bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical and functional outcomes of brachytherapy for young men (≤50) with prostate cancer.
Authors: Shasha Daniel , Boo Dorothy , Perlow Leora , Salant Robert , Harrison Louis Benjamin
Published: February 2017

245

Background: NCCN guidelines endorse prognostic risk grouping to select therapy, and lend equal support to surgery and radiation therapy (RT). Despite this, the optimal treatment of prostate cancer in young men remains contentious, with the majority treated surgically. This may be because there are few reports of RT outcomes with long follow-up (FU) in this cohort. Thus, we report long-term biochemical and functional outcomes after prostate brachytherapy (BT) +/- supplemental therapies in men ≤ 50 years old. Methods: With IRB approval we analyzed outcomes of 47 patients ≤ 50 yrs old (median 48, range 48-50) implanted with curative intent by a single physician (DS) at Beth Israel Medical Center (New York City) between 2000-2009. Supplemental external beam therapy (45-50.4 Gy) was delivered to patients with NCCN intermediate risk (IR) and high risk (HR) disease, and to select patients with high volume low risk (LR) disease. Androgen deprivation therapy (ADT) was used in all HR patients, for pre-implant prostate downsizing, and for biopsy demonstrating very high volume disease. Biochemical failure (BF) was defined as “nadir +2.” Genitourinary (GU), gastrointestinal (GI) and erectile functional outcomes are included. Results: Median follow up (FU) was 5.2 yrs (range: 2-11). Only 1 patient experienced BF, thus, overall freedom from BF was 97.9%. Grade 2 acute and late 2 GU toxicity were reported in 10.6 % (n = 5) and 8.5% (n = 4), respectively. Grade 2 proctitis was seen 4.3 % (n=2). Erectile function was preserved in 41 of 47 men (87.2 %) with or without phosphodiesterase-5 inhibitors. Conclusions: With median FU of 5.2 years, excellent biochemical control with minimal toxicity was achieved in men ≤ 50 years old. The finding of only a single patient exhibiting BF over the 11 years of FU in this study is highly encouraging. Erectile preservation rates were high, and acute and late GI and GU toxicity were low. These results support prostate BT as an excellent option for patients in this age group.
First-line chemotherapy with gemcitabine, etoposide, and cisplatin in combined-multimodality treatment for patients with advanced urothelial carcinoma.
Authors: Urakami Shinji , Yonese Junji , Fujii Yasuhisa , Yamamoto Shinya , Yuasa Takeshi , Kitsukawa Shinichi , Sakura Mizuaki , Yano Akihiro , Saito Kazutaka , Masuda Hitoshi , Fukui Iwao
Published: February 2017

262

Background: We had previously reported the phase I/II study of a combination regimen of gemcitabine, etoposide, and cisplatin (GEP) in second-line treatment for patients with advanced UC. This study sought to examine the combination chemotherapy of GEP as first-line treatment for advanced urothelial carcinoma (UC) to assess efficacy, feasibility, prognostic factors, and the impact of postchemotherapy surgery on outcomes. Methods: Forty-two patients were treated with GEP as first-line treatment for metastatic or unresectable locally advanced UC. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m2 and 20 mg/m2, respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m2. Results: The median patient age was 64 years. Twenty-three male patients and 19 female patients were included. The primary cancer site is urinary bladder in 21 patients, and upper urinary tract in 21 patients. Nineteen had visceral/bone metastases, 16 had disease restricted to lymph nodes, and the remaining 7 had unresectable disease at primary site. The median number of GEP courses was 4. Thirty of 42 assessable patients (71.4%) demonstrated objective responses. At a median follow-up of 14.6 months, the median overall survival time (OS) was 16.2 months. Twenty-four of 30 responders underwent postchemotherapy surgeries. Median OS in the patients with postchemotherapy surgery was 25.4 months. In the multivariable analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. In addition, being male and anemic were independent poor prognostic factors in patients with postchemotherapy surgery. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 84%, 73% and 57%. There were no treatment-related deaths. Conclusions: GEP as first-line chemotherapy in combined-multimodality treatment is active and moderately tolerable for advanced UC. Postchemotherapy surgery may yield favorable outcomes in patients who achieved objective responses. Anemia and visceral/bone metastasis were independent pretreatment predictors for OS.
Cisplatin-based combination chemotherapy in elderly patients with metastatic urothelial cancer.
Authors: Bamias Aristotelis , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Moshier Erin L. , Sonpavde Guru , Godbold James H. , Oh William K. , Koutras Angelos , Pu Yeong-Shiau , Galsky Matt D.
Published: February 2017

269

Background: Cisplatin-based combination chemotherapy is considered standard first-line treatment for patients with metastatic urothelial carcinoma. However, cisplatin-based chemotherapy is frequently avoided in elderly patients due to concerns regarding treatment-related toxicities. We analyzed the efficacy, and tolerability, of cisplatin-based chemotherapy in two age groups (< 70 versus ≥ 70 years old). Methods: Individual patient data was pooled from eight phase II and III trials evaluating cisplatin-based first-line chemotherapy in patients with metastatic urothelial carcinoma. Toxicities, treatment delivery, response proportions, and survival outcomes were compared between patients < 70 versus ≥ 70 years old. Results: Of the 543 patients included in the analysis, 162 patients (30%) were ≥ 70 years old. Patients ≥ 70 years old had a significantly lower baseline calculated creatinine clearance (57 vs. 73 ml/min, p<0.0001). All other baseline characteristics, including PS and visceral metastases were well balanced between the two age groups. Patients ≥ 70 years received a median of 1 cycle less of chemotherapy compared with younger patients (median cycles 5 versus 6; p = 0.004). There was no significant difference in the proportions of patients experiencing Grade 3-4 renal failure, febrile neutropenia, or treatment-related death. Response rate among patients ≥ 70 years old was 50% compared to 52% for patients < 70 years old (p=0.65). There was no significant difference in survival between the age groups (p=0.91). The median survival of the patients ≥ 70 years old was 12.1 months compared to 12.8 months for patients < 70 years old. There was no significant difference in survival between age groups when controlling for baseline performance status and/or the presence of visceral metastases. Conclusions: Elderly patients, with adequate renal function and other baseline characteristics suitable for clinical trial enrollment, tolerate cisplatin-based chemotherapy similarly, and achieve comparable clinical outcomes, compared with their younger counterparts. Cisplatin-based therapy need not be withheld from such patients.
Cisplatin-associated nephrotoxicity in clinical trials using serum creatinine (SCr) versus calculated glomerular filtration rate (GFR) as inclusion criterion: A meta-analysis.
Authors: Dahal Arati , Bellows Brandon Kyle , Sonpavde Guru , Galsky Matt D. , Agarwal Neeraj
Published: February 2017

272

Background: Treatment with cisplatin (CIS) is associated with increased risk of nephrotoxicity and SCr is commonly used to screen patients for renal dysfunction prior to enrollment in trials using CIS. However, GFR is known to better estimate renal function than SCr. The objective of this trial-level meta-analysis was to indirectly compare incidence of WHO grade ≥3 nephrotoxicity associated with CIS therapy when renal function was assessed using SCr vs. calculated GFR during screening for these trials. Methods: A PubMed literature search was used to identify randomized trials comparing treatment regimens including CIS to those without CIS. Studies were included if they were performed between 1990 and 2005, reported SCr or GFR as inclusion criteria, and reported WHO grade ≥3 nephrotoxic events for both the CIS and non-CIS treatment arms. Studies were excluded if they were review articles, observational, phase 1, non-randomized, did not have a comparator group, or were not reported in English. Inverse variance weighted fixed effects (FE) and random effects (RE) methods were used to estimate the relative risk (RR) associated with CIS vs. non-CIS containing regimens with sub-group analyses of studies using SCr, GFR, and either SCr or GFR for screening. Results: The literature search identified 2359 studies. After exclusion criteria, 549 were reviewed and 24 studies (N=5524 patients) met all inclusion criteria for analysis. Of these, 16 studies used SCr (N=3955), 3 used GFR (N=692), and 5 used SCr or GFR (N=877) for screening. Overall incidence proportion of nephrotoxicity was higher for CIS vs. non-CIS regimens (2.1% vs. 0.7%). Overall RR for CIS vs. non-CIS regimens was 2.49 (95%CI 1.37-4.51, p=0.003). In sub-group analyses, the RR was 2.63 (95%CI 1.29-5.39, p=0.008) for SCr compared to 2.39 (95%CI 0.53-10.64, p=0.26) for GFR and 2.03 (95%CI 0.46-9.02, p=0.35) for either SCr or GFR. The RRs did not differ between the FE and RE methods. Conclusions: This indirect comparison meta-analysis shows CIS is associated with a higher likelihood of nephrotoxicity vs. non-CIS regimens, and may be higher when SCr is used instead of GFR as eligibility criteria.
Prediction of survival in patients with muscle-invasive bladder cancer (MIBC) by neutrophil (NTP) infiltration in benign lymph nodes (LNs).
Authors: Pal Sumanta Kumar , Liang Wei , Jove Richard , Yuh Bertram E. , Chan Kevin , Wilson Timothy G. , McConkey David James , Lerner Seth P.
Published: February 2017

273

Background: In preclinical models, NTPs appear to establish a pre−metastatic niche that fosters the invasion of metastases (Kowanetz et al PNAS 2010). This observation still requires clinical validation in MIBC. Methods: Benign LN tissue was obtained from patients (pts) who had undergone cystectomy and LN dissection for documented MIBC. Immunohistochemical (IHC) staining for CD15, a NTP marker, was performed for the entire cohort. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3), vascular endothelial growth factor receptor−1 (VEGFR1), and CD68 (a macrophage marker) were further assessed in an initial cohort (detailed subsequently) via IHC. Positively staining cells were counted and averaged over 8 high power fields (hpfs). Pts were stratified by the median cell count for each biomarker. Analyses of overall survival (OS) were performed using the Kaplan−Meier method and log−rank test. Results: In an initial cohort of 19 pts who had received no neoadjuvant chemotherapy (NC), a median CD15 count of 284/hpf was noted. Median OS was higher in those pts with low CD15 as compared to high CD15 (158.7 mos v 36.9 mos, P=0.02). Median OS was also improved in those with high pSTAT3 v low pSTAT3 (not reached v 106.4 mos, P=0.04), but no difference was noted in OS in groups stratified by clinical stage, VEGFR1 staining, or CD68 staining. To determine if the prognostic value of CD15 staining was retained in pts with exposure to NC, the cohort was expanded to include an additional 36 pts who had received either preoperative GC (n=17) or MVAC (n=19) chemotherapy. In this group, no significant difference in OS was noted based using the previously applied CD15 cutoff. Conclusions: NTP recruitment to benign LNs may be prognostic of OS in pts with MIBC who have not received NC. pSTAT3, a putative mediator of NTP recruitment, may play a role in this phenomenon. VEGFR1 and CD68, which may mediate pre−metastatic niche through a different mechanism, do not predict OS in our dataset (Kaplan et al Nature 2005). Bolstered by these findings, the prognostic value of NTP recruitment will be examined prospectively in SWOG 1011, a trial comparing limited v extended LN dissection in pts with MIBC.
Peroxisome proliferator-activated receptor gamma (PPARG) gene amplifications in urothelial carcinoma (UC).
Authors: Bambury Richard M. , Iyer Gopa , Riester Markus , Werner Lillian , Schultz Nikolaus , Stack Edward C. , Park Rachel , Loda Massimo , Ostrovnaya Irina , Kantoff Philip W. , Bajorin Dean F. , Solit David B. , Michor Franziska , Bellmunt Joaquim , Rosenberg Jonathan E.
Published: February 2017

279

Background: PPARy is a steroid hormone receptor encoded by the PPARG gene (Chr 3p25). Data are conflicting regarding its role in UC. Some studies suggest activation has antiproliferative effects, and preclinical data indicate a potential role for PPARy agonists in cancer treatment. However, recent findings show that use of the PPARy agonist thiazolidinones (TZD) in type 2 diabetes is associated with increased risk of developing UC. To define the spectrum of PPARy aberrations in UC, DNA was evaluated to detect copy number gains/losses (CNG/CNL) of PPARG in three clinically annotated UC cohorts. Methods: Cohort A contained 97 patients with high-grade UC. Cohort B contained 94 patients with primary bladder tumors who developed metastatic UC. Cohort C had 33 patients with metastatic UC, including both primary and paired metastatic tissue for 14 patients. DNA from all tumors was subjected to copy number analysis (array comparative genomic hybridization for cohorts A and B and molecular inversion probe array for cohort C) to identify focal areas of CNG/CNL. Statistical analysis using RAE (cohort A) or GISTIC 2.0 (with CNG defined as log2 copy number ratio >0.8) in cohorts B/C was used to identify significant alterations. Results: The region containing PPARG showed CNG in 7%, 10%, and 15% of cohorts A, B and C, respectively. In cohort A, RAE p value was 5.36E-05 at the amplicon containing PPARG. In cohorts B and C GISTIC 2.0 q values were 9.75E-12 and 6.04E-10. PPARG CNG had no impact on survival in the cohorts with available survival data (A and B). Paired biopsies from primary and metastatic sites showed discordance in PPARG CNG in 2 cases. In 1 case CNG was present in the metastasis but not in the primary and in 1 case the opposite occurred. Conclusions: PPARG shows significant CNGs in 7-15% of UC. Notably the RAF1 locus (a known oncogene) lies close to PPARG and could also represent the driver alteration within this amplicon. Investigation of the functional relevance of these CNGs is clearly warranted as it may be a driver of bladder cancer growth and progression. Determination of PPARG CNG status in UCs in a TZD treated population may provide mechanistic insights into the increased incidence of UC in patients treated with these agents.
The effect of therapeutic anticoagulation on overall survival (OS) in men receiving docetaxel chemotherapy for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pratz Caroline F. , Brodsky Robert A. , Antonarakis Emmanuel S.
Published: February 2017

28

Background: Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. We sought to examine the effect of therapeutic anticoagulation on OS in men with mCRPC receiving first-line docetaxel chemotherapy. Methods: We retrospectively reviewed the records of 247 consecutive mCRPC patients who received first-line docetaxel chemotherapy between 1/1/1998 and 1/1/2010. Information on anticoagulant use, type of anticoagulant administered, indication for anticoagulation, and duration of anticoagulation were captured. Univariate and multivariable Cox proportional hazards regression models were developed to investigate the effect of anticoagulant use on OS. Results: In all, 29/247 men (11.7%) received anticoagulation (LMW heparin: 17/247; warfarin: 12/247). The indication was DVT in 15/247, PE in 9/247, and both DVT and PE in 5/247 men. In univariate analysis, anticoagulant use was associated with improved OS (any anticoagulant, HR 0.61 [95%CI 0.40–0.94] P=0.024; LMW heparin, HR 0.58 [95%CI 0.34–0.99] P=0.048; warfarin, HR 0.82 [95%CI 0.55–1.28] P=0.23). Median OS was 20.9 mo (with any anticoagulant) versus 17.1 mo (with no anticoagulant). In multivariable analysis, anticoagulant use remained a significant predictor of OS after adjusting for other prognostic factors (Table). Conclusions: Anticoagulant use is an independent predictor of OS in men with mCRPC receiving docetaxel. This finding is surprising given that the occurrence of venous thrombosis might be expected to negatively influence OS. If validated, these data may provide the impetus to explore the antitumor potential of anticoagulants in prospective clinical trials. [Table: see text]
Antioxidant stimulation as the adaptation mechanism in patients with metastatic urothelial cancers (MUC) treated with gemcitabine and cisplatin (GC).
Authors: Palacka Patrik , Kucharska Jarmila , Mego Michal , Obertova Jana , Rajec Jan , Svetlovska Daniela , Sycova-Mila Zuzana , Mataseje Anna , Mardiak Jozef , Gvozdjakova Anna
Published: February 2017

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Background: The role of oxidative stress inpatients with MUC treated with GC is unknown. The objective of this ongoing study is to determinate plasma antioxidants, lipid peroxidation, and lipids in pts. with MUC before and after GC treatment, and to compare them with control. Methods: From May 2010 – January 2012, 42 MUC patients were enrolled into this study. The median of age was 65 years (range 44–81), median of metastasis sites was 2 (range 1–7). All patients were treated with gemcitabine 1000 mg/m2 i.v. days 1 and 8 with cisplatin 75 mg/m2 i.v. day 1, the new cycle of treatment started on day 22. Plasma samples were collected before and after 3 cycles of chemotherapy with GC. The control consisted of 22 subjects without cancer with age median 61 years (range 39–66). Results: In MUC patients, plasma γ-tocopherol before treatment were significantly lower (1.77±0.70 vs 2.13±0.70 μmol/L, P<0.04) and plasma TBARS higher vs control (5.76±1.32 vs 4.51±0.56 μmol/L, P<0.001). When compared baseline plasma levels to values after 3 cycles of GC, significant changes were noticed: γ-tocopherol (1.77±0.70 vs 2.29±1.14 μmol/L, P<0.04), α-tocopherol (24.23±5.14 vs 29.25±6.24 μmol/L, P<0.003), CoQ10-TOTAL (0.43±0.15 vs 0.56±0.16 μmol/L, P=0.003). TBARS concentrations were significantly decreased (5.76±1.32 vs 4.85±1.08 μmol/L, P=0.01). The concentrations of plasma lipids after GC were increased: Cholesterol (4.61±0.99 vs 5.47±1.21 mmol/L, P<0.004), TAG (1.30±0.65 vs 1.74±0.81 mmol/L, P<0.02), LDL cholesterol (2.94±0.73 vs 3.46±0.86 mmol/L, P<0.02), VLDL cholesterol (0.59±0.30 vs 0.81±0.37 mmol/L, P<0.02), and HDL cholesterol (1.08±0.39 vs 1.24±0.43 mmol/L, NS). Conclusions: GC in patients with MUC stimulated antioxidant defence system, increased plasma lipids, and decreased lipid peroxidation. The antioxidant stimulation might be one of the adaptation mechanisms that protect organism and might prevent or reduce chemotherapy side-effects. Acknowledgement: Study is supported by VEGA 1/0614/12 and Ministry of Health, Slovakia, grant 2007/29-UK-06.
Bladder cancer: Predicting response to BCG.
Authors: Nunez-Nateras Rafael , Stanton Melissa L. , Ferrigni Erin N. , Protheroe Cheryl A. , Lee Nancy A. , Lee James J. , Castle Erik P.
Published: February 2017

287

Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3+ (Th2) vs. T-bet+ (Th1) T cells, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3+) and Th1 (T-bet+) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3+ and T-bet+ tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.
Correlation of abnormal upper tract cytology and tumor histology in patients who have undergone a nephroureterectomy for urothelial carcinoma with disease recurrence in the bladder.
Authors: Sverrisson Einar Freyr , Kim Timothy , Espiritu Patrick , Sexton Wade Jeffers , Pow-Sang Julio , Dhillon Jasreman , Spiess Philippe E.
Published: February 2017

288

Background: 15-50% of patients with upper tract urothelial carcinomas (UTUC) will have a bladder recurrence. Abnormal upper tract cytology (UTC) is an indicator of higher grade tumors but has not been associated with bladder recurrence. We were interested in investigating the role of UTC as a predictor of bladder cancer recurrences in patients with no prior history of bladder cancer presenting with UTUC. Methods: Of 67 patients who had an UTC collected prior to their nephroureterectomy (NU) in 2004-2012, we identified 17 patients with a recurrent disease in the bladder who met the criteria of having no previous history of bladder cancer at the time of their NU. UTC and histology were reviewed and analyzed with the bladder pathology data. Positive or suspicious cytology was defined as abnormal and atypical or reactive as benign. Results: 15 (88%) of 17 patients (11 men and 6 women) who met our criteria were diagnosed with bladder cancer within one year after their NU (average 7.5 months (range 2-26)). 10 (59%) of 17 patients had abnormal UTC with a calculated sensitivity and specificity of 59% and 22%, respectively. 7 (70%) of 10 patients with abnormal UTC compared to 5 (71%) of 7 patients with benign cytology had high grade (HG) bladder cancer (p=1.0). Muscle invasive tumors were found in 5 (29%) of 17 patients and 3 (60%) of those had abnormal UTC. All six women had HG bladder cancer compared to 6 of 10 men (p=0.23). HG tumors were slightly more common in the bladder compared to the upper tract (75% vs 65%, p=0.70) and 14 (87.5%) of 16 bladder tumors had the same tumor grade in the upper tract. Conclusions: Abnormal UTC is a poor predictor of bladder recurrence in patients with a history of UTUC. The majority of patients who developed bladder recurrence presented within one year from NU with HG disease which underscores the importance of aggressive surveillance and the consideration of prophylactic intravesical therapy at the time of NU in this patient cohort.
Presence of variant histology (VarHst) in transurethral resection of bladder tumor (TURBT) biopsies and its prognostic significance on pathologic complete response (pCR) rates to neoadjuvant chemotherapy (neo-CTx).
Authors: Pedrosa Jose Alexandre , Rice Kevin , Thomas Derek E. , Johnston Paul , Moore Marietta L. , Reed Angela D. , Cregar Dylan M. , Franklin Cindy , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Gardner Thomas A. , Sundaram Chandru , Powell Charles R. , Beck Stephen , Grignon David A. , Cheng Liang , Hahn Noah M.
Published: February 2017

295

Background: Randomized phase III clinical trial data (S8710) supports an overall survival (OS) advantage with neo-CTx for muscle-invasive urothelial carcinoma (miUC) patients (pts) prior to cystectomy. Recent S8710 subset analyses have demonstrated an OS for pts with both pure UC and VarHst. pCR to neo-CTx has been suggested as a surrogate endpoint for OS. The relationship between VarHist in TURBT specimens and pCR rates is uncertain. Methods: A retrospective review of the Indiana University Simon Cancer Center urology and medical oncology clinical databases was performed spanning the years 1991 – 2012. Subjects with miUC, pathology reports available for both TURBT and cystectomy procedures, and confirmed receipt of neo-CTx with regimen details were included in this analysis. Pts with clinically positive lymph nodes (LN+) were included provided they underwent cystectomy with curative intent and distant metastases were not present. Associations between pCR and pt baseline age, gender, race, clinical stage (T2N0 vs. T3/T4/N+), chemotherapy regimen received (cisplatin combination therapy (CisCTx) vs. non-cisplatin based), and presence of VarHst on TURBT sample were tested by multinomial logistic regression analysis with statistical significance set at p<0.05. Results: 72 miUC pts satisfying the inclusion criteria were identified. Cohort demographics included: age (median) – 59 yrs, 76% male, 93% Caucasian, 63% T2N0, 32% LN+, 81% CisCTx neo-CTx regimen, 42% VarHst on TURBT, pCR for entire cohort 18%. The presence of VarHst on TURBT sample was not associated with decreased rates of pCR (6/30 vs. 7/42) p=0.610. A trend toward significance with age over 59 was also observed. Conclusions: The presence of VarHst in TURBT specimen is not associated with decreased rates of pCR at cystectomy in miUC pts treated with neo-CTx. Further characterization of the amount of VarHst and reproducibility of its recognition in TURBT samples is warranted to determine its ultimate clinical value.
Tumor burden reduction in an orthotopic non-muscle-invasive bladder cancer model using IL-15 analogue (ALT-803) targeting T regulatory cells.
Authors: Gomes Evan , Miyake Makito , Zhang Ge , Goodison Steve , Egan Jack , Rhode Peter , Wong Hing C. , Rosser Charles Joel
Published: February 2017

298

Background: A recent NCI review listed IL-15 as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. Preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results for obtaining prolonged drug half-life and stimulating CD8+ T cells and NK cells. Based on these results, we hypothesized that the administration of ALT-803 will generate an immunologic response which will reduce tumor burden in a rodent carcinogen induced orthotopic non muscle invasive bladder cancer model (NMIBC). Methods: We tested intravesical ALT-803 alone and ALT-803 in combination with Bacillus Calmette-Guérin (BCG) in a rodent carcinogen induced orthotopic NMIBC model. Rats were anesthetized then a 22-gauge Teflon transurethral catheter was placed in the bladder and urine completely drained from the bladder. Next, the saline (negative control), ALT-803 (experimental agent) or BCG (positive control) therapy was delivered by transurethral instillation and allowed to dwell in the bladder for 1 hr by occlusion of the urethra with a purse string suture. The intravesical therapy was administered weekly for a total of six weeks to mimic intravesical BCG therapy in humans. Results: Herein we demonstrate that ALT-803 was safe and well tolerated alone or in combination with BCG. Furthermore, ALT-803 alone reduced tumor burden by 23% whereas BCG alone reduced tumor burden by 11% compared to control. The combination of ALT-803 and BCG reduced tumor burden by 30% compared to control. Tumoral responses of the combinational treatment were associated with 76% and 80% reduction in angiogenesis and proliferation, respectively, whereas combinational therapy was associated with a 7.7-fold increase in apoptotic index compared to control. Immune monitoring suggested that the antitumor response was linked to the activation of CD8+ cells and NK cells. Conclusions: The enhanced therapeutic index provided by ALT-803 plus BCG therefore provides a powerful justification for the development of this agent for future clinical trials in subjects with non-muscle invasive bladder cancer.
Using micro-RNA expression to predict response to neoadjuvant chemotherapy in urothelial carcinoma of the bladder.
Authors: Leibowitz-Amit Raya , Fridman Eduard , Bossel Noa , Zehavi Liron , Urban Damien , Cohen Yehudit , Dotan Zohar A. , Domany Eytan , Berger Raanan
Published: February 2017

299

Background: Urothelial carcinoma of the bladder is among the 5 most common cancers in the US. Despite several clinical trials attempting to determine the best approach to muscle-invasive disease, the optimal treatment modalities and their sequence have not been established. Specifically, the decision to administer neo-adjuvant chemotherapy is currently based solely on clinical parameters, with no validated biomarkers. Micro-RNAs (miRNAs) are short RNA molecules that have roles in post-transcriptional gene expression regulation by binding to mRNAs. They were shown to have cardinal roles in many cancers, and their potential to serve as biomarkers is extensively studied. Our goal was to study whether miRNAs can serve as predictive biomarkers for response to neo-adjuvant chemotherapy in urothelial carcinoma. Methods: miRNAs were extracted from paraffin-embedded pre-operative muscle-invasive tumor biopsies of patients diagnosed with urothelial carcinoma, whose pathological surgical specimen was later found to either show complete or no-response to neo-adjuvant chemotherapy (termed 'responders' and 'non-responders', respectively). The expression pattern of approximately 900 miRNAs was compared using a commercial miRNA array, and the levels of candidate miRNAs was further assessed by quantitative real-time PCR (qRT-PCR). Results: The vast majority of miRNAs exhibited a similar expression pattern in the two patient groups, but two miRNAs were significantly lower in the responders (p <0.001 and q<0.1 using the false detection rate (FDR) method). Interestingly, both miRNAs can potentially target the mRNA of PTCH1 and SP5, two genes with known tumor-suppressor functions. qRT-PCR showed that high levels of one of the miRNAs correlated with lack of response to chemotherapy. Conclusions: This retrospective analysis identified two miRNAs that are differentially expressed between chemotherapy responders and non-responders. One of these miRNAs was confirmed to correlate with lack of response to neo-adjuvant chemotherapy. A prospective trial assessing the predictive values of these miRNAs is currently underway. Future research directions and potential implications will be discussed.
Paragangliomas of the urinary bladder: Experience at the National Cancer Institute.
Authors: Weintraub Michael , Siddiqui Minhaj , Vourganti Srinivas , Shuch Brian , Agarwal Piyush , Linehan W. Marston
Published: February 2017

307

Background: Bladder paragangliomas (BP, also referred to as bladder pheochromocytomas) represent 0.06% of bladder tumors. They occur both sporadically and with familial cancer syndromes such as von Hippel-Lindau (VHL) or Succinate Dehydrogenase-B (SDH-B) deficiency. Here we describe the clinical manifestations and management of BP at our institution. Methods: A retrospective review was performed of all cases of BP treated by the Urologic Oncology Branch at the National Institutes of Health (NIH) Clinical Center from 1989 – 2012. Using an approved database, we reviewed the demographics, radiologic, pathologic, laboratory data, surgical approach, and clinical outcome of patients with BP. Results: A total of 7 patients were treated for BP. Five were part of familial syndromes (3 with VHL, 2 with SDH-B deficiency, mean tumor volume (TV): 4cc), while 2 were sporadic cases (mean TV: 43cc). There was no significant age or gender difference in sporadic versus familial patients. 6 of the 7 patients presented with at least two of the three classic symptoms of headache, palpitations, and diaphoresis. 3 patients had micturition-related symptoms. For diagnosis, urine and plasma normetanephrines and urine norephinephrine showed the greatest sensitivity (0.75, 0.75, and 0.8, respectively). MRI was performed in all patients and had a sensitivity of 100% for detection of the mass. MIBG scan was also 100% sensitive, but was only performed in 3 of the 7 patients. CT missed the lesion in one patient. 3 patients were treated with TURBT (mean TV: 2.2cc), 2 underwent partial cystectomies (mean TV: 11.6cc), and one had a radical cystectomy (TV: 63cc). 2 patients had metastatic disease detected 7 and 9 years after initial treatment. No difference was seen in outcome based on the treatment modality. Conclusions: BP in familial and sporadic cases present with similar characteristics except for size. BP is best detected with catecholamines and MIBG/MRI. Surgical management is largely dictated by the extent of disease and includes TURBT, partial, and radical cystectomy. Long-term monitoring is recommended as distant recurrences can occur.
Clinical outcomes in focal versus extensive micropapillary bladder cancer at the time of diagnostic transurethral resection.
Authors: Willis Daniel Levi , Fernandez Mario , Dickstein Rian J. , Guo Charles , Czerniak Bogdan , Parikh Sahil , Shah Jay Bakul , Pisters Louis L. , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M.
Published: February 2017

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Background: It has been postulated that the outcome of patients with micropapillary bladder cancer (MPBC) is dependent on the extent of MPBC component relative to conventional urothelial carcinoma. Herein, we reviewed the clinical outcomes of patients with MPBC and evaluated the outcomes based on extent of disease in the transurethral resection (TUR) specimen. Methods: An IRB-approved institutional review of our bladder cancer database identified 255 patients with MPBC. Dedicated GU pathologists at our institution quantified MPBC as being "focal" or "extensive" in 201 patients, who form the basis of this report. Univariate analysis was performed with the chi square test and the Kaplan-Meier estimator, while multivariate analysis was performed using Cox Regression analysis. Results: Overall, 127 (63%) patients were reported as having focal MPBC and 74 (37%) patients had extensive micropapillary histology. Survival analysis demonstrated that patients with focal MPBC had a greater overall median survival of 54 mo. vs. 22 mo. for those with extensive MPBC (p=0.002). The extent of MPBC also correlated with cT stage as extensive MPBC was seen with higher stage disease (p=0.035). When stratified by cT stage, patient survival correlated with the extent of MPBC such that median survival for focal versus extensive MPBC was 122 vs. 62 mo. for cT1 (p=0.04), 54 vs. 22 mo. for cT2 (p=0.008), and 12 vs. 4 mo. for cT3 patients (p=0.017). In the cT1 cohort, patients with extensive MPBC were 2.3 times more likely to have disease progression on BCG therapy than those with focal disease (p=0.02). Extensive MPBC in the TUR specimen was also associated with higher rates of clinical lymph node metastasis (34% vs. 19%, p=0.018). The association of the extent of MPBC with overall survival remained significant after multivariate analysis with other prognostic variables including lymphovascular invasion and clinical T stage (p=0.05). Conclusions: The extent of micropapillary architecture in the TUR specimen is associated with stage of tumor at presentation. However, even when controlling for stage, patients with "extensive" MPBC on TUR specimen have independently worse outcomes compared to those with focal MPBC.
Outcome of patients with micropapillary bladder cancer treated with neoadjuvant therapy and radical cystectomy.
Authors: Willis Daniel Levi , Fernandez Mario , Dickstein Rian J. , Parikh Sahil , Siefker-Radtke Arlene O. , Guo Charles , Czerniak Bogdan , Shah Jay Bakul , Pisters Louis L. , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M.
Published: February 2017

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Background: Micropapillary bladder cancer (MPBC) is an uncommon and aggressive variant of urothelial carcinoma for which the role of neoadjuvant chemotherapy (NAC) is not well-defined. Here we report a retrospective analysis of patients with MPBC undergoing radical cystectomy (RC) with and without NAC. Methods: An IRB-approved review of our radical cystectomy database demonstrated 159 patients with a preoperative diagnosis of MPBC. Of these, 131 patients presented with surgically resectable (≤cT4aN0M0) disease and form the basis of this report. Disease-specific (DSS) and overall survival (OS) were estimated using the Kaplan-Meier estimator and compared by log-rank test. Results: The clinical stage breakdown was cT1:50; cT2:66; cT3:15; and cT4a:0. NAC was administered to 61 patients (47%) with 78% receiving cisplatin-based regimens. Patients were more likely to receive NAC if they presented with cT3 disease, hydronephrosis, or lymphovascular invasion (LVI) in the transurethral resection (TUR) specimen. After a median follow-up of 44 mo., 50% of patients recurred and 41% died of disease, resulting in a 5-year estimated DSS of 58.4% for all 131 patients. Survival analysis was performed for comparable groups according to our established risk factors. For the low risk patients (i.e. cT1-T2, no hydronephrosis, and no LVI) RC upfront (n=47) resulted in a 73% 5-yr DSS compared to 83% with NAC (n=19) (p=0.47). In the high-risk group (cT3 or cT2 with LVI and/or hydronephrosis), 41 patients were treated initially with NAC and 5-yr DSS was 40%, which was similar (p=0.74) to the 31% 5-yr DSS for those treated with RC upfront (n=20). The most important overall prognostic factor was pathologic downstaging to pT0, pTa, or pTis at cystectomy (seen in 52% after NAC and 19% after TUR alone) which conferred a significant survival advantage (5-yr DSS 93% vs. 40% in those not downstaged; p<0.001). Conclusions: Despite incorporation of a multimodal treatment strategy, patients with MPBC and high risk features (LVI, hydronephrosis and/or cT3 stage) have poor outcomes. Further studies are necessary to define the optimal treatment strategy in this challenging subset of patients with urothelial cancer.
Neoadjuvant carboplatin in stage IIa and IIb seminoma.
Authors: Horwich Alan , Dearnaley David Paul , Sohaib Aslam , Pennert Kjell , Huddart Robert Anthony
Published: February 2017

321

Background: Approaches to managing stages IIa and IIb seminoma post-orchidectomy range from combination chemotherapy (typically 3 cycles of BEP) to extended field radiotherapy (typically 36 Gy to para-aortic and ipsilateral pelvic lymph nodes. Survival rates are very good, which highlights the need to minimise toxicity risks. We report on the role of a single cycle of neoadjuvant carboplatin prior to limited field radiotherapy. Methods: In a single arm study fifty one patients were treated between May 1996 and November 2011 with a single cycle of carboplatin at an AUC of 7 mg.mins/ml followed by radiotherapy. The radiation field was reduced to just the para-aortic region and the dose to 30Gy in 39 patients. Results: After a median follow-up of 55 months (range 8-151 months) with 38 (74%) of the patients having been followed for more than 2 years, there have to date been no relapses (95% confidence limits of 5 year relapse free survival of 93-100%). Toxicity has been low with grade 3 toxicity limited to 4 patients with grade 3 haematological toxicity (with no clinical sequelae) and 1 patient with grade 3 nausea (during radiotherapy). No patients experienced grade 4 toxicity. Conclusions: The results of this pilot study suggest that a single cycle of neoadjuvant carboplatin prior to radiotherapy may reduce recurrence risk and permit a smaller radiation field, and this approach is proposed for further investigation.
Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ-cell tumors (GCT): Long-term efficacy and safety outcomes.
Authors: Necchi Andrea , Mariani Luigi , Nicolai Nicola , Raggi Daniele , Farè Elena , Giannatempo Patrizia , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Pizzocaro Giorgio , Gianni Alessandro M. , Salvioni Roberto
Published: February 2017

328

Background: Second-line chemotherapy (CT) of advanced GCT is vividly debated and no standard of care has been established. Since 1985 we introduced the modified PEI combination with the aim to reduce toxicity while maintaining efficacy over the original regimen. Methods: We retrieved data of pts who received ifosfamide at 2.5 gr/m2 (with mesna) on days 1-2, etoposide and cisplatin at 100 mg/m2 and 33 mg/m2, respectively, on days 3-5 every 21 days for a maximum of 4 cycles, followed by surgery of residuals. Multivariable analysis (MVA) was undertaken for pre-specified variables and IGCCCG-2 score was analysed as a continuous covariate. ITT analysis was applied. Results: From 02/85 to 01/12, 189 pts failing cisplatin, bleomycin, and vinblastine (PVB, N=25) or etoposide (PEB, N=164) were treated. 87% had a gonadal primary, 50.3% were MSKCC poor risk, 74.7% were IGCCCG-2 intermediate-to-very high risk, 21.8% had liver, bone or brain (LBB) mets, 16.7% were late relapses. 35 pts (18.5%) had a complete response (CR), 68 (35.9%) a marker normalization (PRm-) (major response-rate: 54.4%). 41/68 PRm- were rendered disease-free (total NED-rate: 40.2%). After a median follow-up of 122.1 mos (IQR 71.4-232), median (95%CI) PFS was 7.2 mos (6.2-9.5) and median OS was 21.7 mos (16.7-69.5). 2yr PFS was 34.3% (28.1-41.9) and 5yr OS was 42.1% (35.3-50.2). Mediastinal primary (HR 3.06, 95%CI, 1.68-5.58), LBB mets (HR 2.02, 95%CI, 1.30-3.16), and AFP>1000 ng/mL (HR 2.78, 95%CI, 1.51-5.14) were negative prognostic factors for OS at MVA while no effect was seen according to IGCCCG-2 category. 70.3% of grade 3-4 neutropenia (25% febrile neutropenia), 48.1% thrombocytopenia, 21.1% anemia, 3% neurotoxicity, and no severe renal toxicity were recored. 81 pts (78% before 2000) had a dose reduction of ≥1 drug for ≥1 cycle. No discontinuations for toxicity occurred. Conclusions: Dose-modified Italian PEI showed activity comparable with the best ones achievable by conventional-dose CT (CDCT) in an unselected patient population, and a favorable toxicity profile. Results are among the most robust available for a CDCT, and should be considered as an appropriate benchmark to be compared with high-dose CT.
Use of radiotherapy for seminoma patients with low-volume infradiaphragmatic nodal disease.
Authors: Sridharan Swetha , Chung Peter W. M. , Jewett Michael A. , Atenafu Eshetu , Bedard Philippe , Moore Malcolm J. , Warde Padraig Richard
Published: February 2017

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Background: Radiation therapy (RT) is established as standard management in testicular seminoma patients with low volume (< 5cm in maximum diameter) retroperitoneal lymphadenopathy. Increasingly multi-agent chemotherapy (CT) is being recommended as first line therapy with its attendant toxicity. To further examine this issue, we reviewed the outcomes for such patients managed at our institution. Methods: After ethics board approval, data on 106 patients identified from a prospectively maintained institutional database with low volume retroperitoneal disease (<5cm) were retrospectively reviewed. All patients were treated between 1995-2010 and had either relapsed Stage I disease on surveillance (59 pts) or Stage IIA/B at diagnosis (47 pts). Fifty eight patients had nodal disease of <2cm (57 treated with RT, 1 with CT), and 48 had disease 2-5cm (30 treated with RT, 18 with CT). Median age was 37 years (range 24-83). The preferred treatment policy was to use RT when possible (25 Gy in 20 fractions to para-aortic and pelvis with 10 Gy boost to gross disease). Reasons for using chemotherapy included multiple enlarged nodes with largest node at least 3cm (n=11), disease proximity to renal hilum (n=4), inflammatory bowel disease (n=3) and patient choice (n=1). Seventeen-patients received EP (4 cycles) chemotherapy and 2 received BEP (3 cycles). Results: With a median follow-up of 73 months, there were no disease or treatment related deaths. The 5-year overall and relapse-free survival was 100% and 91%. Of 58 patients with LN size ≤ 2 cm, 5 relapsed, all initially treated with RT. Of 48 patients with LN size 2-5cm, 4 relapsed (3/30 treated with RT, 1/18 treated with CT). Acute toxicity (CTCAE v4 >grade 1) was not observed in any patient treated with RT. In patients treated with CT, 7 developed G3/4 neutropenia, 2–grade 3 anemia, 2–grade 3 diarrhea, and 1 patient grade 3 weight loss. All relapsed patients were successfully salvaged by CT. Conclusions: A policy of routine use of RT in patients with low-volume nodal disease gives excellent results with >75% of patients avoiding CT and only 6% of patients receiving both RT and CT. Retroperitoneal RT should be strongly considered as the treatment of choice in these patients.
Survivorship care in Canadian genitourinary oncology: Toward a multidisciplinary perspective.
Authors: Richter Sue , AlMatar Ashraf , Lalani Nafisha , Bender Jackie , Wiljer David , Legere Laura , Massey Christine , Alkazaz Nour , Maganti Majula , Catton Pamela , Sridhar Srikala S. , Jewett Michael A.
Published: February 2017

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Background: Genitourinary (GU) cancer survivors comprise nearly 25% of cancer survivors and >50% of all male survivors. To further improve care of this patient population, we need to better understand physician specialist perceptions of survivorship care. Methods: All medical oncologists, urologists and radiation oncologists treating GU cancers in Canada were surveyed with a web−based questionnaire. A total of 27 multiple choice and Likert scale questions were developed in 5 domains: i) demographics, ii) current post cancer treatment care practices, iii) perceived barriers, iv) accessibility to survivorship resources and v) perceptions of advocacy groups. Participants were identified through their respective professional associations. Results: There were 306 responses and 260 were eligible for analysis; 45 medical oncologists, 125 urologists and 90 radiation oncologists. A total of 56% of physicians discharged GU cancer survivor follow-up care to a primary care practitioner (PCP) at some point after treatment. Compared to urologists and radiation oncologists, medical oncologists were least likely to share care with a PCP (4%). Only 47% of all physicians consistently provided a written follow up plan to the PCP and only 25% of these provided lifestyle recommendations. Lack of time and resources were the most commonly reported barriers. About half of physicians reported access to cancer rehabilitation programs as difficult and British Columbia was the most frequently cited region without access. Medical oncologists compared to other subspecialties accessed genetic counseling more easily while access to pain management programs was cited as the most difficult. In general, physicians in community hospitals had the most difficulties. Utilization of advocacy groups was limited, e.g. 23% for prostate cancer. The most underutilized advocacy group was for testis cancer (4%). Conclusions: To our knowledge this is the first study to address the challenges of GU cancer survivorship care in Canada. The barriers to care and underutilization of advocacy groups quoted in this study may be used to stimulate nationwide initiatives to further long-term strategies in GU survivorship management planning.