bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA damage response (DDR) gene mutations (mut), mut load, and sensitivity to chemotherapy plus immune checkpoint blockade in urothelial cancer (UC).
Authors: Galsky Matt D. , Uzilov Andrew V. , McBride Russell Bailey , Wang Huan , Patel Vaibhav G. , Sfakianos John , Wang Li , Akers Nicholas , Iyer Gopa , Solit David B. , Saito Takuro , Castillo-Martin Mireia , Hahn Noah M. , Pal Sumanta K. , Fleming Mark T. , Hauke Ralph J. , Losic Bojan , Gnjatic Sacha , Chen Rong , Bhardwaj Nina 
Published: March 2017

300 Background: Somatic mut in DDR genes have been associated with increased sensitivity to cisplatin in UC. Higher mut load has correlated with response to immune checkpoint blockade. We hypothesized that DDR mut result in higher mut load and DDR mut UC may be particularly sensitive to both chemotherapy and immune checkpoint blockade. Methods: Three cohorts were utilized: (1) TCGA UC cohort (n = 389), (2) Mount Sinai (MS) cohort (n = 67) of UC (cystectomy) specimens subjected to targeted exome sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab (GCI) in metastatic UC from which 28/36 enrolled patients (pts) had specimens suitable for whole exome sequencing. DDR mut were defined as somatic alterations in one of 52 genes. Deleterious (del) mut were defined as nonsense, frameshift, splice site, or hotspot point mut. Results: The mut load using all genes in the TCGA cohort, and restricted to the 341 IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between del DDR mut and mut load are shown (Table). In the MS cohort, CD8+cells/mm2 by IHC were higher in tumors with del DDR mut versus no DDR mut (p = 0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative predictive value of a del DDR mut for objective response to treatment was 40.9% (95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 12.6-56.6%), respectively. Median progression-free survival in the GCI cohort was 308 days (95% CI 270-NR) in del DDR mut and 196 days (95% CI 185-372) in others (p = 0.24). Notably, 2/9 pts with del DDR mutations, and with the highest mut loads, achieved complete responses after GCI and are alive without evidence of disease at 2.1+ and 1.8+ years. Conclusions: DDR mut are associated with higher mut load in UC, a high likelihood of response to GCI, and may identify a subset of pts achieving durable disease control. GC plus PD-1/PD-L1 blockade should be explored in DDR mut UC. Clinical trial information: NCT01524991. [Table: see text]
Next generation sequencing of non-muscle invasive bladder cancer to reveal potential biomarkers and rational therapeutic targets.
Authors: Pietzak Eugene J. , Cha Eugene K. , Bagrodia Aditya , Drill Esther N. , Iyer Gopa , Isharwal Sumit , Li Qiang , Baez Priscilla , Berger Michael F. , Zehir Ahmet , Ostrovnaya Irina , Schultz Nikolaus , Bajorin Dean F. , Rosenberg Jonathan E. , Dalbagni Guido , Al-Ahmadie Hikmat , Solit David B. , Bochner Bernard H. 
Published: March 2017

302 Background: We examined a cohort of index pre-treatment NMIBC tumors using Next Generation Sequencing to identify genetic alterations with potential clinical implications. Methods: 105 patients on a prospective IRB-approved protocol had their pre-treatment index NMIBC tumor and matched germline DNA sequenced with a 341 cancer-associated gene panel in a CLIA-certified clinical laboratory. A genitourinary pathologist reviewed representative H&E slides to confirm grade, stage, and urothelial histology. Restaging TUR was performed in all HGT1 tumors. Results: To characterize the genomic landscape of NMIBC, we analyzed 105 tumors across the disease spectrum including LGTa (n = 23), HGTis (n = 12), HGTa (n = 32) and HGT1 (n = 38). The most frequently altered genes in NMIBC were the TERT promoter (74%), FGFR3 (50%), KDM6A (47%), ARID1A (28%), PIK3CA (27%), KMT2D (24%), STAG2 (21%), and CDKN2A (17%). 81% of tumors had inactivating alterations in a chromatin-modifying gene. Alterations in the RTK/RAS/PIK3 pathway occurred in 83% of tumors, including 58% of high-grade NMIBC having alterations in either ERBB2 or FGFR3. Of the 105 patients, 62 were treated uniformly with a 6-week induction course of BCG without maintenance. We investigated all genes altered on the 341-gene panel in at least 5 patients for their association with recurrence after BCG therapy in this 62 patient cohort. On cox-regression analysis, only truncating mutations in the chromatin-modifying gene ARID1A were associated with recurrence after BCG (HR = 3.14 [95%CI = 1.51, 6.51] p = 0.002). This remained significant when adjusting for multiple comparisons (p = 0.04) and when including ARID1A missense mutations of unknown significance (p = 0.002). Conclusions: Next Generation Sequencing of index pre-treatment NMIBC tumors identified an association between ARID1A mutations and recurrence after BCG therapy. Further investigation is needed to determine whether ARID1A mutations are a potential predictive/prognostic biomarker or therapeutic target. Moreover, most NMIBC tumors had at least one potentially “actionable” alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy.
Characterizing the costs of complications after cystectomy: Can we target the primary drivers?
Authors: Mossanen Matthew , Krasnow Ross E , Ingham Matthew , Kibel Adam S , Preston Mark A , Chang Steven Lee 
Published: March 2017

304 Background: Radical Cystectomy (RC) is subject to substantial morbidity and patients face complication rates as high as 64% at 90-days. Understanding the costs of complications after RC is essential to improving care. We studied the financial cost of different categories of complications after RC in order to identify drivers of expenditures. Methods: Using the Premier Hospital Database we identified adult patients who underwent RC for bladder cancer from 600 hospitals across the US from 2003-2013. Ninety-day complications were captured using ICD9 codes. Complications were categorized according to Agency for Healthcare Research and Quality Clinical Classification Software. The primary outcome was cost of complication and secondary outcomes were mortality, length of stay (LOS), and discharge disposition. A generalized liner model conforming to a gamma distribution was used to evaluate cost data. Analyses were survey weighted, and all models were adjusted for patient (age, race, obesity, marital status, payer), hospital (bed size, teaching affiliation, rural, region), and surgery characteristics (lymphadenectomy, continent diversion, robotic, operative time, transfusion, surgeon volume, hospital volume) and clustered by hospital. Results: We identified 9,137 RC patients, representing a weighting population of 57,553 patients. The top four most costly complications were venous thromboembolism (VTE $17547), soft tissue ($13523), gastrointestinal (GI $8663), and infectious (non-wound, i.e. sepsis, $7930). Pharmacy related costs were the primary driver of VTE costs. LOS was increased in each complication by 1.7 days for infectious, 4.5 days for soft tissue, 3.5 days for GI, and 3 days for VTE. Being married, having fewer comorbidities, larger hospitals, teaching hospitals, shorter operations, lack of transfusions, high volume hospitals, and high volume surgeons were associated with statistically significantly lower costs of complications after cystectomy. Conclusions: VTE, soft tissue, and GI complications are the most expensive complications after cystectomy, and thereby highlight potential candidates for future quality improvement initiatives.
Investigation on relationships between reduction of cisplatin and anticancer effects in patients with bladder cancer.
Authors: Miyata Yasuyoshi , Matsuo Tomohiro , Ohba Kojiro , Sakai Hideki 
Published: March 2017

306 Background: Cisplatin (CDDP)-based chemotherapy is recognized as standard treatment for patients with advanced urothelial cancer (UC). In patients having lowered renal function, dosage of CDDP must be decreased for prevention of adverse events. However, relationship between reduction of CDDP and anti-cancer effects is not fully understood. The main aim is to clarify the influence of pathological anti-cancer effects by decreasing of CDDP in muscle invasive bladder cancer (MIBC). In addition, anti-cancer effects of radiation therapy in patients with decreased dosage of CDDP are also investigated. Methods: One hundred thirty three patients with MIBC selected CDDP-based intra-arterial chemotherapy. Biopsy was performed before intra-arterial chemotherapy, and then complete resection by trans-urethral resection was done after the therapy. Decreased dosage was defined as reduction ratio is over 20%, and 34 patients were judged as decreased dosage group. Two courses of chemotherapy with CDDP (70 mg/m2) and doxorubicin (30 mg/m2 / epirubicin (30 mg/m2) were administered, and each course of chemotherapy was repeated approximately every 4 weeks. In 78 patients (58.6%), radiation therapy (total 40 – 60 Gy) began the day after chemotherapy administration. Results: The rate of down-stage after the chemotherapy in standard dosage group (63 of 99, 63.6%) was significantly higher (P=0.046) than that in decreased dosage one (15 of 35, 50.5%). In regard to pathological complete response (p-CR), patients with p-CR in decreased dosage group (n=9, 26.5%) were significantly lower (P=0.015) than those in standard dosage one (n=50, 50.5%). When similar analysis were performed in patients without radiation therapy, rate of p-CR in decreased dosage group was just 10.0%. On the other hand, p-CR was achieved in 33.3% in patients with radiotherapy of decreased dosage group. Conclusions: Reduction of CDDP may decrease its anti-cancer effects in patients with MIBC. On the other hand, combination of radiotherapy can increase the rate of p-CR in patients who treated with decreased dosage of CDDP. We believe our results are useful for discussion on treatment strategies in UC patients having lowered renal function.
Association of prior pelvic radiation with long-term oncologic outcomes following radical cystectomy.
Authors: Zaid Harras B. , Tollefson Matthew K. , Frank Igor , Parker William P. , Thompson Robert Houston , Tarrell Robert F. , Thapa Prabin , Cheville John C. , Boorjian Stephen A. 
Published: March 2017

308 Background: Receipt of pelvic radiotherapy (PRT) prior to radical cystectomy (RC) has unclear association on oncologic outcomes. Methods: The Mayo Clinic Cystectomy Registry was queried to review 2139 patients undergoing RC for M0 bladder cancer between 1990 and 2010. We then identified patients receiving PRT prior to RC, and matched these cases to non-radiated controls (~1:2) on the basis of age, sex, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Cancer-specific survival (CSS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results: Of 2139 patients undergoing RC, 104 (4.9%) had received PRT prior to surgery. These patients were matched to 191 non-radiated control patients (no PRT). Overall, patients were well-matched on disease and patient characteristics. Median follow-up was 9.6 years (IQR 6.0, 14.8). During this time, 108 patients experienced disease recurrence and 218 died, including 122 who died from bladder cancer. Five-year CSS among patients who did versus did not receive PRT was 55% versus 63% (p=0.10), while the 5-year PFS was 55% versus 61% (p=0.32). Furthermore, the pattern of disease recurrence (abdominal/visceral, urothelial, local/pelvic, thoracic, soft tissue/other) did not differ between the no PRT and PRT groups (all p>0.05). Conclusions: Receipt of PRT prior to RC is not associated with worse oncologic outcomes. While prior PRT may increase surgical complexity, CSS, PFS, and patterns of recurrence are similar to patients who have not received PRT.
Comparison of genomic alterations in bladder urothelial tumors with and without telomerase reverse transcriptase promoter mutation using a next-generation sequencing assay.
Authors: Isharwal Sumit , Audenet Francois , Pietzak Eugene J. , Cha Eugene K. , Iyer Gopa , Zehir Ahmet , Taylor Barry S. , Berger Michael F. , Tickoo Satish , Reuter Victor E. , Rosenberg Jonathan E. , Bajorin Dean F. , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Al-Ahmadie Hikmat 
Published: March 2017

310 Background: Telomerase reverse transcriptase (TERT) is the most frequently altered gene in urothelial cancer (UC), detected across all grades and stages of disease. We sought to characterize TERT alterations within a prospective cohort of UC treated at our institute and compare the frequency of genomic alterations in TERT promoter mutant vs wild-type UC specimens. Methods: Patients diagnosed with bladder urothelial tumors were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed for somatic point mutations, truncations, copy number alterations, and insertions/deletions using the MSK-IMPACT NGS assay that detects alterations in all exons and select introns of 410 oncogenes and tumor suppressor genes as well as the entire TERT promoter region. Results: 329 UC were sequenced of which 236 (71.7%) harbored TERT mutations, the majority being promoter region hotspots (chr5: 1295228 G > A [81%] and chr5:1295250 G > A [16%]). Patients with TERT promoter mutations were significantly older than those without (69.01±10.70 years vs. 65.44±11.78 years, p = 0.0317). UC with TERT promoter mutations had significantly higher mutation count [median 10 (range: 2-76) vs median 5 (range: 0-119)] as well as copy number alterations [median 0.11 (range: 0-0.68) vs median 0.047 (range: 0-0.65)]. Between UC with and without TERT promoter mutations, there was a very significant difference in mutation frequencies of ARID1A(33% vs 11%), PIK3CA(28% vs 13%), FGFR3(32% vs 16%), CREBBP(19% vs 4%), CDKN1A(17% vs 2%), ERBB2(26% vs 9%), ERCC2(15% vs 3%), TSC1(11% vs 0%), MT2C(17% vs 9%) (all with p < 0.005). Conclusions: TERT is the most frequently altered gene in bladder cancer with the majority of TERT alterations comprised of two hotspot mutations. UC with TERT promoter mutations tends to occur in older patients and is associated with overall higher mutation count and copy number alterations. A number of genes are differentially mutated in UC with and without TERT promoter mutations and may suggest a link between TERT promoter mutations and distinct mutations profiles in UC.
A phase I trial for the use of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) in the treatment of BCG-refractory nonmuscle invasive urothelial carcinoma of the bladder.
Authors: DeCastro Guarionex Joel , Sui Wilson , Pak Jamie S. , Abate-Shen Corinne T. , Lee Shing Mirn , Anderson Christopher B. , Holder Dara , McKiernan James M. 
Published: March 2017

313 Background: Salvage intravesical chemotherapy has shown benefit in patients with high-risk non-muscle invasive bladder cancer who fail first line therapy. Our preclinical murine intravesical trial showed a combination therapy was superior to single-agents. Our objective was to investigate the safety of intravesical triple agent salvage chemotherapy consisting of cabazitaxel, gemcitabine and cisplatin (CGC). Methods: Patients with BCG refractory or recurrent high-risk non-muscle invasive bladder cancer who refused radical cystectomy were enrolled. All patients underwent a pre-treatment transurethral resection of bladder tumor and then received a 6-week regimen. All patients received the same dose of gemcitabine (2000mg) while the dose of cisplatin and cabazitaxel were escalated as shown in table 1. Toxicity was categorized according to CTC for Adverse Events v4 and included hematuria, dysuria, bladder spasm, urinary retention or frequency. A complete response (CR) was defined as a negative random bladder biopsy and negative cytology six weeks after treatment. Results: Median age of the 9 patients was 74 years (table 1) and the median number of prior intravesical therapies was 4 (range 2-5). All patients completed 6 weeks of induction CGC. Any local toxicity was found in 7 patients with 5 experiencing at least 1 grade 1 toxicity and 4 experiencing at least 1 grade 2 toxicity. Seven of eight patients were complete responders and initiated maintenance therapy. Conclusions: CGC appears to be a well-tolerated intravesical salvage chemotherapy regimen for the treatment of BCG-refractory NMIBC. Clinical trial information: NCT02202772. [Table: see text]
Treatment patterns and economic burden of illness in patients with advanced bladder cancer receiving second-line therapy.
Authors: Rao Sumati , Gooden Kyna McCullough , Landsman-Blumberg Pamela , Yue Binglin , Lankford Maria L. , Dreicer Robert 
Published: March 2017

320 Background: Second-line chemotherapies (SLCT) for bladder cancer (BC) are high in toxicity and yield low objective response rates resulting in low overall survival (OS). BC in general is an expensive malignancy to treat, but real-world SLCT treatment patterns and the associated burden of illness are absent from the published literature. The objective of this study was to describe chemotherapy regimens and evaluate the clinical and economic burdens of advanced BC in the second-line setting. Methods: Patients aged ≥18 years with newly diagnosed stage 3 or 4 BC (4/2011–9/2014) were identified from the Truven Health MarketScan Databases. Patients were continuously enrolled in health benefits 12 months before advanced diagnosis date through death, end of enrollment, or end of study period (12/2014) with no pre-diagnosis evidence of other primary cancers, HIV, or pregnancy. SLCT regimens, time on therapy, OS, and BC-specific resource use and costs were computed using the Kaplan-Meier sampling average method with bootstrap and reported from SLCT initiation to the end of available follow-up. Results: A total of 475 patients with advanced BC received SLCT (Table). Their median age was 64.0 years, 76% were male, and median duration of SLCT was 56 days. The median OS was 7.8 months from SLCT initiation and 15.8 months from the date of advanced diagnosis. Mean per-patient BC-specific medical costs from SLCT initiation were $54,226 (95% CI, $41,878–$63,055), of which 44% was attributable to chemotherapy and related services. Inpatient stays (35%) and other outpatient services (33%) were the other major contributors to medical costs. Conclusions: This is the first known study evaluating real-world advanced BC treatment patterns and costs in a nation-wide cohort of SLCT recipients.Immunotherapeutic agents recently approved and in development provide oncologists with additional treatment options for these patients. [Table: see text]
Neoadjuvant vascular targeted photodynamic therapy in urothelial cancer: Preclinical data.
Authors: Rosenzweig Barak , Corradi Renato B , Budhu Sadna , Alvim Ricardo , Recabal Pedro Guiraldes , LaRosa Stephen , Somma Alex , Monette Sebastien , Scherz Avigdor Joshua , Kim Kwanghee , Coleman Jonathan 
Published: March 2017

321 Background: Recurrence and progression following surgical treatment of locally advanced urothelial cancer is high spurring a need to develop effective, well-tolerated neoadjuvant strategies. We examined the efficacy and immunotherapeutic mechanism of neoadjuvant sub-ablative vascular targeted photodynamic therapy (sbVTP) in urothelial cancer. Methods: Following urothelial tumor implantation, mice were randomized to receive neoadjuvant sbVTP (WST-11; TOOKAD Soluble, Steba Biotech, France) or sham treatment 17 days prior to surgical resection. Therapeutic efficacy was evaluated by local and systemic response and survival studies. Immunohistochemistry and flow cytometry were used to elucidate mechanism. Kaplan-Meier, Mann-Whitney and Fischer exact test were used to analyze the data. All statistical tests were two-sided. Results: On the day of surgery, tumor volume was 1222 mm3 (95% CI 976-1468 mm3) vs. 135 mm3 (95% CI 66-204 mm3, p < 0.0001) and systemic progression was 30% vs. 7% (p<0.05), for control vs. sbVTP treated animals, respectively. Median progression free survival and overall survival were 45 and 55 days respectively for surgery only group and significantly longer (50% not reached, p<0.05) for the sbVTP + surgery group. Local recurrence rates were significantly lower in neoadjuvant treated animals. Neoadjuvant sbVTP was associated with increase in early antigen presenting cells followed by long term memory, effectory and active T-cell increase in spleen, lungs and blood. Conclusions: Neoadjuvant sbVTP treatment demonstrates evidence of therapeutic efficacy through an immune mediated response in this murine urothelial cancer model by delaying local and systemic progression, prolonging progression free and overall survival, and reducing local recurrence. Evaluation of this form of therapy in clinical trials is warranted.
Examining gemcitabine and docetaxel for recurrent NMIBC.
Authors: Milbar Niv , Kates Max , Chappidi Meera , Schoenberg Mark , Bivalacqua Trinity J. 
Published: March 2017

322 Background: BCG relapsing/unresponsive patients who are poor surgical candidates or prefer bladder preservation vs. radical cystectomy (RC) may be offered intravesical therapies. Often in the literature, a “recurrence” after these therapies includes low-grade (LG) lesions, though stage progression and RC may be more meaningful outcomes for therapeutic efficacy. Including LG endpoints may make 2nd line therapies appear less efficacious. 2nd line intravesical Gemcitabine (GEM) with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Our objective was to evaluate JHH experience with GEM/DOCE, and to address whether LG vs high-grade (HG) recurrence endpoints influenced outcomes. Methods: 33 patients who received full induction courses of GEM/DOCE since 2011, per the protocol adapted from Michael O’Donnell at U. Iowa, were identified in the IRB-approved JHH NMIBC database. Multivariable logistic regression determined factors associated with recurrence. Cox proportional hazard models evaluated risk factors for all-grade recurrence-free survival (AG-RFS) and HG recurrence-free survival (HG-RFS). Results: Median AG-RFS was 7.6 months with 42% 1-year and 27% 2-year AG-RFS. Median HG-RFS was 17.5 months with 57% 1-year and 44% 2-year HG-RFS. No adverse effects of GEM/DOCE were observed. There were 5 LG recurrences, 11 HG recurrences, and 3 progressions. Of these, 7 patients had RCs. Within initial LGTa presentation, 80% (4/5) had LG and 20% (1/5) had HG recurrence. Within initial HG-NMIBC presentation, 46% (13/28) had HG recurrence. Only in univariable cox models, LGTa presentation showed increased risk of AG-RFS (HR 3.18, 95% CI 1.08-9.40, p=0.036), but comparable HG-RFS (HR 0.32, 95% CI 0.04-2.47, p=0.275). Conclusions: GEM/DOCE is a well-tolerated alternative to immediate RC for highly selected patients with HG-NMIBC. As anticipated, including LG recurrence as an endpoint for RFS made GEM/DOCE appear less efficacious. However, since standard of care for LG recurrence is further intravesical therapy, this endpoint may not be appropriate, as its recurrence often does not result in RC or worse cancer outcomes. Future studies of 2nd line therapies for NMIBC should identify HG endpoints based on clinically meaningful outcomes.