bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age at diagnosis and treatment for prostate cancer (PC) in two distinct integrated health care systems.
Authors: Cross Deanna S. , Islam Rezwan , Jacobson Crystal , Ritter Mark A. , Mullins C. Daniel , Nallu Anitha , Hussain Arif 
Published: February 2017

240 Background: An older age at diagnosis may affect the stage at which PC is diagnosed as well as the treatment decisions made by the providers and/or the patients. Here we compare two geographically and ethnically distinct PC cohorts to determine whether age affects treatment decisions. Methods: Populations- Marshfield Clinic (MC): individuals were included in the cohort if they were diagnosed with PC between January, 2005 and December, 2010 and enrolled in a population based biorepository. Veterans Affairs (VA):– cohort included individuals diagnosed with PC between January, 2010 and December, 2010 within the Baltimore VA Medical Center (BVAMC). Retrospective chart review using electronic abstraction from the EMR was performed at each site. Statistical analysis was performed using the chi-square test for categorical variables or Fisher's exact test if the cell size was under 5. Results: Compared to the MC population, the VA population had a younger median age at diagnosis (63 vs. 68), more African American men (63% vs. 0.5%) and exhibited higher median PSA at diagnosis (7.92 vs 5.78 ng/dL). Seventy nine percent of VA and 87% of MCpatientswere stage 1 or 2 at diagnosis (p=0.03). Stage was not associated with older age (age >/= 75) in either population. Individuals in the VA system were more likely to receive radiation (48% vs. 16%) and less likely to receive surgery than the MC population (18% vs. 59%). There were also several similarities in treatment decisions amongst these different populations. For instance, individuals with an older age (>/= 75 vs. other age categories) at diagnosis were more likely to receive non-aggressive treatments such as hormonal therapy or no treatment (>67% vs. <15% p=0.0001). Because the stage at diagnosis may affect treatment decisions, we also investigated treatments for stage 2 disease; in this category, individuals >/= 75 were still more likely to receive less aggressive treatment at both MC and BVAMC (>29% versus <3.4%, p=0.0001). Conclusions: This initial analysis suggests that individuals with an older age at diagnosis are more likely to receive non-aggressive treatment even when the stage of disease is the same as that of a younger individual across two distinct patient populations.
Novel definition of BCG failure to enhance recruitment into clinical trials.
Authors: Willis Daniel Levi , Lee Eugene K. , Dickstein Rian J. , Anderson Roosevelt , Pretzsch Shanna M. , Nogueras-Gonzalez Graciela M. , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M. 
Published: February 2017

246 Background: Designing clinical trials after BCG failure can be problematic without a reasonable control arm. Thus, there is a need for early identification of BCG failure relevant to clinical trial design which allows one arm to continue on BCG. Here we present a definition of BCG failure based on FISH profile at 6th week of induction BCG that would facilitate such trials. Methods: The definition presented is based on findings from our IRB-approved, prospective clinical trial where Urovysion FISH assays were performed serially during the normal course of BCG therapy (SWOG protocol) at various time points (pre-BCG, 6 weeks, 3 and 6 mo.). Herein we incorporated the FISH analysis at 6 weeks in patients with a negative 3 month cystoscopy and correlated the result with recurrence and progression rates at 24 months. A novel definition of BCG failure was proposed by focusing the analysis on 84 patients with high grade disease (cTa: 33, cT1: 44, cTis 7). The 6 week FISH was selected as this would allow the control arm to proceed with BCG maintenance in a timely fashion, taking into account the time required for obtaining FISH results, registration of patients, and randomization. Results: Of the 36 patients with a positive FISH at 6 weeks (and no tumor at 3 months), 17 recurred (PPV = 47%) and 11 progressed (PPV = 31%), while among those with a negative FISH, 5 recurred (NPV = 90%) and 4 progressed (NPV = 92%) (p<0.001). Kaplan Meier estimates of recurrence free survival with a positive 6 week FISH were 67% and 52%, and for progression free survival were 75% and 52%, at 1 and 2 years respectively. Therefore, if patients with a positive 6 week FISH (and negative 3 month cystoscopy) were considered as "molecular" BCG failures, a prospective clinical trial with 101 patients in the control (i.e. BCG maintenance) and experimental arms to detect a 20% difference in recurrence rates (α=0.05) with 80% power. Conclusions: Using the FISH status of patients at the 6 week interval on BCG therapy would allow a clinical trial design that incorporates one arm with continued BCG therapy, while enriching for events of interest, namely recurrence and progression. This would allow meaningful comparisons while negating any ethical concerns regarding a lack of “standard treatment” in BCG failure studies.
The role of post-cystectomy radiation in treatment of squamous cell carcinoma of the bladder: A combined retrospective analysis.
Authors: Li Baoqing , Stessin Alexander Michael , Nori Dattatreyudu 
Published: February 2017

259 Background: Squamous cell carcinoma (SCC) is the most common nonurothelial histology in bladder cancers. Given the high locoregional recurrence as the primary cause of death, radiation therapy (RT) is often recommended in the post-operative setting. Large-scale randomized trials that are dedicated to bladder SCC would be difficult to accrue to adequate numbers. Therefore, we utilized the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The SEER (1998-2007) was queried for patients with muscle-invasive (stage II-IV) squamous cell carcinoma of the urinary bladder who underwent complete cystectomy. Kaplan-Meier survival analysis and Cox regressions were used to assess survival outcomes. Additionally, records were reviewed for patients treated at New York Presbyterian Hospital-Weill Cornell Medical College (NYP-WCMC) between 1991 and 2010. Results: A total of 331 patients from the SEER were included in the analysis; Majority were received cystectomy alone (n=297), while 10% (n=34) received post-operative RT. Factors associated with post-operative RT were younger age (p=0.03) and more advanced stage at diagnosis (p<0.001). Median survival was 40 months for patients treated with surgery alone and 18 months for post-operative RT (p<0.05). In the institutional record review, 17 patients underwent cystectomy; of these, 5 received post-cystectomy RT. Those who underwent post-operative RT had better performance status (80% vs 25%) and a higher rate of positive surgical margins (67% vs 20%). Median survival was 38 months for patients treated with surgery alone and 22 months for post-op RT. Conclusions: RT has been employed as a post-operative treatment for some patients with muscle-invasive SCC of the urinary bladder. Younger age, better performance status, advanced stage, and positive margins may prompt the use of post-operative RT. However, both SEER and single institution retrospective analyses failed to show any survival advantage associated with the use of post-operative therapy. Further studies are needed to identify any subsets of patients with bladder SCC who may benefit from post-cystectomy radiation.
Augmentation of urothelial cancer cells' response to gemcitabine and cisplatin by a Smac mimetic.
Authors: Lee Eugene K. , Gerald Jinesh , Laing Naomi , Choi Woonyoung , McConkey David James , Kamat Ashish M. 
Published: February 2017

261 Background: Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. Despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Methods: A panel of 10 urothelial cancer cell lines was exposed to gemcitabine and cisplatin, a Smac mimetic, and the combination. Sensitivity was determined using a DNA fragmentation assay. Constitutive expression of select members of the IAP family (XIAP, cIAP-1, cIAP-2, Survivin), the BCL family (BCL-2, BCLXL, BAX) and Smac were evaluated by gene expression profiling and Western blotting. Changes in protein expression under treatment conditions were examined using Western blotting. TNF-a blocking antibody was used to explore the contribution of autocrine TNF-a in cellular death. Lastly, a mouse model of bladder cancer was used to determine the effectiveness of the drug combination. Results: UMUC-3, UMUC-13 and RT4v6 were considered sensitive to the combination of gemcitabine and cisplatin based on an apoptosis assay. Three additional cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, UMUC-18). The constitutive RNA and protein expression of SMAC, select members of the IAP family, and members of the BCL family did not correlate to drug sensitivity. Autocrine TNF-a demonstrated a partial contribution to cell death in UMUC-12. In an in vivo mouse model, the Smac mimetic alone and in combination with gemcitabine and cisplatin resulted in decreased tumor volume and increased apoptosis compared to the chemotherapy treatment alone. The combination resulted in decreased cellular proliferation and decreased microvessel density. Conclusions: Smac mimetic is able to augment the activity of gemcitabine and cisplatin based chemotherapy in vitro and in vivo. This may be an effective treatment strategy in patients with urothelial carcinoma and warrants further investigation.
A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).
Authors: Siefker-Radtke Arlene O. , Wen Sijin , Shen Yu , Stigall Kristi , McConkey David James , Millikan Randall E. 
Published: February 2017

263 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase I design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
Sequential chemotherapy with gemcitabine plus carboplatin followed by additional docetaxel for older patients with advanced bladder cancer.
Authors: Yoneyama Takahiro , Sugiyama Naoki , Suzuki Yuuichirou , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

266 Background: We retrospectively evaluated the feasibility and effectiveness of a sequential chemotherapy wihtout cisplatin for the patients 70 years or older with advanced bladder cancer. Methods: Fourty-seven patients with advanced bladder cancer (33 men and 14 women) with the age of 70 years or older were enrolled. They were treated at our clinic between August 2004 and December 2010. Their average age was 80.0 years old (70–86), average Ccr was 37.0 ml/min (14.5–113.0), and an average follow-up period was 17.4 months (10–55). There were 15 recurrent cases after radical surgery and 32 inoperable cases (T4b or metastatic). As for prior chemotherapy, 6 underwent MVAC therapy. The therapeutic regimen consisted of 2 lines: gemcitabine/carboplatin (GCarbo) therapy as the first line, with two courses as a set; GCarbo/docetaxel (GCarboD) therapy as the second line if the response in the first line was insufficient. If this regimen was effective, another 2 courses of GCarbo was performed. Treatment efficacy was checked every 2 course according to the RECIST version 1.1. Results: Of the 47 subjects who had undergone the GCarbo therapy, the response rate was 38.3% (CR+PR) with 5 and 12 subjects exhibiting a complete response (CR) and a partial response (PR), respectively; the average response duration was 15.7 months (2–42). Of the subjects with MVAC resistance, 1 exhibited a CR and 3 showed a PR. The response rates of 9 instances of GCarboD was 11.1%; the overall median survival was 15.0 months throughout the sequential chemotherapy. Adverse events (AE) of grade 3 or higher occurred in 30 of those who had undergone the GCarbo therapy (63.8%). Conclusions: Although the present study is small and preliminary, the present sequential chemotherapy is safe and active for advanced bladder cancer of the patients seventy years or older. GCarbo regimen achieved acceptable response rate (38.3%) in advanced bladder cancer including M-VAC-resistant case. The median overall survival of 15 months is acceptable when average age of 80 year for the subjects is took into consideration. However, GCarboD had limited effectiveness for non-responder of GCarbo.
Different effects of sunitinib, sorafenib, and pazopanib on inducing cancer cell death: The role of autophagy.
Authors: Santoni Matteo , Amantini Consuelo , Morelli Maria Beatrice , Farfariello Valerio , Nabissi Massimo , Liberati Sonia , Bonfili Laura , Mozzicafreddo Matteo , Eleuteri Anna Maria , Burattini Luciano , Berardi Rossana , Cascinu Stefano , Santoni Giorgio 
Published: February 2017

270 Background: Tyrosine kinase inhibitors (TKI), such as sunitinib, sorafenib and pazopanib, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). However, their use in sequential or combined strategies is limited by the lack of evidences on the ability of TKIs to induce cell death in cancer cells. Aim of our study was to evaluate the different mechanisms responsible of the cytotoxic effects induced in vitro by µM doses of sunitinib, sorafenib and pazopanib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with the anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Necrosis and apoptosis, (ΔΨm) dissipation and ROS generation were determined by Annexin-V/PI, JC-1 and DCFDA staining, respectively and cytofluorimetric analysis. The cathepsin B activity was evaluated by ELISA. Finally, by mRNA estraction and RT-PCR array the pazopanib-induced gene profile expression was evaluated. Results: We found that treatment of 5637 and J82 BC cells with the three TKI agents markedly reduced cell viability. Treatment for 24 h with sunitinib and sorafenib at 20 µM dose, triggers an incomplete autophagy of BC cells. In addition, inhibition of autophagy induced by sunitinib and sorafenib triggers cell death of BC cells. Thus, sunitinib by imparing the cathepsin B activity induces lysosomal-dependent necrosis. Similarly, sorafenib by defective lysosomial degradation triggers ROS- and mitochondrial-dependent apoptosis. As regard to pazopanib, we first demonstrate that treatment of BC cells for 72 hrs (20 µM) induces autophagic Type II cell death, which was markedly reversed in a dose-dependent manner by 3MA and chloroquine autophagic inhibitors. Finally, pazopanib upregulates the mRNA expression of α-glucosidase (GAA) and TP73 belonging to the p53 tumor suppressor genes. Conclusions: Overall, our results showing different TKI-induced cell death mechanisms provide the rationale for the sequential use of these agents and the biological basis for novel molecularly targeted approaches.
Long-term efficacy and safety outcomes of the modified (simplified) combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as front-line therapy for unresectable or metastatic urothelial cancer (UC).
Authors: Necchi Andrea , Mariani Luigi , Giannatempo Patrizia , Raggi Daniele , Farè Elena , Pizzocaro Giorgio , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Milani Angelo , Gianni Alessandro M. , De Braud Filippo G. , Nicolai Nicola , Salvioni Roberto 
Published: February 2017

284 Background: MVAC and cisplatin-gemcitabine (CG) are the established standard of care for untreated patients (pts) with locally advanced-metastatic UC. CG is the preferred choice in most cases due to the better toxicity profile. Modifying MVAC by reducing side-effects may have the potential to improve efficacy. Methods: Data relative to unresectable T/N+/M+ pts entering sequential single-institution trials were collected. Chronologically, these changes to classic MVAC were provided: deletion of day 22 and administration of 25 mg/m2CDDP d2-5 (modified MVAC [mMVAC]); deletion of day 22 only, and deletion of days 15 and 22 in a 3-week schedule (simplified [s]MVAC1 and 2). 4-6 cycles were provided. Multivariable analysis was undertaken for recognized clinical variables. ITT analysis was applied. Results: From 09/86 to 04/12, 157 pts were treated (25 mMVAC, 72 sMVAC1, 60 sMVAC2). 84% had a bladder primary, 70% had distant metastases, 53% and 36% had nodal and visceral mets, respectively. 43.9% had a Bajorin score 1-2. 65.8% attained a complete (19.1%) or partial response (46.7%), 24.3% a stable disease, with no difference among regimens. After a median follow up of 87 mos (IQR 37-161), median (95% CI) PFS was 10.2 mos (8.4-10.8) and median OS was 19.5 mos (16.3-24.1). 2yr (95% CI) PFS and 5yr OS were 30.9% (23.8-40.1) and 25.3% (18.8-34.1). Responses were mainly seen in nodal mets (OR: 2.48, 95%CI, 1.12-5.54). Presence of visceral (HR: 2.42, 95%CI, 1.37-4.30), nodal mets (HR: 1.70, 95%CI, 1.07-2.69) and mMVAC regimen (HR: 1.73, 95%CI, 1.02-2.92) were negative prognostic factors for OS. G3-4 toxicities were similar among regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. 2 pts died for toxicity. Conclusions: Simplifying MVAC schedule may result in improved activity and efficacy while reducing toxicity. Though retrospective, the combined results of MVAC modification would claim a benefit over either classic/dose-dense MVAC or CG in terms of efficacy and safety. A reappraisal of the upfront management of advanced/metastatic UC is warranted.
High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: Results of a phase III randomized study.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent François , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline 
Published: February 2017

3 Background: Radiotherapy (RT) and long term androgen blockade (AB) is standard treatment for patients with high risk prostate cancer. However, the optimal duration of AB is not yet defined. The purpose of this randomized study was to compare outcomes between 36 vs. 18 months of AB in high risk prostate cancer treated with RT (PCS IV trial, Clinical Trials.gov, #NCT00223171). Methods: PCS IV randomized patients with node negative high risk prostate cancer (T3-4, PSA >20 ng/ml or Gleason score >7), to pelvic RT (whole pelvis 44 Gy/4 ½ weeks, prostate 70 Gy/7 weeks) and 36 (arm 1) vs. 18 months (arm 2) of AB (neo adjuvant, concomitant, adjuvant). AB consisted of bicalutamide 50 mg for one month plus goserelin 10.8 mg every three months for 36 vs. 18 months. Overall survival was the primary end point. Overall and cancer specific survival rates were compared between arms with Kaplan-Meier log rank test and Cox regression. Results: From October 2000 to January 2008, 310 patients were randomized to arm 1 and 320 to arm 2. Patients’ characteristics were well balanced between the two arms (median age 71 years, median PSA 16 ng/ml, median Gleason score 8). Most patients had T2-3 disease. At a median follow-up of 77 months, 71/310 patients (22.9%) in arm 1 and 76/320 (23.8%) in arm 2 had died (p=0.802). Overall, 116 patients died of causes other than prostate cancer. Overall and cancer specific survival hazard ratios were 1.15 (0.83-1.59), p=0.398 and 1.13 (0.61-2.08), p=0.153, respectively. 5 year overall and disease specific survival rates were 92.1% (89.1-95.1) vs. 86.8% (83.0-90.6), p=0.052 and 97.6% (95.9-99.4) vs. 96.4% (94.2-98.6), p=0.473 and 10 year overall and disease specific survival rates were 63.6% (55.7-71.5) vs. 63.2% (54.7-71.7), p=0.429 and 87.2% (81.0-93.3) vs. 87.2% (80.9-93.6), p=0.838 for arm 1 and arm 2, respectively. There were no significant differences in the rates of biochemical, regional or distant failure between arms. Conclusions: Our study shows that long term AB can be safely reduced from 36 to 18 months without compromising outcomes. Analysis of treatment impact on quality of life is now under review. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: Clinical Trials.gov, #NCT00223171.