bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Outcomes by prior therapy.
Authors: Perez-Gracia Jose Luis , Loriot Yohann , Rosenberg Jonathan E. , Powles Thomas , Necchi Andrea , Hussain Syed A. , Morales Rafael , Retz Margitta , Niegisch Guenter , Duran Ignacio , Theodore Christine , Grande Enrique , Thastrom Ann Christine , Li Shi , Abidoye Oyewale O. , Van Der Heijden Michiel Simon
Published: March 2017

323

Background: Atezo is approved in the US for mUC and non-small cell lung cancer after prior treatment with chemotherapy. > 40% of mUC pts in the Phase 2 IMvigor210 study received ≥ 2prior metastatic regimens (Rosenberg, Lancet 2016). This analysis was performed to assess the impact of prior therapy on atezo outcomes in mUC. Methods: mUC pts in the platinum-pretreated IMvigor210 cohort (NCT02108652) received atezo 1200 mg IV q3w until loss of clinical benefit. Study endpoints analyzed by the number of prior treatment regimens included RECIST v1.1 ORR (central review), complete response (CR) rate, median durations of response (mDOR) and survival (mOS) and adverse event rate. Results: Evaluable pts (N = 310) had a median age of 66 years, and 78% had visceral mets (31% liver). 82% of pts had prior systemic treatment for mUC; number of prior regimens ranged from 1 to ≥ 4 (Table). 73% of pts received prior cisplatin, and 26% had carboplatin (no cisplatin). Objective responses, including CRs, occurred regardless of the number of prior therapies and were ongoing in 65% of responders at the July 4, 2016 data cut off (median follow-up, 21 mo [range, 0.2+-24.5]). mDOR was not reached in any subgroup based on number of treatments, except in pts who received only perioperative chemotherapy (mDOR, 16 mo [95% CI: 6.2, NE]). Similarly, mOS was generally consistent despite number of prior regimens (Table). Atezo remained generally well tolerated with similar overall safety and tolerability by line of therapy. Conclusions: Clinically meaningful benefit was observed in pts treated with atezo notwithstanding number of prior systemic mUC regimens. Minimally and heavily pre-treated pts had durable responses, encouraging OS and no major differences in safety signals. Clinical trial information: NCT02108652. [Table: see text]
Molecular subtyping of metastatic urothelial bladder cancer.
Authors: Ackerman Charlotte , Mariathasan Sanjeev , Nickles Dorothee , Gomez De Liano Lista Alfonso , Wimalasingham Akhila Ganeshi , Szabados Bernadett , Powles Thomas
Published: March 2017

326

Background: TCGA molecular sybtyping is established in metastatic urothelial bladder cancer (UBC). It remains unclear if it is of prognostic importance with chemotherapy in metastatic UBC. Data into immune therapy suggests TCGA subtyping is predictive to response. Methods: Archival formalin-fixed paraffin embedded (FFPE) tissue were analysed from 170 patients that had consented into a clinical trial (NCT00949455) after first line chemotherapy for metastatic disease. Gene expression levels were quantified by NanoString technology. Molecular subtypes were assigned according to The Cancer Genome Atlas (TCGA) subtypes. Clinical information was available for all patients and analysis on individual genes were explored. Results: 170 patients were analysed, 75% male. 107 (64%) patients received cisplatin based first-line chemotherapy, with 36% receiving carboplatin based regimen. Median overall survival (OS) was 15.73 months [95% CI: 13.87-17.58], and median progression free survival (PFS) was 10.71 months [95% CI: 8.97-12.45]. Samples were initially clustered into luminal (n=109) and basal (n=61) subtypes. Response to first line chemotherapy occurred in all subtypes but was shown to be significantly higher in the luminal subtype versus the basal subtype [58% vs 20%, p=0.01]. PFS was superior in luminal subtypes [11.8 months vs 8.9 months, p=0.005]. Exploratory analysis showed that luminal II subtype had the best outcome for OS [20.3 months, p=0.03] compared to the other subtypes. Outcomes with other genes including immune markers were explored. TCGA outcomes can be summarised in the table. Conclusions: In metastatic urothelial cancer, TCGA subclassifying influences outcome of patients post chemotherapy. [Table: see text]
Assessing bone response to cabozantinib in patients (pts) with metastatic urothelial carcinoma (mUC) using 18F-Sodium Fluoride (NaF) PET/CT.
Authors: Lin Jeffrey , Lindenberg Liza , Steinberg Seth M. , McKinney Yolanda , Weaver Juanita , Francis Deneise C , Berniger Marilise Anne , Parnes Howard L. , Davarpanah Nicole N. , Choyke Peter L. , Apolo Andrea B.
Published: March 2017

328

Background: NaF PET/CT is a radiotracer used for the assessment of bone metastases (mets). The goal of our study was to assess bone mets using NaF PET/CT imaging in mUC pts treated with cabozantinib. Methods: We conducted a single-arm phase II trial of cabozantinib in pts with mUC. Pts with known bone mets underwent a NaF PET/CT scan at baseline and every 8 weeks until progression. At each scan, we captured, the number of lesions per pt and per anatomical site, the maximum standardized uptake values (SUV), and serum alkaline phosphatase (AP). Bone responses (bone response (BR), stable disease (SD), progressive disease (PD)) were assigned to each pt based on the NaF report. Change from baseline to the time of best response for SUV, the number of lesions, and AP were compared between BR + SD vs PD were analyzed using an exact Wilcoxon rank sum test. The Kaplan-Meier method was used to determine the association of progression free survival (PFS) or overall survival (OS) with baseline SUV and number of lesions. Results: 68 pts enrolled on study, 22 pts had bone mets at baseline (6 bone only and 16 with bone and soft-tissue mets) (median OS 4.6 mo (95% CI: 3.4-7.7 mo), and median PFS 2.0 mo (95% CI: 1.8-3.9 mo)) of which 15 pts had follow up NaF scans. At baseline, 147 total lesions were analyzed, and the lesion distribution was: spine 29%, ribs 21%, pelvis 18%, skull 11%, femur 6%, scapula 3%, humerus 3%, sternum 3%, sacrum 3%, fibula 1%, and clavicle 0.7%. 5/15 pts had BR (and remained on study 238, 252, 182, 161, and 56 days), 4/15 SD, and 6/15 PD at best response. Sites of PD occurred in bone 10/22, bone and soft-tissue 5/22, and soft-tissue 7/22. The percent difference in number of lesions among responders and non-responders was 43% (p = 0.0039). At baseline, there was no association with PFS or OS and number of lesions (p = 0.84, p = 0.97), SUV (p = 0.83, p = 0.97), or AP (p = 0.97, p = 0.33). Conclusions: Pts with mUC and bone disease have poor overall outcome. Most bone lesions were found in the spine, ribs, and pelvis. Larger studies are needed to assess the correlation of NaF response with clinical outcome in mUC. We have an ongoing study using NaF PET to assess bone mets in mUC treated with cabozantinib/nivolumab/ipilimumab. Clinical trial information: NCT01688999.
Is neoadjuvant chemotherapy beneficial before radical cystectomy? Examining the external validity of the SWOG-8710 trial.
Authors: Hanna Nawar , Trinh Quoc-Dien , Sammon Jesse , Seisen Thomas , Vetterlein Malte , Moreira Raphael Brandao , Preston Mark A , Lipsitz Stuart R. , Bellmunt Joaquim , Menon Mani , Choueiri Toni K. , Abdollah Firas
Published: March 2017

331

Background: The use of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is supported by results from several randomized control trials, including SWOG-8710. We sought to test the applicability of the SWOG-8710 study in the general population. Methods: We used the National Cancer Data Base (NCDB) to identify patients with non-metastatic muscle-invasive urothelial carcinoma of the bladder who underwent RC between 2004 and 2012. The primary endpoint was overall survival (OS). Secondary endpoints were rates of downstaging (pT0), positive pathologic lymph nodes (pN+), margin status, postoperative readmission, length of hospital stay (LOS), and 30 and 90-day postoperative mortality rates. OS comparison using Cox regression analysis was conducted. Furthermore, logistic regression models examining secondary outcomes were fitted. To adjust for potential selection bias, propensity score weighted analyses were performed. Results: Of 8732 patients who underwent RC, 1619 (19%) received NAC. Compared to the SWOG-8710 cohort, our population was older, more commonly female (p=0.002), and had higher clinical stage (p<0.001). Following propensity score adjustment, receipt of NAC was associated with an OS benefit (Hazard Ratio [HR]: 0.88, p=0.017). On secondary outcome analysis, higher downstaging rates (Odds Ratio [OR]: 5.03, p<0.001) and lower 30-day (OR: 0.49, p=0.019) and 90-day (OR: 0.61, p=0.009) postoperative mortality rates were recorded in patients who received NAC. Conclusions: Despite baseline differences between patients from the SWOG-8710 trial and general urologic practice, NAC is associated with an OS advantage relative to RC alone. Continued efforts should focus on promoting the use of NAC in appropriate patients.
Impact of variant histology on disease-specific mortality and survival in patients with non-muscle invasive bladder cancer (NMIBC): A population-based analysis.
Authors: Tripathi Abhishek , Preston Mark A , Hirsch Michelle S. , Trinh Quoc-Dien , Stewart James A. , Bellmunt Joaquim , Choueiri Toni K. , Kibel Adam S. , Harshman Lauren Christine
Published: March 2017

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Background: Prior studies have reported that variant histology is associated with poor outcomes in NMIBC. We utilized the Surveillance, Epidemiology and End Results (SEER) database to compare disease specific survival (DSS) and mortality (DSM) among the different variant histologies and urothelial carcinoma (UC). Methods: Patients diagnosed with NMIBC (Ta, Tis, T1) between 2004 and 2012 were eligible for analysis. Patients were separated into cohorts based on histology: UC and variant histology which included micro-papillary variant (MPV), neuroendocrine (NEC), squamous (SCC), adenocarcinoma (AC) and other variants (e.g., lymphoepithelial, giant cell, undifferentiated/anaplastic, sarcomatoid). Univariate and multivariable Cox proportional hazard analysis was used to evaluate the impact of variant histology on DSM after adjusting for other covariates. DSS was estimated amongst the different histologic and treatment groups using the Kaplan-Meier method and compared using Log-rank test. Results: We identified 111,756 patients, who were predominantly Caucasian (90%) and older than 70 years (57.5%; n=64,314). Variant histology accounted for 1.2% (n=1354) of cases. AC and SCC were the most common variant subtypes (26.4%; n=357 and 25.6%; n=347 respectively) followed by NEC (11.2%; n=151) and MPV (7.1%; n=96). On multivariable analysis adjusting for age, sex, race, T-stage, histologic grade and number of primary tumors, all variant subgroups except MPV were associated with increased DSM compared to UC (p<0.001). SCC had the worst 5-year DSS (53.8%; P<0.001) followed by NEC (65.1%) and AC (77.8%). Compared to treatment with TURBT or intravesical BCG, cystectomy was associated with improved DSS for variant histology patients with T1 tumors (75.8% vs. 66.3%; P<0.001). Conclusions: Variant histology, specifically SCC and NEC, was associated with significantly worse 5-year DSS in NMIBC. MPV, which is generally thought to be aggressive, had outcomes comparable to UC. Cystectomy was associated with improved DSS in patients with T1 disease and should be considered for NMIBC with variant histology.
Effect of defective ERCC2 on cisplatin and ionizing radiation (IR) sensitivity in bladder cancer cells.
Authors: Li Qiang , Bell Andrew , Jordan Emmet , Gao Sizhi Paul , Ma Jennifer , Pietzak Eugene J. , Dalbagni Guido , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. , Riaz Nadeem , Iyer Gopa
Published: March 2017

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Background: Genetic alterations within ERCC2 correlate with extraordinary responses to neoadjuvant cisplatin-based chemotherapy and bladder-sparing ionizing radiation (IR) in muscle-invasive bladder cancer (MIBC). Two studies correlated ERCC2 mutations with pathologic response to chemotherapy and improved disease-free and bladder intact survival following trimodality therapy. We sought to characterize the biological significance of these mutations in bladder cancer cells using CRISPR/Cas9-mediated ablation of ERCC2 function. Methods: The ERCC2 T484A/M point mutation was the most common alteration (4 of 36 patients) within a prospectively collected cohort of 299 bladder cancer patients sequenced at our institution. We infected the ERCC2 wild-type KU19-19 bladder cancer cell line with a CRISPR/Cas9 lentivirus targeting residues 481-487 of ERCC2 and identified a cell clone harboring an ERCC2 in-frame deletion (M483_T484del). Following exposure to cisplatin and IR, cell viability was examined using Cell-titer Glo and clonogenic assays. Apoptosis was gauged by subG1 cell fraction measurement by flow cytometry. Results: ERCC2 mutant cells exhibited significantly increased cisplatin sensitivity compared to parental cells (IC50 0.3uM vs 2.0uM, p < 0.0001). Cisplatin treatment after 48 hours resulted in increased apoptosis in ERCC2 mutant vs parental cells (sub-G1 fraction 52% vs 16%, p = 0.01). ERCC2 mutant cells were more sensitive to combined IR (2 Gy) and cisplatin (1uM) compared to parental cells (SF2Gy (surviving fraction) 17 % vs 60%). Conclusions: ERCC2 mutations enhance cisplatin and IR sensitivity in a bladder cancer cell line model. ERCC2 alterations are likely the genetic basis for extraordinary response to cisplatin chemotherapy and IR in MIBC patients. Prospective genetic sequencing may help select ERCC2 mutant MIBC patients who are most likely to respond to chemotherapy or trimodality bladder-sparing therapy.
Perioperative and readmission rates in open and robotic assisted radical cystectomy: A National Cancer Database analysis.
Authors: Kosinski Kaitlin E. , Fazzari Melissa , Kongnyuy Michael , Katz Aaron E , Corcoran Anthony T
Published: March 2017

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Background: Perioperative mortality and readmission rates are evolving metrics of care being monitored in radical cystectomies (RC). We aim to evaluate these outcomes in open radical cystectomies (ORC) and robotic assisted radical cystectomies (RARC) reported in the National Cancer Database adjusted by surgery type. Methods: Using the National Cancer Database, patients treated with RC from 2003 to 2010 were identified. We evaluated the association between 90-day conditional mortality and readmission with respect to surgery type, adjusted by patient (age, gender, race/ethnicity, Charlson-Deyo score, tumor type, clinical stage, margin status and receipt of neoadjuvant chemo-or radiotherapy) and facility characteristics (overall cystectomy volume and facility type [Academic/Research, Comprehensive Community, or other]). Results: 16,923 RC cases (13,236 ORC, 3,687 RARC) were identified with 480 deaths (3.6%) after ORC and 99 deaths (2.7%) after RARC within 90 days, conditional upon surviving 30 days post-surgery. Comparing <3 ORC/year to >20 ORC/year, 90-day overall conditional mortality rates decreased from 4.0% to 2.5%. In stratified analyses, 90-day conditional mortality rates decreased from 4.2% to 2.7% for ORC and 2.7% to 2.0% for RARC. Center volume was strongly associated with 90-day conditional survival (p=0.002), independent of surgery type. In multivariable analysis of 90-day conditional mortality, age (OR=1.03, 95% CI: 1.02-1.04, p<0.0001), comorbidites (OR=1.4, 95% CI: 1.12-1.6, p=0.0005), margin rates (OR=3.5,95% CI: 2.9-4.3, p<0.0001) as well as facility volume (OR=0.99, 95% CI: 0.98-1.00, p=0.001), were predictive of 90-day conditional mortality. Cystectomy volume did not predict 30 day readmission, but Charlson-Deyo score 1-2 (OR=1.274, 1.112-1.461 95% CI, p=0.0005) and receipt of neoadjuvant chemo- or radiotherapy (OR=1.161, 1.032-1.307 95% CI, p=0.0134) were significantly associated with 30-day readmission. Conclusions: Patients were less likely to incur death following robotic or open cystectomy within 90 days as institutional cystectomy volume increased. 30 day readmission rates were not influenced by institutional cystectomy volume.
Measuring and improving symptom burden in radical cystectomy patients undergoing traditional care compared to enhanced recovery.
Authors: Kukreja Janet Baack , Chang Courtney M , Chen Ting Yu , Shi Qiuling , Wang Xin Shelley , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul
Published: March 2017

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Background: Bladder cancer is a disease of the elderly associated with high morbidity in those undergoing radical cystectomy (RC). The Optimized Surgical Journey (OSJ) uses enhanced recovery after surgery (ERAS) principles for RC patients to improve postoperative pain and shorten hospital stay. There have been few patient reported outcomes studied in OSJ and ERAS patients. The MD Anderson Symptom Inventory (MDASI) is patient reported outcome measures used for clinical and research purposes related to cancer and its treatment. Our objective was to determine if patient reported outcomes using MDASIs are different in patients following the OSJ compared to a traditional care pathway. Methods: From July 2013 to November 2015, MDASIs were collected from 160 RC patients preoperatively and on postoperative days (POD) 1 through 3. The MDASI consists of 19 core symptom burden related questions and 6 questions analyzing how symptoms have interfered with the patient’s life. Using a 0-10 scale, patient’s rate their symptoms. T-test, Man-Whitney where appropriate and logistic regression were used for multivariable cross sectional analysis. Results: The most bothersome symptoms were abdominal discomfort, disturbed sleep, dry mouth, fatigue, and drowsiness. Nausea, vomiting, bowel pattern, bowel control and appetite were all found to be insignificant. Abdominal discomfort was reported significantly less in OSJ patients on PODs 1 and 2 (p = 0.032 and 0.001, respectively). In multivariable analysis OSJ status was predictive of less abdominal pain (p < 0.001). Dry mouth was also significantly burdensome on PODs 1 and 2 (p = 0.022 and < 0.001, respectively) in non-OSJ patients. Less dry mouth was also predicted by OSJ status in multivariable analysis (p = 0.014). Disturbed sleep, fatigue, and drowsiness were significantly less in patients on the OSJ POD 2. Mood was better in OSJ patients PODs 2 and 3 (p = 0.016). Conclusions: The OSJ can significantly reduce the burden of symptoms in RC patients immediately postoperatively. MDASIs maybe a helpful tool to measure symptom burden. This information can be used in the future to create additional interventions for improvement in RC patient recovery experiences.
Updated meta-analysis (MA) of salvage therapy for metastatic urothelial cancer (mUC): Comparing outcomes of immunotherapy (IT) versus single agent and doublet chemotherapy (CT).
Authors: Necchi Andrea , Raggi Daniele , Sonpavde Guru , Giannatempo Patrizia , Mariani Luigi , Galsky Matt D. , Bellmunt Joaquim , Miceli Rosalba
Published: March 2017

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Background: Doublet CT demonstrated improved overall response rate (ORR) and progression-free survival (PFS) compared to single agent CT in a MA of patients (pts) receiving II line CT in trials of mUC ( Raggi et al, Ann Oncol 2016). We aimed to update the analyses adding trials of salvage IT. Methods: We searched for arms of phase 2 or 3 studies of salvage single agent anti-programmed cell death-1/Ligand-1 (PD-1/PD-L1) agents pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, single agent CT and doublet CT. Random-effects models were used to pool trial level data according to treatment arm, including ORR, median PFS (mPFS), median overall survival (mOS). Univariable (UVA) and multivariable (MVA) analyses were performed, adjusting for ECOG-PS 2 and liver metastases. Results: 7 IT trials were analyzed (n=1,041), 22 arms received single agent CT (n=1,202), and 24 doublet CT (n=708). The pooled ORR was: 21.2% (95%CI: 14.9-29.2) with IT, 14.2% (95%CI: 11.1-17.9) with single agent CT and 31.9% (95%CI: 27.3-36.9) with doublet CT. Pooled mPFS was 1.8, 2.69 and 4.05 months, respectively. Pooled mOS was 8.27, 6.98 and 8.50 months. Pooled median ORR and mOS of IT for PD-L1+ pts were: 30.7% (95%CI: 23.2-39.2) and 11.60 months. Results of UVA and MVA are shown in the table. Only UVA was possible for PD-L1+ pts. Conclusions: Among trials of salvage therapy for mUC, IT was associated with significantly higher ORR and mOS in PD-L1+ pts compared with single agent or doublet CT, while significant differences were not seen in unselected pts. These results are hypothesis-generating and suggest the importance of developing companion predictive biomarkers. [Table: see text]
The impact of MRE11 in nuclear to cytoplasmic ratio on outcomes in muscle invasive bladder cancer an analysis of NRG/RTOG 8802, 8903, 9506, 9706, 9906, and 0233.
Authors: Magliocco Anthony Martin , Moughan Jennifer , Simko Jeff , Efstathiou Jason A. , Gray Phillip J , Hagan Michael P , Kaufman Donald S , Tester William J. , Zietman Anthony L. , McCarthy Susan M , Hartford Alan C , Patel Ashish Bharat , Rosenthal Seth A. , McGowan David G , Greenberg Richard H , Schwartz Michael A , Augspurger Mark E , Keech John A. , Winter Kathryn A , Shipley William U.
Published: March 2017

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Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was >1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.
Patient derived xenografts of upper tract urothelial carcinoma: A potential tool for personalized medicine.
Authors: Kim Kwanghee , Murray Katie S , Bagrodia Aditya , Audenet Francois , Jebiwott Sylvia , Gordon Benjamin , Somma Alex , LaRosa Stephen , Dong Yiyu , Alvim Ricardo , Hakimi A. Ari , Hsieh James , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Solit David B. , Coleman Jonathan
Published: March 2017

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Background: Historically, upper tract urothelial carcinomas (UTUC) are treated similarly to urothelial carcinoma of the bladder (UCB). However, compared to UCB, UTUC demonstrates a more aggressive clinical course which may be explained by significant differences in mutational frequencies between UTUC and UCB that were reported using a customized exon capture sequencing assay (the MSK-IMPACT assay). A major limitation in the advancement of the UTUC field is the lack of appropriate models specific to the disease. The objective of this study was to develop and evaluate preclinical models that would recapitulate treatment responses observed in patients. Methods: 35 surgical specimens from nephroureterectomy of patients with UTUC were implanted into immunocompromised NOD-SCID IL2Rg−/− (NSG) mice. The histological and the genomic characterization of patient tumors and PDXs were examined by a board certified pathologist and MSK-IMPACT assay, respectively. Cell lines were also established to assess histologic and genetic fidelity. Chemosensitivity of PDX models was assessed using a 4 week cycle of gemcitabine/cisplatin (or carboplatin) administration and analysis of tumor growth was performed using a Two-way ANOVA test. Results: 12 patient-derived xenograft (PDX) models were established with a success rate of 34% (12/35) and a 14% (3/21) success in developing cell lines. Both models were highly reflective of their original tumors in terms of histology and genomic characteristics in mutation status and copy number alterations. For a representative PDX, chemosensitivity experiments identified gemcitabine/carboplatin as a potentially effective combination, which was also used in the clinical scenario with a therapeutic response. Chemosensitivity of additional PDXs is continuing to be investigated to potentially guide post-operative decision making for treatment of the patient’s clinically. Conclusions: We developed a cohort of stable PDX models and cell lines for UTUC that maintains the genetic characteristics of the patient’s initial tumor. The continued development of these models may facilitate personalized medicine strategies in the treatment of UTUC.