bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center.
Authors: Siefker-Radtke Arlene O. , Kamat Ashish M. , Corn Paul G. , Matin Surena F. , Grossman H. Barton , Millikan Randall E. , Dinney Colin P.N. 
Published: February 2017

261 Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to <=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to <= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to <= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 21 months, the 2-year OS and DSS was 78% and 85%, respectively (bladder 2-yr OS and DSS 75%, 82%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in < 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.
Influence of preoperatively detected circulating tumor cells on the outcome of patients with urothelial carcinoma of the bladder treated with radical cystectomy.
Authors: Rink Michael , Soave Armin , Chun Felix K. , Dahlem Roland , Minner Sarah , Kluth Luis A. , Ahyai Sascha A. , Heinzer Hans , Heuer Roman , Eichelberg Christian , Engel Oliver , Shariat Shahrokh F. , Pantel Klaus , Fisch Margit , Riethdorf Sabine 
Published: February 2017

268 Background: Circulating tumour cells (CTC) are frequently detectable in the peripheral blood of patients with urothelial cancer of the bladder (UCB) prior to radical cystectomy (RC). We hypothesize that CTC can predict advanced stages, nodal status and disease outcome after radical cystectomy and therefore represent an optimal biomarker for treatment decision making and patient counseling. Methods: Blood samples of 120 consecutive, clinically non-metastatic UCB patients scheduled for RC were prospectively investigated for CTC. Preoperatively collected blood samples (7.5 ml) were analysed for CTC using the CellSearch system (Veridex, USA). Uni- and multivariable models evaluated the association of CTC status and number of CTC with clinical and nodal stage and disease outcome. Results: CTC were detectable in 30/120 patients (25%) with an average number of 5.7±18.3 CTC (range:1-100; median:1). Eighteen patients (60.0%) had 1 CTC/7.5mL, 8 patients (26.7%) had 2-5 CTC and 4 patients (13.3%) had >5 CTC, respectively. CTC status was not associated with tumour stage, grade, lymph node metastases or lymphovascular invasion. Moreover, increasing numbers of CTC were not associated with higher stages or increasing numbers of lymph node metastases. However, at a median follow-up of 18 months (range:1-48 months) CTC detection prior to RC was an independent risk factor for disease recurrence (p<0.001, HR=4.9, 95%CI 2.1–11.7) and cancer-related death (p=0.002, HR=4.9, 95%CI 1.7-13.6). Disease recurrence and cancer-related death were not associated with the number of detected CTC. Conclusions: Although CTC can not predict pathological or nodal stage, they are associated with inferior disease outcome. Detection of even 1 CTC/7.5 mL blood in UCB patients prior to RC is an independent predictor for disease recurrence and cancer-related death. These findings are very important for future investigations, as they are in contradiction to theories supporting a cut-off value of 5 or more CTC needed for accurate outcome prediction. Therefore, CTC may represent a feasible biomarker for monitoring response to neoadjuvant and adjuvant chemotherapy.
Phase I trial of sorafenib with concurrent radiotherapy (RT) in patients with invasive bladder cancer treated with bladder-sparing intent: A Spanish Oncology Genitourinary Group study.
Authors: Martin Liberal Juan , Maroto José Pablo , Mellado Begoña , Ferrer Ferran , Sancho Gemma , Rovirosa Angels , Vigues Francesc , Palou Joan , Ribal Maria Jose , Bellmunt Joaquim , Garcia del Muro Xavier 
Published: February 2017

270 Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT. Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR. Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder. Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.
Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: Median 3-year follow-up.
Authors: Smith Angela , Nix Jeffrey W. , Nielsen Matthew Edward , Wallen Eric , Pruthi Raj 
Published: February 2017

284 Background: We reported our results on a prospective, randomized trial of open vs. robotic cystectomy in 2008. Three years later, we report our findings with regard to overall (OS) and disease-specific survival (DS), recurrence rates and long-term complications. Methods: A prospective, randomized study comparing open vs. robotic cystectomy for bladder cancer was initiated at our institution with IRB approval in 2008. A target accrual of 40 patients was established to evaluate for non-inferiority based upon nodal yield. Peri-operative and pathologic results were reported in 2008. We now report our median 36-month follow-up for this patient cohort. Results: Of the 41 patients, 21 were randomized to robotic and 20 to open. On surgical pathology, in the robotic group 14 patients had <= pT2, 3 pT3/T4, and 4 N+ disease. In the open group, 9 had <= pT2, 5 pT3/T4, and 7 N+ disease. No positive margins were noted. With median follow-up of 35 and 36 months in the robotic and open arms, OS was 65% (13/20) and 81% (17/21) respectively (p=0.3058). DSS was 68% in the open group (13/19) and 85% in the robotic group (17/20) (p=0.2733). There were 7 recurrences (35%) in the open cohort compared to 3 patients (14%) undergoing the robotic procedure (p=0.1589). Examining overall complications, there were no differences between the open and robotic groups when evaluating 30-day complications and >=90 day complications (p=0.8651). The open and robotic cohorts demonstrated 2 strictures in each cohort. Two parastomal hernias were noted in the open group compared to none in the robotic group. On multivariate analysis, controlling for age, BMI and pathologic stage, cystectomy type did not predict OS or DSS, recurrences, or complications. Conclusions: Median 3-year follow-up evaluating open versus robotic cystectomy demonstrates no differences with regard to OS, DSS, cancer recurrence or long-term complications. Although this study was not powered to assess survival differences, this is the first randomized study to report such data in a non-selected population with 3-year median follow-up.
Effect of lenalidomide on the response of bladder cancer to BCG immunotherapy in an in vivo murine model.
Authors: Lee Eugene K. , Gerald Jinesh , Kamat Ashish M. 
Published: February 2017

288 Background: Intravesical BCG is the gold standard for non-muscle-invasive bladder cancer (NMIBC). However, many patients do not respond to therapy while others relapse and/or progress. As a result, there remains a need for therapies that can enhance the efficacy of BCG. We explore the efficacy of lenalidomide, an immunomodulatory agent used in multiple myeloma and myelodysplastic syndrome, in combination with BCG in vitro and in an in vivo bladder cancer model. Methods: We studied the effects of lenalidomide in combination with BCG induced cytokines in MBT-2 cells using PI-FACS. For in vitro studies, we used 10 and 100 nM of lenalidomide in combination with TNF-a and FasL. We then performed Western blotting for cell cycle and apoptosis regulatory proteins. Subsequently, we tested the efficacy of this combination in an immunocompetent murine model of bladder cancer with MBT-2 cells in C3H mice using the flank injection method. Drug dosages were 30 mg/kg for lenalidomide and 105 CFU of BCG. Tumor growth curves were created for the control, lenalidomide, BCG and combination treatment mice groups. Immunohistochemistry (IHC) was then performed using antibodies against proteins related to cell cycle, apoptosis, angiogenesis and immune response. Results: PI-FACS identified increased DNA fragmentation in the combinations of lenalidomide and TNF-a and FasL compared to control and each agent alone. Using Western blotting, we demonstrated that the combination resulted in apoptosis via caspase-3 activation. In the murine model, combination therapy resulted in a statistically significant decreased tumor size compared to the control group. While the BCG alone and lenalidomide alone groups did show a trend toward smaller tumor, they did not reach statistical significance. Furthermore, the TUNEL assay showed a substantial increase in apoptosis only in the combination group. Immunohistochemistry demonstrated decreased angiogenesis in all treatment groups compared to control, as well as, decreased T-cell infiltration. Conclusions: Our study demonstrates a potential role for the immunomodulatory agent, lenalidomide, in combination with BCG for NMIBC. This in vivo model serves as a template for future clinical trials.
Use of next-generation deep sequencing to improve FGFR3 mutation detection in the urine of patients with bladder cancer.
Authors: Millholland John M. , Li Shuqiang , Fernandez Cecilia A. , Shuber Anthony P. 
Published: February 2017

289 Background: FGFR3 mutations have been identified in ∼60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ∼30% of the urine samples, which is < 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ∼67%, near the expected detection if every mutation found in tissue could be detected in urine. Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Taqman probes were used to determine if sufficient DNA was present in each sample. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation. Results: Urine samples from 29 patients with stage Ta bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Of the 29 samples, 2 did not have sufficient DNA for analysis by sequencing. Using ultra-deep amplicon sequencing, 18 out of 27 (66.7%) were positive for FGFR3 mutations, while only 3 out of 27 (11.1%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05%. The sensitivity achieved using deep sequencing approximates the FGFR3 mutations observed in tissue. Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at < 1% of the sample and suggests > 90% concordance with the expected mutations in Ta tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.
Chronic kidney disease and the risk of incident renal and urothelial cancer in a population-based cohort of 1.2 million adults.
Authors: Lowrance William Thomas , Udaltsova Natalia , Ordoñez Juan , Russo Paul , Go Alan S. 
Published: February 2017

351 Background: Prior studies have observed an increased risk of cancer in patients with end stage renal disease, but whether less severe chronic kidney disease influences the risk of cancer is uncertain. Methods: Among 1,190,538 adults at least 40 years of age and no prior dialysis, renal transplant or known cancer who received care within Kaiser Permanente Northern California, we examined the independent association between estimated glomerular filtration rate (eGFR) and the risk of cancer, overall and by type, between 2000 and 2008. Incident cancers were identified from a comprehensive regional cancer registry and potential confounders were ascertained using validated algorithms based on health plan electronic medical records. The impact of time-varying eGFR on incident cancer risk was examined using multivariable extended Cox regression, after excluding any cancers detected during the first two years of follow-up and any eGFR values within 3 months before a cancer diagnosis to reduce potential biases. Results: During 6,000,420 person-years of follow-up, 76,809 incident cancer diagnoses were identified among 72,875 patients (38,744 M, 34,131 F). After adjustment for possible confounding factors, the risk of renal cancer increased with lower eGFR (ml/min/1.73 m2): the adjusted hazard ratio [HR] for renal cancer was 1.35 (95% CI: 1.18–1.55) for eGFR 45–59, HR 1.65 (1.37 to 1.97) for eGFR 30–44, and HR 2.09 (1.62 to 2.70) for eGFR <30. There was a similar association between eGFR and urothelial cancer. However, there was not a significant multivariable association between eGFR and prostate, colorectal, lung, breast, or any cancer. Conclusions: We observed a graded, independent increased risk of renal and urothelial cancer risk with lower eGFR in a large, population-based cohort. However, lower eGFR was not significantly associated with other major cancer types. Additional research is needed to understand potential contributing mechanisms between reduced renal function and renal or urothelial malignancies, as well as whether differential cancer screening strategies are effective in patients with chronic kidney disease.
A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results.
Authors: Choueiri Toni K. , Vaishampayan Ulka N. , Rosenberg Jonathan E. , Logan Theodore , Harzstark Andrea Lynne , Rini Brian I. , Srinivas Sandy , Adams Laurel M. , Sherman Laurie Jill , Ottesen Lone Harild , McDermott David F. , Bottaro Donald P. , Linehan W. Marston , Srinivasan Ramaprasad 
Published: February 2017

355 Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition. Methods: Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1–5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed. Results: Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from −2% to −75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting. Conclusions: In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.
A retrospective analysis of data from two trials of sunitinib in patients with advanced renal cell carcinoma (RCC): Pitfalls of efficacy subgroup analyses based on dose-reduction status.
Authors: Khosravan Reza , Huang Xin , Wiltshire Robin , Lechuga Mariajose , Motzer Robert John 
Published: February 2017

363 Background: Patients requiring sunitinib dose reduction who received a novel dose/schedule modification scheme had longer progression-free survival (PFS) than patients who did not require dose reduction and remained on 50 mg Schedule 4/2 (4 weeks on, 2 weeks off) (Bjarnason 2011). Our analysis compared sunitinib efficacy in advanced RCC patients with/without dose reduction using the label-approved, dose-reduction scheme (ie, 50 mg/37.5 mg/25 mg) and schedule (Schedule 4/2) and explored potential causes of any differences. Methods: Data from a Phase 3 and a Phase 2 trial, sunitinib Schedule 4/2 arms only (N=375 and 146, respectively), were retrospectively analyzed, and pharmacokinetics and baseline characteristics of patients with/without dose reduction compared. Results: In the Phase 3 trial, median (95% CI) PFS was 14.0 (13.1–16.2) months (mos) and 8.1 (6.3–10.6) mos with (n=194) and without (n=181) dose reduction, respectively. In the Phase 2 trial, corresponding PFS values were 13.4 (9.8–19.8) mos and 5.8 (3.9–8.5) mos (n=51 and 95, respectively). In the Phase 2 trial, steady-state mean (SD) total drug trough concentrations were 96.0 (42.2) ng/mL and 85.8 (43.4) ng/mL on Day 29 of Cycle 1 in patients with/without dose reduction, respectively. In both studies, the percent of patients with baseline Memorial Sloan-Kettering Cancer Center risk factors of 0 (favorable), 1–2 (intermediate), and 3 (poor) were 37–47%, 53–57% and 0–6% with dose reduction vs. 25–28%, 65–72%, and 0–10% without dose reduction. The mean (range) time to dose reduction was 7.2 (0.03–40.4) mos in the Phase 3 trial and 4.5 (0.4–22.6) mos in the Phase 2 trial. Conclusions: Patients with dose reduction remaining on Schedule 4/2 appeared to have longer PFS than patients with no dose reduction. The differences were not caused by differences in plasma drug exposures; they appeared to be due, at least in part, to 1) differences in patients’ baseline prognostic factors and 2) patients’ PFS or longevity affecting their dose-reduction status. Thus, efficacy subgroup analysis based on patients’ dose-reduction status appears to be confounded, leading to biased results.