45) of patients with > 2 HRF (p=0.0403). Presence of HRF were not significant for a decreased OS (p=0.076), DSS (0.425), and RFS (p=0.103). No patients without HRF got NAC, and 41/196 (21%) of patients with HRF received NAC. There was no effect of NAC on pT upstage (OR 1.184, 95% CI 0.355-3.954, p=0.7834) or rate of LN+ disease (OR 1.758, 95% CI 0.669-5.606, p=0.2525) on multivariate analysis. There was no effect of NAC on OS (p=0.122), DSS (0.437), or RFS (0.7483). Conclusions: Presence of certain high risk features in the T1HG setting does have increased risk of pT upstage and LN+ disease in patients treated with cystectomy. However, there is no effect seen on survival outcomes. Use of NAC did not significantly alter outcome in our cohort and should be reserved for the muscle invasive setting.