bluuebunny/crossref_metadata_2025 huggingface dataset:
Laser versus electrical en bloc resection of bladder tumors: Results of a European multicenter study (EBRUC).
Authors: Kramer Mario W. , Martov Alexey , Baykov Nikolay , Klein Jan , Rassweiler Jens J. , Lusuardi Lukas , Janetschek Guenter , Hurle Rodolfo , Wolters Mathias , Abbas Mahmoud , Leitenberger Armin , Riedl Markus , Nagele Udo , Merseburger Axel S. , Kuczyk Markus A. , Babjuk Marek , Herrmann Thomas R. W.
Published: February 2017

310

Background: The quality of transurethral resection of bladder tumors strongly determines patient’s tumor after-care and prognosis. En bloc resection of bladder tumors (ERBT) might improve staging quality, perioperative morbidity and influence tumor recurrence. This is the first European multi-center study which was initiated by ESUT and was conducted to evaluate the safety, efficacy and recurrence rates of electrical vs. laser ERBT. Methods: Transurethral ERBT was performed on 221 prospectively collected patients in six academic centers with either monopolar/bipolar current or holmium/thulium laser energy. Staging quality measured by detrusor muscle involvement, various perioperative/surgical parameters and 12 months follow-up data were analyzed. Results: 156 and 65 patients were treated with electrical and laser ERBT, respectively. Median tumor size was 2.1 cm with biggest up to 5 cm. Detrusor muscle was available in 97.3%. A switch to conventional TURBT was significantly more frequent in the electrical ERBT group (26.3% vs. 1.5%, p<0.001). Median operation duration (25 min), postoperative irrigation (1 day) and catheterization time (2 days) as well as hospitalization (3 days) were similar in both groups. Overall complication rate was low (Clavien ≥3, n=6 (2.7%)). Hemoglobin was significantly more decreased after electrical ERBT (p=0.0013), however overall hemoglobin loss was not clinically relevant (0.38 g/dl). 148 patients with first diagnosis of urothelium carcinoma of the bladder were followed for 12 months of which 33 (22.3%) recurred. 63.6% of recurrences occurred out of the ERBT resection field. No difference was noticed between both ERBT groups. Conclusions: ERBT is safe and reliable regardless of the energy source used and offers high quality resections of tumors >1 cm. Recurrence rates did not differ within both groups although the majority of recurrences were noticed out of the ERBT resection field. Laser device might be an alternative for the treatment of patients with higher risk of postoperative bleeding due to its efficient hemostatic effect.
Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.
Authors: Choudhury Noura , Campanile Alexa , Wade James Lloyd , Antic Tatjana , Stadler Walter Michael , Nakamura Yusuke , O'Donnell Peter H.
Published: February 2017

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Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
Expression of PDL1 (B7-H1) before and after neoadjuvant chemotherapy (NAC) in urothelial carcinoma.
Authors: Alva Ajjai Shivaram , McDaniel Andrew , Zhan Tianyu , Xiao Hong , Chinnaiyan Arul M. , Lee Cheryl T. , Mehra Rohit
Published: February 2017

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Background: Expression of the co-stimulatory ligand PDL1 (B7-H1) of the PD-PDL immune checkpoint on tumor cells enables evasion of anti-tumor immunity. The PD-PDL checkpoint is a therapeutic target in UC. We sought to characterize the impact of cytotoxic NAC on PDL1 expression before and after NAC to inform optimal sequencing/combination strategies of immune/cytotoxic therapies. Methods: Immunohistochemical (IHC) staining for PDL1 was performed using a murine anti-B7-H1 monoclonal antibody (clone 5H1) on a tissue microarray with matched pre-NAC T1/T2 transurethral resection (TURBT) samples (T0=2; Tx=1; T1=1; T2=23, T3=11; T4=2) and post-NAC cystectomy samples (pT0N0=15, TisN0=1, T1N0=3, T2N0=6, T3N0=9, T3Nx=1, T4Nx=1, T2N1=1, T3N2, T4N2=1, T3N3=1) from 40 patients (pts) treated from 1999-2011 at the University of Michigan. NAC was cisplatin-based in 13 pts and carboplatin-based in 26 pts. IHC was scored as the product of tumor cell staining intensity (0-3) and percentage of cells positive (0-100). Correlations of T stage at TURBT with the score were analyzed with unpaired t-test and Wilcoxon test. ANOVA analysis and paired t-tests were done to correlate pStage with the score. Results: PDL1 expression was significantly higher in post-NAC cystectomy specimens (mean IHC product score= 217.5) compared to the matched pre-NAC TUR specimens (mean IHC product score= 176.6, p value=0.0196 by Student's paired T test). Among the 21 non-pT0 pts with data at both time-points, PDL1 expression increased after NAC in 16 pts. The % of PDL1 positive cells in the residual tissue increased in 15 pts. The PDL1 expression product score in pre-NAC or post-NAC tissue did not correlate with clinical or pathologic stage, or with recurrence-free or overall survival. Conclusions: PDL1 expression in locally advanced UC in pts receiving NAC did not correlate with clinical outcomes in our small cohort. However, the expression of PDL1 in post-NAC tissue was elevated compared to pre-NAC. The increased PDL1 expression following NAC informs rational combinations and sequencing of cytotoxic chemotherapy with anti-PD1/PDL1 immunotherapies in UC particularly in adjuvant therapy for residual disease after neoadjuvant therapy.
Correlation of the clinical frailty scale with long-term survival after radical cystectomy.
Authors: Kramer Mario W. , Hennig Martin JP , von Klot Christoph A. J. , Wegener Gerd , Heinisch Annika , Peters Inga , Herrmann Thomas R. W. , Kuczyk Markus A. , Tezval Hossein , Merseburger Axel S.
Published: February 2017

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Background: Demographic changes account for an increasingly large proportion of elderly patients with urothelial carcinoma of the bladder. It remains under debate to which extent a patient might benefit from major surgery such as the radical cystectomy. Current tools for preoperative assessment of biological age might be of limited significance. The frailty concept, which refers to a biological syndrome of decreased reserve to stressors and resistance to stressors, has gained recent recognition for measuring patient’s physiological reserve and has been linked to adverse outcomes after surgery. Methods: Clinical, surgical and pathological data of patients undergoing radical cystectomy and lymph node dissection at Hannover Medical School with a minimum age of 60 years were retrospectively collected from 2000 to 2010. Frailty was assessed using the clinical frailty scale by Rockwood et al. derived from the Canadian Study of Health and Aging (CSHA). The relationship between frailty and various risk assessment tools such as the ASA-score, Charlson Comorbidity Index (CCI) and Karnofsky score (KS) in regard of long-term follow-up data was analyzed. Results: Our cohort included 255 patients (male 197, female 58). Mean age was 70 years (SD ±6.14). Patients were categorized into “not frail” (n=53, 21%), “vulnerable and mildly frail” (n=156, 61%), and “moderately/severely frail” (n=46, 18%). Higher CSHA was associated with increased CCI and higher rate of perioperative complications (each p<0.001). 179 (70%) patients had died during follow-up (mean follow-up, 61 months). Median survival differed significantly between groups (68 vs. 29 vs. 12 months, p<0.0001). In univariate analyses ASA, CCI, KI, and CSHA correlated with long-term survival (each p<0.001). In multivariate analysis only CSHA remained predictor of survival besides age, lymph node involvement, resection margins, and T-stage. Conclusions: The clinical frailty scale is an easy to use tool. It correlates with survival and perioperative complications after radical cystectomy. This study warrants further assessment of the frailty concept; however, it still has to be determined whether the clinical frailty scale is superior to other frailty assessment schemes.
Patient-derived xenograft platform to guide precision medicine in bladder cancer.
Authors: Pan Chong-Xian , Zhang Hongyong , Lin Tzu-yin , Tepper Clifford , Keck James , Ghosh Paramita , Airhart Susan D. , Bult Carol J. , Gandara David R. , Evans Christopher P. , Liu Edison T. , deVere White Ralph
Published: February 2017

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Background: The prognosis for bladder cancer has not changed in 30 years. No targeted agents have been approved even though reproducible genetic abnormalities have been identified. The goal of this project was to develop and characterize a patient-derived xenograft (PDX) platform to determine the efficacy of molecularly guided targeted and chemotherapy therapy, drug re-purpose, study resistance mechanisms, and design novel therapy to overcome resistance. Methods: PDXs were developed from direct implantation of uncultured patient bladder cancer specimens into immunodeficient NSG mice. Deep sequencing in combination with computational biology was performed to characterize PDXs and identify druggable genetic aberrations that guided efficacy screening and mechanistic studies. Results: Nineteen PDXs have been established with annotated clinical information. PDXs retained morphology and 92-97% genetic aberrations of parental patient cancers. Deep sequencing revealed multiple druggable genetic aberrations, including the fibroblast growth factor receptor 3 (FGFR3) and other tyrosine kinase receptor pathways. Compared to the progression-free survival (PFS) of 9.5 days in the control arm, matched therapy with an FGFR3 inhibitor BGJ398 prolonged PFS to 18.5 days (p=2.61 X 10-6) in PDXs overexpressing FGFR3. Serial biopsies during treatment revealed reactivation of the downstream pathways coincided with development of resistance while targeting these downstream effectors reversed resistance (12 vs. 22 days, p=0.001). Efficacy studies also revealed that PDXs had differential response to chemotherapeutic drugs that could potentially guide selection of chemotherapeutic drugs for first- and second-line therapies. To determine the clinical applicability of non-myoinvasive bladder cancer, we further developed an orthotopic PDX model that mimiced disease progression to invasive and metastatic bladder cancer. Conclusions: The PDX platform allows screening for multiple targeted therapy, chemotherapy or combinations simultaneously for the most efficacious drugs or combination, and serial biopsies during treatment to study drug resistance, a task not possibly replicable at the clinical setting.
Quality of life in long-term survivors of muscle-invasive bladder cancer.
Authors: Mak Kimberley S. , Smith Angela , Eidelman Alec , Clayman Rebecca Helen , Cheng Jed-Sian , Matthews Jonathan , Niemierko Andrzej , Nielsen Matthew Edward , Feldman Adam S. , Lee Richard J. , Zietman Anthony L. , Shipley William U. , Chen Ronald C. , Milowsky Matthew I. , Efstathiou Jason Alexander
Published: February 2017

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Background: Health-related quality of life (QOL) is not well-studied in survivors of muscle-invasive bladder cancer (MIBC). This cross-sectional multi-institutional study compared long-term QOL in MIBC patients treated with bladder-sparing trimodality therapy (TMT) vs. radical cystectomy (RC). Methods: Patients with non-metastatic cT2-T4 MIBC, diagnosed in 1990-2011 and disease-free for ≥2 years were identified. A questionnaire using validated general and disease-specific QOL instruments was administered (score ranges: 0-100). Results: Of 226 eligible patients, 173 returned the questionnaire for a response rate of 77%. Sixty-four received TMT and 109 RC (89 with ileal conduit and 18 with neobladder diversions). The median time from diagnosis to questionnaire was 9 vs. 6 years, respectively (p=0.009). Comparing TMT to RC, there was no significant difference in age at diagnosis or questionnaire, gender, smoking, clinical stage or comorbidities. On univariable analysis (UVA), patients who received TMT had significantly better general QOL than patients who received RC by 4.8 points on the EQ-5D 3L and 7.4 points on the EORTC QLQ-C30 (Table). On multivariable analysis (MVA), adjusting for age, time from diagnosis, year of treatment, gender and comorbidities, patients who received TMT had significantly better general QOL by an average 6-7 points. On MVA, TMT was associated with significantly better bowel function by an average 4.5 points on the EPIC bowel function subscale, but with no difference in bowel bother. Urinary QOL was equivalent between groups, as measured by the EORTC QLQ-BLM30. Conclusions: While both TMT and RC provide good long-term outcomes, TMT appears to be associated with higher general QOL and bowel function compared to RC. [Table: see text]
Cancer-specific nanotheranostics to improve the diagnosis and treatment of bladder cancer.
Authors: Pan Chong-Xian , Lin Tzu-yin , Zhang Hongyong , Li Yuanpei , Airhart Susan D. , deVere White Ralph , Lam Kit S.
Published: February 2017

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Background: We recently developed a bladder cancer-specific targeting ligand named PLZ4, nanometer-scale micelles and nanoporphyrin. Here we report the diagnostic and therapeutic applications of these nanotheranostics coated with PLZ4. Methods: PLZ4 was synthesized through solid phase synthesis. Bladder cancer-specific PLZ4-coated nanomicelles (PNM) and nanoporphyrin (PNP) were developed through conjugating the nanotheranostics with PLZ4 on the surface, and loaded with therapeutic and/or imaging agents in the core. Bladder cancer cell lines and patient-derived xenografts (PDXs) were used to determine the diagnostic and therapeutic applications. Results: In vitro studies with cell lines revealed that both PNM and PNP could specifically deliver the drug load to bladder cancer cells, but not to adjacent confounding cells. After intravenous injection, PNM loaded with paclitaxel could specifically deliver the drug load to xenografts developed from a human and a dog bladder cancer cell line, and a PDX, but not to lung cancer xenografts in the same mice. These paclitaxel-loaded PNM could overcome cisplatin resistance, and prolong the overall survival of mice carrying PDXs from 27 days with free paclitaxel to 76 days (p<0.0001). PNP can be used for photodynamic diagnosis and therapy while being able to chelate gadolinium for cancer-specific magnetic resonance imaging (MRI), and load chemotherapeutic drugs for cancer-specific targeted chemotherapy. It is over 50 times more potent that 5-aminolevulinic acid in photodynamic therapy (p<0.0001). After intravesical instillation into the bladder cavity of an orthotopic PDX model, PNP could specifically target bladder cancer cells, but not adjacent normal urothelial cells in the same bladder. Conclusions: PNM and PNP can potentially be used for diagnosis, imaging detection and cancer-specific targeted delivery of therapeutic agents of both non-myoinvasive and advanced bladder cancer. A phase I clinical trial of PNM for intravesical instillation in human patients with non-myoinvasive bladder cancer, and another phase I trial with PNP for photodynamic diagnosis and therapy in dog bladder cancer patients have been funded.
Assessing the impact on morbidity and mortality of neoadjuvant chemotherapy in patients with high-risk and muscle invasive bladder cancer eligible for radical cystectomy.
Authors: Di Trapani Ettore , Sanchez-Salas Rafael , Rocchini Lorenzo , Gandaglia Giorgio , Moschini Marco , Lizee Daphne , Barret Eric , Rozet Francois , Galiano Marc , Colombo Renzo , Briganti Alberto , Montorsi Francesco , Cathelineau Xavier
Published: February 2017

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Background: Despite the increasing number of studies confirming the importance of neoadjuvant chemotherapy in patients addressed to radical cystectomy (RC) for bladder cancer (BC), its association remains controversial. We aimed to test the safety and the efficacy of neoadjuvant chemotherapy in pts underwent RC for BC in a multistitutional retrospective study Methods: We analyzed 768 pts who underwent RC and PLND with / without neoadjuvant chemotherapy in two European high volume centers between 2007 and 2013. Complete demographic, pre and postoperative functional data and oncologic outcomes were collected. T-tests and Chi-square analyses were used to evaluate the differences between the groups. Kaplan-Meier curves were used to assess time to cancer specific mortality (CSM) free and overall mortality (OM) free survival. Univariable (UVA) and multivariable (MVA) logistic and Cox regression analyses were developed to address predictors of perioperative complications and CSM- and OM-free survival. Results: The mean follow up was 20 months (range 1-24). Mean age at surgery was 67 yrs (median 67 yrs). Patients had mainly pT2 disease (79,6%). Overall, 14% of pts had preoperative cisplatinum based neoadjuvant chemotherapy. We did not find any difference in pre-operative and post-operative blood tests assessment (all p>0.1). Intraoperative blood loss was higher in patients who went directly to surgery (mean 1.200 vs 740 cc; p<0.001) but the number of transfusions was similar (p=0.77) as well as the hospital stay (p=0.8). The complication rate was not significant at the MVA logistic regression analysis (p=0.74) even after evaluating per Clavien-Dindo groups (p=0.11). Neoadjuvant chemotherapy showed a better CSM-free survival at UVA (p=0.035) and at MVA (p= 0.043; OR 0.44). Then a nomogram was developed to predict the 60 months CSM-free rate showing an accuracy of 72.6%. Conclusions: Neoadjuvant chemotherapy is associated with a better CSM-free survival in patients with high-risk bladder cancer eligible for RC and it’s not linked with perioperative morbidity. We finally developed the first nomogram predicting the CSM-free rate in these patients.
Trends in utilization, perioperative outcomes, and costs among open, laparoscopic, and robotic nephroureterectomies: A 10-year population-based analysis.
Authors: Gelpi-Hammerschdmidt Francisco Jose , Allard Christopher B. , Chung Benjamin I. , Chang Steven L.
Published: February 2017

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Background: Nephroureterectomy (NU) is the standard treatment for upper tract urothelial carcinoma (UTUC). Minimally invasive (MI) laparoscopic or robotic-assisted approaches have been introduced in an effort to reduce morbidity. We performed a population-based study to evaluate contemporary utilization trends, morbidity, and costs associated with NUs in the United States. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), a nationally representative discharge database with data from over 600 non-federal hospitals in the United States, we captured patients who underwent a NU (ICD-9 55.51) with diagnoses of renal pelvis (189.1) or ureteral (189.2) neoplasms from 2004 to 2013. We fitted regression models, adjusting for clustering by hospitals and survey weighting to evaluate 90-day postoperative complications, length of stay (LOS), OR time, and direct hospital costs among open, laparoscopic, and robotic NU. Results: The weighted cohort included 17,245 open, 13,298 laparoscopic, and 3,745 robotic NUs. MI surgeries increased from 36% to 54% from 2004 to 2013, while the number of NUs decreased by nearly 20% during the same period (Figure 1). The overall 90-day mortality, major (Clavien 3-5), and minor (Clavien 1-2) complication rates were 1.89%, 9.4%, and 27.7%, respectively, with no statistically significant differences between the three approaches based on adjusted logistic regression analyses. The LOS was decreased for laparoscopic (Incidence Risk Ratio [IRR]: 0.87, 95% CI: 0.82-0.92, p<0.001) and robotic (IRR: 0.76, 95% CI: 0.7-0.83, p<0.001) NU compared to open NU. OR time was 10.35 (p<0.05) and 56.35 (p<0.001) minutes longer for laparoscopic and robotic NU. Adjusted 90-day median direct hospital costs were $1,354 and $3,533 higher for laparoscopic and robotic NU (p<0.001). Conclusions: During this contemporary 10-year study, the use of MI NUs increased to over half of procedures with a recent surge in robotic NUs, along with a concurrent reduction in total NUs performed in the United States. Comparable perioperative outcomes suggest that the morbidity profile may be driven primarily by patient-specific characteristics as opposed to surgical approach.
Determining the optimal timing for radical cystectomy after neoadjuvant chemotherapy.
Authors: Mmeje Chinedu O. , Benson Cooper , Nogueras-Gonzalez Graciela M. , Jayaratna Isuru Sampath , Navai Neema , Gao Jianjun , Siefker-Radtke Arlene O. , Kamat Ashish M. , Dinney Colin P. N. , Shah Jay Bakul
Published: February 2017

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Background: We present the largest series reviewing complications and pathologic outcomes following neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), to determine whether the interval between chemotherapy and surgery (ICS) affects 90-day post-operative morbidity and lymph node metastasis. Methods: We analyzed 338 patients treated with NAC followed by RC from January 1995 through December 2013. The association of ICS with 90-day surgical morbidity, incidence of major complication, 90-day readmission, and lymph node metastasis was determined. Generalized linear models were used to determine potential predictors of each endpoint. Patients were stratified into four groups by ICS days (18 – 42; 43 – 64; 64 – 85; > 85). Complications were classified using the Clavien system. Results: The overall morbidity of the cohort was 59%, with 66% being minor, and 34% being major complications. The median ICS was 46 days (18 – 199 days). There was no difference in the overall morbidity, readmission, or major complication rates among the four groups. Patients with an ICT > 85 days had the highest incidence of lymph node metastasis (40%), though this was not found to be significant (p = 0.1). On multivariate analysis including predictors of perioperative morbidity, extravesical (pT3 – 4) disease (OR = 1.97; p = 0.01) was an independent predictor of overall morbidity, while age at cystectomy (OR = 1.05; p = 0.004), and surgical time ≥ 7 hrs (OR = 2.87; p = 0.001) were independent predictors of major complications. Only surgical time ≥ 7 hrs (OR = 2.24; p = 0.006) was found to be a predictor of readmission. In a separate multivariate analysis that included risk factors for pathological node positivity, the predictors for lymph node metastasis included variant histology (OR = 2.06; p = 0.026) and extravesical disease (OR = 2.76; p = 0.002). Patients with an ICT > 85 days had a higher risk of node metastasis though this was not significant. Conclusions: Patients can undergo RC anytime between 2.5 – 12 weeks after NAC with no difference in risk of surgical complications or nodal metastasis.
Incidence and predictors of prostate cancer death in men with other prior malignancies: An analysis from SEER Database.
Authors: Dinh Kathryn Tindell , Mahal Brandon Arvin Virgil , Ziehr David R. , Muralidhar Vinayak , Chen Yu-Wei , Viswanathan Vidya Bhavani , Nezolosky Michelle Daniel , Beard Clair , Choueiri Toni K. , Orio Peter F. , Martin Neil E. , Sweeney Christopher , Trinh Quoc-Dien , Nguyen Paul Linh
Published: February 2017

34

Background: Men with cancer are screened 22% more for prostate cancer (PCa) than men without cancer, yet very little has been published on their prostate cancer outcomes. We aim to describe PCa death and clinical factors associated with dying from PCa in this population. Methods: We studied 22,769 men in the Surveillance, Epidemiology, and End Results database diagnosed with PCa as a second cancer from 1973 to 2006. Proportions of PCa death versus primary-cancer death were calculated, stratified by the nine primary cancers with highest incidence among US men and then further stratified by PCa grade and interval between primary and PCa diagnoses. Results: Urinary-bladder (30.4%), colorectal (27.9%) and lung cancer (10.5%) were the most common primary cancers. Overall, 12.4% of men died from PCa. A greater proportion of patients died from PCa than their first cancer with primary melanoma (11.7 vs 6.97%) and oral cavity/pharynx cancer (15.3 vs 6.98%), a similar proportion for colorectal (14.8% vs 13.7%) and kidney/renal pelvis cancer (11.1 vs 12.7%), but a lower proportion for lung (11.3 vs 42.1%) and bladder cancer (10.8 vs 17.4%). When the interval between cancer diagnoses was more than 5 years, PCa was the leading cause of death for five of the nine cancers. Patients who died from PCa compared to those who died from their primary had higher baseline PSA (39.5 vs 16.9 ng/mL, p<0.001), more Gleason 8-10 (36.7 vs 18.2%, p<0.001), more N1/M1 PCa (2.35 vs 0.30%, p<0.001), were older at PCa diagnosis (74.7 vs 71.9 years, p=0.015), and had a longer interval between diagnoses (63.9 vs 28.8 months, p<0.001). Conclusions: PCa remains a significant cause of mortality when diagnosed as a second cancer, especially if the interval from prior cancer is greater than 5 years, suggesting that treatment of aggressive prostate cancer may be reasonable for many patients with prior cancers.
Preliminary study of combined use of PDD and NBI for detection for flat urothelial lesion.
Authors: Naya Yoshio , Oishi Masakatsu , Ueda Takashi , Naitoh Yasuyuki , Nakanishi Hiroyuki , Hongo Fumiya , Nakamura Terukazu , Kamoi Kazumi , Okihara Koji , Miki Tsuneharu
Published: February 2017

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Background: This prospective preliminary study is a first report to compare photodynamic diagnosis (PDD) with narrow band imaging (NBI) in the same patients with flat suspicious lesions of carcinoma in situ (CIS) of bladder. Methods: PDD was approved by the ethics committees of our institution for 10 patients with non muscle invasive bladder cancer. Between November 2012 and April 2013, 10 patients with abnormal cytology (class III or more) but undefined papillary mucosa underwent TURBT using PDD and NBI in same time. Each patient received 1.0g ALA hydrochloride (Cosmo Bio Co., Tokyo, Japan) dissolved in 50 mL water, and was given orally 3 hours before the TURBT. The bladder was mapped first under white light (WL), then under NBI, and subsequently under blue light (BL) in odd-numbered patients. The bladder was mapped first under WL, then under BL, and subsequently under NBI in even- numbered patients. Biopsies were carried out from all suspicious areas noting if NBI, PDD or both detected lesions. Random cold cup biopsies were performed from negative lesions of PDD and NBI. Results: The sensitivity and specificity of PDD for detection CIS were 1.00 and 0.714, and those of NBI were 0.75 and 0.814, respectively. There were no cancer and dysplasia in 43 lesions both PDD and NBI negative. Of 50 lesions with negative PDD, only 2 (4%) were dysplasia and there was no cancerous lesion. Of 60 lesions with negative NBI, 3 (5%) were cancer and 6 (10%) were dysplasia. The AUC for detection CIS in PDD, in NBI and in combined use of PDD and NBI were 0.869, 0.782 and 0.964, respectively. Conclusions: When both PDD and NBI were negative, the possibility of CIS might be very low. The usefulness of the combination of PDD with NBI was suggested in this study. [Table: see text]
Impact of socioeconomic factors on the incidence of urothelial cell carcinoma in Germany.
Authors: Brandt Maximilian Peter Johannes Karl , Gust Kilian , Vallo Stefan , Mani Jens , Bartsch Claudia , Schertzer Adrien , Tsaur Igor , Reiter Michael Andreas , Schilling David , Haferkamp Axel , Herrmann Eva , Bartsch Georg
Published: February 2017

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Background: In the European Union (EU) differences in tumor incidence for urothelial cell carcinoma (UCC) have been reported. Besides occupational exposure, tobacco smoke and nitrite have been identified as risk factors for UCC. No study has evaluated the regional incidence of UCC in Germany in consideration of socioeconomic landscape. We investigated if a different allocation to agriculture (A), industrial use (I) and land settlement (S) are associated with the incidence of UCC. Methods: In collaboration with the German Centre for Cancer Registry Data, Robert Koch Institute, Berlin, all new cases of UCC between 2003 and 2010 were included, with partly dropped out information due to incomplete reporting. Kulldorff spatial cluster test was used to detect clusters with high incidence rates. Furthermore, information within the different administrative areas of Germany from 2010 for land use factors A, I and S were obtained from the Regional Database Germany, and calculated as both, a proportion of the total area of the respective administrative region and as a smoothed proportion including values from neighbouring regions. A negative binomial model was used to test the association of the area information in addition to the expected cases information for age and sex distribution. All tests were two-sided and a significance level of α=5% was used. Results: In a follow up of 437,847,835 person years, 171,086 incident cases of UCC were identified. Cluster analysis revealed areas with a significant higher incidence of UCC than others (p=0.0002). Multivariate analysis on land use (as smoothed proportion) in all available counties showed that each such factor is an independent risk factor for UCC (p< 0.00001, respectively). The interquartile range of the respective proportions and the relative risk (RR) for raising the respective proportion from first to third quantile of different land use were 35%-60% (RR 1.10), 0.5%-2.3% (RR 1.07) and 10%-29% (RR 1.21) for all three factors A, I, and S, respectively. Conclusions: This study displays regional differences in UCC incidence in Germany. Furthermore, results suggest that environmental exposure based on socioeconomic factors may present a relevant carcinogenic risk for UCC.
Patterns of lymphatic metastases in upper tract urothelial carcinoma: Experience from three comprehensive cancer centers.
Authors: Matin Surena F. , Espiritu Patrick , Coleman Jonathan A. , Sfakianos John P. , Spiess Philippe E.
Published: February 2017

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Background: Data on patterns of lymph node metastasis (LNM) for upper tract urothelial carcinoma (UTUC) is sparse despite its critical relevance for staging and therapeutic potential, with only 1 prior study detailing patterns of spread in 23 pathologically confirmed cases (Kondo T et al, Urol. 2007). Methods: We retrospectively identified and reviewed patients with pTany N+ M0 UTUC at 3 comprehensive cancer centers which routinely perform template-based dissections for UTUC. Anatomic locations of the primary tumor and positive lymph nodes based on the pathological specimens were analyzed, and maps of the location and incidence of LNM constructed. Results: A total of 92 patients with pN+ UTUC were identified, 63 of whom had renal pelvis (n=43) or proximal ureteral (n=20) tumors. LNM from left renal pelvis tumors occurred to the hilar (29.4%), pre- and para-aortic (50.0%) regions, with secondary spread to suprarenal (1.8%), interaortocaval (5.9%), and common iliac (2.9%) regions. LNM from right renal pelvic tumors occurred to the hilar (24.1%), pre- and para-caval (38.0%), retrocaval (13.8%), and inter-aortocaval (24.1%) areas. Left proximal ureteral tumors primarily had LNM to the hilar (46.1%), para-aortic (46.1%), and retro-aortic (7.7%) regions. Right proximal ureteral tumors had LNM to the hilar (36.4%), paracaval (54.5%), and retrocaval (9.1%) regions. A significant difference in survival was noted with patients who had organ confined tumor (p = 0.002) and a lymph node density of less than 25% (p = 0.005). The 1, 2, and 5-year cancer-specific survival rates of the overall cohort were 69%, 49%, and 27%, respectively. Conclusions: Our multi-institutional study provides data regarding the primary landing zones for LNM in renal pelvis and proximal ureter UTUC as well as guidance for developing anatomic dissection templates for prospective studies in UTUC incorporating surgical methodologies as a variable.
Radiosensitivity of orthotopic ileal neobladders.
Authors: Ballas Leslie K. , Bian Shelly X. , Miranda Gus , Daneshmand Siamak
Published: February 2017

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Background: A prior report from our institution documented that Kock ileal reservoirs can tolerate doses of 45-50.4Gy. This study provides retrospective information on the radiosensitivity of orthotopic neobladders by reviewing the acute and late toxicity in patients who underwent post-operative radiotherapy following radical cystoprostatectomy with orthotopic ileal neobladder reconstruction. Methods: The USC bladder cancer database was queried for all patients who underwent cystoprostatectomy and neobladder reconstruction followed by adjuvant radiation therapy related to their bladder cancer. The original patient charts and radiation therapy records were reviewed to determine the dose of radiation received by the neobladder. The patient charts were also reviewed to determine acute and late toxicity related to radiation. Results: From 1980 to 2013, 1,742 patients underwent radical cystoprostatectomy with orthotopic neobladder reconstruction. Of those 1,742 patients, 10 patients met the criteria of the study. The median age of the patients who received post-operative radiotherapy was 66.9 years. Forty percent of the study population received a dose of 50.4Gy, 50% received a dose of 45-46.8Gy and one patient, while prescribed a dose of 61.2Gy, only received 39.6Gy secondary to progression of disease on treatment that required termination of RT. All patients received 1.7-1.8Gy per fraction. The most common indications for radiotherapy were close or positive surgical margins. Two patients were treated with IMRT while the rest of the patients received 4 field or AP-PA beam arrangements. Of the patients that completed radiation, 3 had grade 2 or less CTCAE v4.0 acute GI toxicity; no patients reported acute GU toxicity. Two patients reported chronic grade 1 GU toxicity, likely related to their neobladders, with no reports of chronic GI toxicity. No patients experienced neobladder perforation, leak, or fistula. Conclusions: The use of moderate doses of pelvic radiotherapy (45-50.4Gy) was well tolerated among the 10 patients who had radiotherapy following cystoprostatectomy with orthotopic neobladder creation. This data supports the use of post-operative radiotherapy to moderate doses in this patient population when clinically indicated.
ERCC1 as a prognostic factor for survival in patients with advanced urothelial cancer treated with platinium-based chemotherapy: A systematic review and meta-analysis.
Authors: Urun Yuksel , Leow Jeffrey J. , Fay Andre Poisl , Albiges Laurence , Choueiri Toni K. , Bellmunt Joaquim
Published: February 2017

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Background: Platinium based chemotherapy (CT) is an essential part in the treatment of advanced urothelial cancer (AUC). However, not all patients derive benefit. A body of evidence suggests that excision repair cross-complementation group 1 (ERCC1) expression level may correlate with outcome in platinum treated patients. We thought to perform a systematic review and meta-analysis to better elucidate its role in AUC. Methods: A comprehensive literature review was performed to identify all studies comparing platinum-based regimens according to expression levels of ERCC1 for patients with AUC. The search included the PubMed, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to June 2014. Pooled analyses were conducted using fixed and random effects models. Results: A total of 554 patients included in eight studies were evaluated. ERCC1 expression was positive in 270 (49%) patients and negative in 284 (51%) patients. The median age of patients was 63 years. The overall survival (OS) was significantly better in patients with negative ERCC1 expression (pooled hazard ratio (HR) 1.90 (95% confidence interval [CI], 0.98–3.67; p=0.006). There was moderate amount of between-study heterogeneity present (I-square 70%). Conclusions: This study's findings support the hypothesis that low ERCC1 expression is associated with benefit from cisplatin-based treatment. The substantial amount of between-study heterogeneity may indicate the need for standardized methods to classify ERCC1 expression level. Prospective studies are necessary to determine the role of ERCC1 levels for treatment selection in patients with AUC.
VICTOR: Vinflunine (Vin) in advanced metastatic transitional cell carcinoma of the urothelium (TCCU)—A retrospective analysis of use of Vin in multicenter, real life setting as second-line chemotherapy (ChT) through free-of charge-programme (FOCP) for patients (pts) in the UK.
Authors: Hussain Syed A. , Ansari Jawaher , Huddart Robert Anthony , Wylie James , Vilarino-Varela Maria , Faust Guy , Tan Melissa , Lyons Jeanette , Hassall Alison , Escriu Carlos , Chauhan Seema , Jackson Richard
Published: February 2017

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Background: There is no standard of care currently in UK for second line ChT for pts with advanced TCC. Vin is approved for TCCU for pts who have failed a platinum-based regimen and is now the standard ChT in 2nd line in Europe based on large phase III randomised trial data showing 2.6 months survival advantage. ESMO guidelines recommended it as the only option for pts in the 2nd line setting. Vin is not currently available in NHS practice in UK as it is not on the approved list of drugs on cancer drug fund. Methods: Data are collected retrospectively on pts who received Vin as a 2nd line treatment through FOCP. The dose of Vin was 240-320 mg/m2 every 3 weeks. The aim was to document the toxicity, radiological RR and OS for pts treated with Vin in real life setting within the FOCP. Results: At the time of analysis data from 37 pts from 6 sites were available. Median pts age was 64 years(range: 57-69), 24m; 13 f. All pts had advanced metastatic TCC. 9 pts had bone or liver mets, 3 pts had PS 2 and 5 pts had HB <10, all known poor prognostic indicators in palliative ChT setting. Total of 179 cycles have been delivered (median 3 ; mean 5; range1-16). Grade 3 / 4 toxicity: Anaemia 2/179, Neutropenia 2/179, Neutropenic infection 2/179, Constipation 4/179, Fatigue 3/179. Grade 2 toxicity; Anaemia 5/179, Neutropenia 13/179, Thrombocytopenia 2/179, Febrile infection 1/179, Constipation 9/179, Fatigue 20/179, Abdominal pain 2/179, Vomiting 8/179. 30 pts were evaluable for response. 11 pts had PR, 6 had SD, 13 had PD and 7 were not evaluable. Partial RR was 30 % with ITT and 37% for evaluable pts. Median OS was 9.5 (95% CI; 5.9- 16.9) months. Conclusions: Real life data showing a median OS of 9.5 m by ITT for all pts are encouraging and consistent with real life data from Europe (Spanish, German and French) presented at ESMO 2013. Toxicity has further improved with the use of prophylactic laxatives and oral antibiotics.
Programmed death-ligand 1 characterization of circulating tumor cells and white blood cells in muscle-invasive and metastatic bladder cancer patients.
Authors: Friedlander Terence W. , Lu David , Krupa Rachel , Premasekharan Gayatri , Welty Christopher J. , Paz Rosa , Jendrisak Adam , Landers Mark , Louw Jessica , Orr Sarah , Marrinucci Dena , Fong Lawrence , Dittamore Ryan Vance , Paris Pamela
Published: February 2017

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Background: Muscle invasive(MIBC) and metastatic (mBCa) bladder cancer patients have few options to extend survival. Recent studies have shown that PD-1 and programmed death-ligand 1 (PD-L1) checkpoint inhibitors have activity even in chemotherapy refractory patients and it has been proposed that PD-L1 expression on tumors or lymphocytes may correlate with response to therapy. To identify potential patients who may benefit from PD-1/PD-L1 targeted immunotherapeutics, we utilized a non-invasive, real-time blood test for PD-L1 protein expression in circulating tumor cells (CTCs) and white blood cells (WBCs) of bladder cancer patients. Methods: Twelve blood samples from unique patients with MIBC or mBCa were collected and shipped to Epic Sciences. All nucleated cells were plated onto glass slides and subjected to IF staining and CTC identification by fluorescent scanners and algorithmic analysis. CTCs, defined as traditional (CK+ CD45- w/ intact DAPI nuclei and morphologically distinct) or CK- (CK-, CD45-, intact and distinct) were identified. PD-L1 biomarker characterization was assessed by IF staining, and UroVysion FISH testing was used to assess genomic abnormalities in a subset of patient samples. Additionally, WBCs (CD45+ cells) were assessed for PD-L1 expression. Results: Traditional CTCs were detected in 6/12 (50%) patients. 3/12 (25%) patients had PD-L1+ cells, 2 of these patients were exclusively CK-/PD-L1+ CTCs, which were confirmed as cancer via FISH. CK- CTCs were detected in 83% (10/12) patients. 5 patients had greater than 4 fold PD-L1 positivity in WBCs as compared to healthy donor controls. Conclusions: MIBC and mBCa patients have detectable CTCs with a high frequency of CK-/PD-L1+ CTCs. Utilization of a liquid biopsy to identify patients with PD-L1+ CTCs and PD-L1+ WBCs may enable both patient selection or short term therapeutic monitoring for measuring pharmacodynamics to ensure therapy effectiveness. Further studies are planned to investigate association of PD-L1+ CTCs and WBCs with response to PD-1 and PD-L1 checkpoint immunotherapy.
A novel tool to predict outcomes following radical cystectomy using age and co-morbidity status.
Authors: Nayak Jasmir Gopal , Holt Sarah , Gore John L. , Dash Atreya
Published: February 2017

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Background: Substantial morbidity and mortality is associated with radical cystectomy. Utilizing administrative data, we sought to develop a novel model combining age and co-morbidity status to determine the risk of clinically relevant outcomes including: prolonged length of stay (LOS), disposition to skilled nursing facility (SNF), mortality on index admission, and hospital readmission rates following radical cystectomy. Methods: From the Premier Perspectives Database, we identified patients who underwent radical cystectomy for bladder cancer between 2007-2013 using ICD-9 codes. Comorbidity was determined using the Elixhauser method. Prolonged LOS was defined as admissions exceeding 10 days. Hospital readmissions were flagged if they occurred in the month of surgery or the month after regardless of the reason. Probabilities were derived from multivariable logistic regression models that additionally adjusted for provider volume (based on quartiles), payer, patient marital status, and hospital urban/rural status. Results: We identified 6,460 radical cystectomy patients, of whom 16% were discharged to a SNF, 37% had a prolonged LOS, and 2% died during the index admission. Among patients who were discharged home after surgery, 27% were readmitted. Prolonged LOS was associated with increasing comorbidities and age >70 (p<0.001). The adjusted likelihood of readmission increased with increasing burden of comorbid conditions (p<0.001) (Table), however, was not associated with age group. The likelihood of being discharged to a SNF increased with increasing age and increasing number of comorbidities (p<0.001). Mortality was associated with 3 or more comorbidities and age >70. Conclusions: We present adjusted disposition and mortality rates following radical cystectomy for bladder cancer stratified by patient age and comorbidity. These data may inform preoperative patient counseling regarding the potential for prolonged recovery and mortality and facilitate improved shared decision-making between patients and clinicians anticipating cystectomy for bladder cancer.
Genetic variants of the organic anion transporter SLCO2B1 as pharmacogenomic determinants of response to androgen deprivation therapy (ADT) for prostate cancer.
Authors: Kantoff Philip W. , Wang Xiaodong , Xie Wanling , Nakabayashi Mari , Pomerantz Mark , Lee Gwo-Shu Mary
Published: February 2017

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Background: Genotypes at three SNPs (rs12422149; rs1789693; rs1077858) within SLCO2B1 were associated with time to progression (TTP) on ADT in the Dana-Farber Cancer Institute (DFCI) Prostate CRIS ADT cohort (J Clin Oncol. 2011 29(18): 2565). Variation at exonic SNP rs12422149 (Gln to Arg) allows more efficient import of DHEAS, enhances AR signaling and cell growth, and as a result, is associated with shorter TTP on ADT. We further externally validated the association of SLCO2B1 variants with TTP on ADT in an independent ADT cohort and estimate their association with overall survival (OS) in both cohorts. Methods: An independent ADT cohort (N=616) was established for validation. TTP was defined using the same criteria as for the original cohort. The associations of genetic variants with TTP on ADT and OS were estimated from multivariable Cox regression and adjusted by known prognostic factors. Effects of one intronic SNP rs1077858 on SLCO2B1 and DHEAS uptake activity were characterized in cell cultures. Results: Association between genotype at rs12422149 and TTP on ADT was confirmed in univariable (P= 0.0187) and multivariable (adjusted HR= 1.31 for GG vs AA/AG, P= 0.0489) analyses. The Median OS from ADT initiation was 6.5 years in all patients (N= 1094, original plus validation cohort). The intronic SNP rs1077858 was significantly associated with the OS from ADT initiation in both univariable (P= 0.0091) and multivariable (adjusted HR= 1.34 for GG vs AA/AG, P= 0.014) analyses. The difference of median OS was 18 months. SLCO2B1 expression in normal prostate tissue carrying the major allele of SNP rs1077858 (AA) was significantly lower than those carrying the risk allele (GG) (Ptrend= 0.0193), suggesting that the association of the SNP rs1077858 with the OS on ADT may be due to its impact on the SLCO2B1 expression. SLCO2B1 knockdown in vitro decreased DHEAS uptake and diminished DHEAS-induced prostate cancer cell growth. Conclusions: Germline variants within SLCO2B1 modulate function or expression of SLCO2B1, subsequently affecting the uptake of androgen precursors and affecting TTP or OS in prostate cancer patients.