bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the clinical activity of ipilimumab (IPI) plus nivolumab (NIVO) in patients (pts) with NIVO-refractory metastatic urothelial cancer (UC).
Authors: Callahan Margaret K. , Kania Brooke Elizabeth , Iyer Gopa , Clement Jessica Mary , Funt Samuel , McCoy Asia S. , Hettich Grace , Ziv Etay , Bluth Mark J. , Wong Phillip , Wolchok Jedd D. , Bajorin Dean F. , Rosenberg Jonathan E. 
Published: March 2017

384 Background: Programmed cell death –1 (PD-1) and its ligand (PD-L1) serve as checkpoints that regulate the interaction between the immune system and tumors. Antibodies blocking PD-1 or PD-L1 enhance antitumor activity in pts with UC. NIVO, a PD-1 blocking antibody, has clinical activity in UC as a single agent. IPI, an antibody blocking the checkpoint molecule CTLA-4, has demonstrated biologic activity in UC. Dual checkpoint blockade with both NIVO and IPI also has clinical activity in UC, but has not been systematically studied in NIVO-refractory UC. We sought to evaluate whether the addition of IPI to NIVO is feasible and clinically beneficial in pts whose UC is refractory to single agent NIVO. Methods: Forty pts with advanced or metastatic UC were treated with NIVO (3 mg/kg every 2 weeks) as part of a single arm, IRB-approved, investigator initiated study (NCT02553642). The study offered the option of treatment with the combination of IPI (1 mg/kg) and NIVO (3 mg/kg) for pts who had confirmed progression after treatment with NIVO monotherapy. The combination was dosed once every 3 weeks for 4 doses and followed by NIVO monotherapy. Pts were monitored for response and toxicity. Results: Ten pts who were refractory to NIVO monotherapy were treated with the combination of IPI and NIVO. There was a modest increase in the frequency of toxicities associated with the combination, compared to NIVO alone. One pt developed grade 3 diarrhea after treatment with the combination. No grade 3/4 toxicities were observed in pts treated with NIVO monotherapy. One pt achieved a confirmed partial response. Three additional pts achieved stable disease after documented progression. Pharmacodynamic changes in peripheral blood immune cells were monitored during treatment with NIVO monotherapy and combination therapy. Conclusions: The combination of IPI and NIVO is well tolerated and may have clinical activity in pts with UC who fail to respond to PD-1 blockade. Further studies to evaluate the magnitude of clinical activity and predictors of response for this combination are needed. Clinical trial information: NCT02553642.
Patient selection using novel RNA-based approaches: Early experience from a phase I study with the pan-FGFR inhibitor BAY 1163877 in patients with urothelial bladder cancer.
Authors: Joerger Markus , Schuler Martin H. , Cassier Philippe Alexandre , Hildebrandt Sandra , Behre Simone , Helmbrecht Corinna , Kerpen Stephanie , Zielinski Dirk , Ince Stuart , Ocker Matthias , Ellinghaus Peter 
Published: March 2017

386 Background: FGFRs play a role in a variety of malignancies, including urothelial bladder cancer (UBC). Whereas genetic alterations of FGFRs in UBC are known, non-genetic and epigenetic activation of FGFR gene expression have also been described. BAY 1163877 is an oral inhibitor of FGFRs 1-3 with antitumor activity in FGFR mRNA overexpressing xenograft models not limited to DNA alterations. We report the results from a phase I expansion cohort in UBC patients pre-screened for treatment with BAY 1163877 based on FGFR1-3 mRNA overexpression and/or activating mutations in the FGFR3 gene. Methods: FGFR mRNA levels were assessed in paraffin-embedded archival or fresh biopsy specimens by RNAscope and NanoString technology and activating mutations by RT-PCR-based mutation assay. Tumor response to treatment was assessed by RECIST, v1.1. Adverse events were assessed using CTCAE v4.03 criteria. Results: A total of 80 patients from multiple indications were enrolled in the phase I study; 800 mg BID was established as the recommended phase 2 dose. Sixty seven UBC patients were screened, with 31 tumor biopsies (46%) determined to overexpress FGFR mRNA: 2 patients each with FGFR1 and FGFR2, and 27 patients with FGFR3. Of the 27 patients with FGFR3 mRNA overexpression, 5 had in parallel an activating mutation in FGFR3 gene. Eight UBC patients met eligibility criteria and entered treatment; all had elevated FGFR3 mRNA expression and 4 had alterations in FGFR3 DNA (3 mutations and 1 translocation). Seven patients (87.5%) had tumor shrinkage in target lesions as best response, with 3/8 partial responses (PR; 37.5%). One patient with a PR presented with elevated FGFR3 mRNA without evidence of aberrant DNA. BAY 1163877 was generally well tolerated and AEs manageable with dose modification. The most common AEs in the overall population were increased phosphorus (66% all grade, 1 grade-3 event) and diarrhea (33% all grade, 2 grade-3 events). Conclusions: Selection of patients for treatment with BAY 1163877 based on FGFR mRNA expression levels in archival tissue was feasible. BAY 1163877 had a favorable safety profile and promising anti-tumor activity in UBC patients. Clinical trial information: NCT01976741.
Neoadjuvant chemotherapy for elderly patients with locally advanced disease: Are we doing enough?
Authors: Correa Andres , Handorf Elizabeth , Joshi Shreyas , Ristau Benjamin T. , Haifler Miki , Kutikov Alexander , Greenberg Richard E. , Chen David , Uzzo Robert G. , Viterbo Rosalia , Geynisman Daniel M. , Smaldone Marc C. 
Published: March 2017

389 Background: The administration of neoadjuvant chemotherapy (NAC) for patients with muscle invasive urothelial carcinoma improves overall survival. Recent reports have shown that the survival benefit may be greater in patients with locally advanced disease. Our objective was to assess the utilization of NAC by stage and age using a large national tumor registry. Methods: Patients who underwent radical cystectomy for cT2-4 N0-1 M0 urothelial carcinoma diagnosed between 2003-2012 were selected from the National Cancer Data Base. We excluded those with planned radiation therapy or who received palliative care. A multivariate logistic regression analysis was constructed to identify factors that affected administration of NAC. Covariates included were clinical stage, age, race, sex, insurance status, income, Charlson index, clinical stage group, demographic location, facility location, and diagnosis year. We also used interaction terms in the regression model to determine if stage effects differed by age group. Results: A total of 16,248 patients met inclusion criteria for the study. The use of NAC increased over the study period with 6% of eligible patients receiving NAC in 2003 vs. 27.7% in 2012 (p < 0.001).Increasing utilization of NAC was noted with increasing stage (cT2N0: 15.7%; cT3N0: 19.8%; cT4N0/TanyN1: 20.9%, p < 0.001) and decreasing NAC utilization was noted with increasing age ( < 65 years: 18.5%; 65-74 years: 18.5%; ≥ 75 years: 9.0%, p < 0.001). Following adjustment, increasing clinical stage was associated with an increase in the administration of NAC, (cT3N0 OR 1.46 [CI 1.24-1.71]; T4/TanyN1 OR 1.88 [CI 1.62-2.18]) compared to cT2 disease. In comparison, increasing age (age 65-74 years OR 0.78 (CI 0.68-0.88]; age ≥ 75 years OR 0.37 [CI 0.33-0.43]) was associated with decreased utilization of NAC compared to patients < 65 years. On interaction analysis the effect of higher stage on the likelihood of receiving NAC was attenuated in older patients ( ≥ 75 years). Conclusions: The administration NAC has increased over the last 10 years and is more likely to be given to patients with locally advanced disease or early nodal stage. However, this trend is substantially attenuated in older patients ( ≥ 75 years).
Cisplatin-based neoadjuvant chemotherapy (NAC) in bladder cancer patients (Pts) with borderline renal function: Implications for clinical practice.
Authors: Koshkin Vadim S. , Barata Pedro C. , Zahoor Haris , Rybicki Lisa A. , Emamekhoo Hamid , Almassi Nima , Tullio Katherine , Redden Alicia M , Fergany Amr Farouk , Kaouk Jihad , Haber Georges-Pascal , Beach Jennifer , Martin Allison , Allman Kimberly D , Garcia Jorge A. , Gilligan Timothy D. , Rini Brian I. , Grivas Petros 
Published: March 2017

390 Background: Cisplatin-based NAC prior to cystectomy is a standard of care in muscle-invasive bladder cancer (MIBC). There are limited data for pts with borderline glomerular filtration rate (GFR) who get cisplatin-based NAC. Methods: A retrospective review of pts who received cisplatin-based NAC at Cleveland Clinic (2005-2016) was done. Pts with pre-NAC GFR of 40-59 mL/min by either CG or MDRD formula (low GFR group; n = 17) were compared to pts with GFR ≥ 60 (nl GFR group; n = 74) for treatment-related toxicities and outcomes, such as pathologic complete (pCR, pT0N0) and partial response (pPR, < pT2N0), overall survival (OS) and recurrence-free survival (RFS). Comparisons were made using Fisher’s exact, Wilcoxon, or log-rank tests. Results: Pts with low GFR were older (median age 69 vs 64, p = .02) with worse PS (44% vs 20% ECOG > 0, p < .05). Gender, race, hydronephrosis rates and TURBT features (stage, grade, LVI, CIS) did not differ. For NAC, 64 pts got Gem/Cis (49 normal GFR, 15 low GFR), 23 got MVAC (22 normal GFR, 1 low GFR), 4 got other. Low GFR pts were less likely to get MVAC (6% vs 30%, p = .08) and more likely to get split-dose cisplatin (38% vs 18%, p = .10) and have NAC modified (delayed, dose reduced or stopped) (69% vs 36%, p = .02). 4/17 pts (24%) with low GFR and 9/73 (12%) with normal GFR did not complete all planned NAC cycles (p = .26). Hematologic toxicity caused most dose delays but renal toxicity was the most common cause of NAC stoppage (4/9 normal GFR, 3/4 low GFR). NAC cycles completed (median 3 / group) and G-CSF use (31/61 normal GFR, 3/9 low GFR) were comparable. No difference was noted in time to cystectomy (mean 107 days for normal vs 103 days for low GFR from NAC start), surgical complications, length of stay, and either post-NAC or post-cystectomy GFR decline from baseline. Combined pathologic response (pCR/pPR) was higher in normal GFR pts (50% vs 18%, p = .02). OS and RFS at 2 years were 89% and 79% for normal GFR and 78% and 58% for low GFR. Conclusions: Low GFR pts were older with worse PS, had more NAC modifications, lower pCR/pPR and trend for shorter OS & RFS, but most completed planned NAC cycles. For very carefully selected pts with GFR 40-59, cisplatin-based NAC is a treatment option.
Tumor mutation burden to predict progression in high-risk non-muscle invasive bladder cancer.
Authors: Meeks Joshua , Carneiro Benedito A. , Pai Sachin Gopalkrishn , Oberlin Daniel , Rademaker Alfred , Fedorchak Kyle , Balasubramanian Sohail , Elvin Julia Andrea , Beaubier Nike , Giles Francis J. 
Published: March 2017

397 Background: The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. Methods: DNA was extracted from formalin-fixed paraffin-embedded sections of tumor from 25 patients with HR-NMIBC (23 with T1HG; 3 with TaHG and carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) (“progressors”). Fifteen patients had no progression (“non-progressors”). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. Results: We identified no difference in the frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of mutations and deletions causing loss of function of CDKN2A and CDKN2B was identified in tumors at progression (37%) compared to non-progressors (6%) (p=0.10). We found a significant decrease in total mutational burden (TMB) comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p=0.02). This association suggests more advanced tumors have decreased neoantigen burden and may potentially explain the mechanism of BCG response in non-progressors. Conclusions: TMB was significantly greater in non-progressors compared to progressors. We found no novel genetic drivers in tumors that progressed and HR-NMIBC had many genetic features similar to metastatic BC. The loss of CDKN2A appears to occur late in the process of invasion of BC and may represent an important step in progression. Further research is necessary to evaluate loss of CDKN2A as a biomarker for progression of NMIBC.
111: A single-arm trial evaluating one cycle of BEP as adjuvant chemotherapy in high-risk, stage 1 non-seminomatous or combined germ cell tumors of the testis (NSGCTT).
Authors: Huddart Robert Anthony , Joffe Johnathan K. , White Jeff D. , Hutton Paul , Lewis Rebecca , Mazhar Danish , Osborne Colin , Piercy Deborah , Wiley Laura , Witts Stephanie , Maynard Lauren , Hall Emma , Cullen Michael H. ,   on behalf of the 111 Trial Management Group
Published: March 2017

400 Background: The standard post-orchiectomy treatment for UK patients (pts.) presenting with high-risk stage 1 NSGCTT is 2 cycles of bleomycin, etoposide (360mg/m2) & cisplatin (BE360P) chemotherapy or surveillance with BEPx3 at recurrence. 111 (CRUK/09/011) investigates whether BE500P x1 would achieve recurrence rates similar to BE360P x2. Methods: Pts aged ≥16 yrs post-orchiectomy for vascular invasion positive stage 1 NSGCTT or combined seminoma + NSGCT, with normalised tumour markers, received 1 cycle of bleomycin30000IU day 1, 8 & 15, etoposide165mg/m2 day 1, 2 & 3, &cisplatin50mg/m2day 1 & 2. All pts received a prophylactic antibacterial & GCSF. Pts were assessed for tumour markers q2m, q3m, q4m in years (yrs) 1, 2, 3, respectively and q6m in yrs 4 & 5. CT scan of chest, abdo and pelvis was performed at 6, 12, 24 & 60months (m) with chest x-ray at other visits. Toxicity was assessed using NCI CTCAE v3. Recurrences were independently reviewed. A sample size of 236 pts excludes a 2-yr recurrence rate of ≥5% if ≤6 recurrences were observed (80% power, 5% α). Results: Between 18/2/2010 and 31/7/2014 246 pts. were recruited at 33 UK centres; 54% with NSGCTT, 46% with combined GCT. Median follow-up was 39.1m (IQR 30.0-50.8). Four patients had malignant recurrences at 5, 8, 12 and 27m. 2 yr recurrence rate in 236 treated pts = 1.3% (95% CI: 0.4 to 4.0%). All 4 pts with recurrences were treated with 2ndline chemotherapy +/- surgery, 3 are alive and free from disease, 1 died at 9m with refractory disease. In addition there were 3 non-malignant recurrences at 7, 10 and 13m with teratoma differentiated in retroperitoneal nodes (3, 4 and 4.4cm). All these pts are disease-free post RPLND surgery. 41% pts had grade 3-4 CTCAE at end of treatment (neutropenia: 31% and febrile neutropenia: 7%). The 2 yr overall survival is 99.2% (95% CI: 96.7, 99.8%). Conclusions: BE500P is safely deliverable & 2 yr recurrence rate is similar to that seen with 2 cycles BE360P. The adoption of BE500P x1 as standard would reduce overall exposure to chemotherapy in this young pt population. 111 is the biggest formal, prospective trial to date investigating adjuvant BEPx1 in high-risk stage 1 NSGCTT. Clinical trial information: ISRCTN37875250.
Molecular dissection of primary mediastinal germ cell tumors.
Authors: Nappi Lucia , Annala Matti , Vandekerkhove Gillian , Fazli Ladan , Gleave Martin , Chi Kim N. , Kollmannsberger Christian K. , Wyatt Alexander William 
Published: March 2017

417 Background: Mediastinal non-seminomas (M-NS) have a poor prognosis compared to non-M-NS germ cell tumours (GCT) (i.e. primary gonadal or mediastinal seminomas (PG-S and M-S) and primary gonadal non-seminoma (PG-NS). M-NS tumors, while having pathological and serological similarity to other nonseminomas, are clinically and biological distinct and are considered IGCCC poor risk. In this study we aimed to evaluate the somatic mutation rate and prevalence of actionable/informative mutations in M-NS compared to M-S and primary GCT to inform consideration of targeted/precision therapy in these patients. Methods: Pre-treatment formalin fixed paraffin embedded specimens were collected from eleven patients with mediastinal and primary GCT patients (4 M-NS, 2 M-S, 3 PG-NS and 2 PG-S). High-density tumor areas were selected for DNA extraction and targeted sequencing of 578 established pan-cancer genes was performed (Roche Nimblegen SeqCaP EZ Comprehensive Cancer Design). Results: Consistent with the known landscape of testicular cancer, we identified five tumors with amplification of chromosome 12p, as well as hotspot mutations in KIT (n = 2) and KRAS (n = 1). Three of the 4 M-NS tumors had a non-synonymous mutation rate > 1 per Mb, which is higher than the primary TGCT and M-S sequenced here (range 0-0.5 per Mb) and the established low mutation rate for TGCT of 0.3-0.9 mutations/Mb. Mutations in TP53 (n = 2) and PTEN (n = 1) were only identified in patients with M-NS. The 2 patients with a TP53 mutation had a high non-synonymous mutation rate (1.3/Mb and 7.3/Mb), extensive metastatic disease with liver metastasis and high tumor markers (β-HCG: 1281 IU/L and α-FPT: 8500 ng/ml) at diagnosis. Both died of their disease and were the only patients in the cohort to have died. Conclusions: This study suggests that M-NS GCTs harbour more somatic alterations than non-M-NS GCTs, potentially underlying their poor prognosis. Our data are consistent with previous reports of an association between TP53 mutations and poor outcomes. Confirmation of our findings could lead to multi-center studies of targeted/precision therapies in patients with M-NS.
Oncologic outcomes of radiation therapy following active surveillance for low- and intermediate-risk localized prostate cancer.
Authors: Ahmad Ardalan , Chua Melvin , Murgic Jure , Raziee Hamid Reza , Hosni Ali , Moraes Fabio Ynoe De , Timilshina Narhari , Bristow Robert G. , Berlin Alejandro , Finelli Antonio 
Published: March 2017

42 Background: To evaluate the oncologic outcomes and potential impact of delayed radical treatment in the form of radiotherapy (RT), in men with localized prostate cancer progressing after active surveillance (AS). Methods: We identified patients on AS subsequently treated with state-of-the-art RT (either dose-escalated image-guided intensity modulated radiotherapy [IG-IMRT] or low-dose-rate brachytherapy [LDR-BT]). Based on the clinical characteristics at time of AS progression, we compared the oncologic outcomes to matched patients treated with upfront RT after diagnose. One to two matching patients per AS case were identified from existing RT databases based on: age (+/- 3 years), clinical prognostic factors (NCCN risk group; PSA +/- 2ng/mL; cT category; primary and secondary Gleason score; percentage of diagnostic cores involved dichotomized at < or > 50%), and treatment modality (IG-IMRT or LDR-BT). We aimed to determine whether patients on AS have potentially compromised outcomes. Results: We identified 215 patients (out of 1070 AS cohort) undergoing RT after a median of 26 months (IQR 16-52.5) on AS. Median follow-up post RT was 4.8 years (IQR 2.9-7.2). No patient died of prostate cancer. At 5-years, the biochemical relapse free-, metastases free- and overall-survival rate were respectively 98.6%, 99.1%, 98.6% in the AS cohort. Matched cohort comprised 400 patients treated with IG-IMRT (71%) or LDR-BT (29%). Adequate matching was confirmed. The median follow-up post RT was 8.2 years (IQR 4.7-10). At 5-years, biochemical relapse free-, metastases free- and overall-survival rates of 98.5%, 98.7%, 93.7% respectively, which were not statistically different compared to those patients treated upon AS progression. Conclusions: Curative-intent radiotherapy (i.e. dose-escalated IG-IMRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Moreover, the delay of therapy after a period of AS does not appear to result in inferior oncologic outcomes compared to patients with similar risk characteristics undergoing upfront radical radiotherapy.
Squamous cell carcinoma of the posterior urethra: Outcomes following radical surgery and adjuvant chemo-radiotherapy.
Authors: Castiglione Fabio , Christodoulidou Michelle , Nigam Raj , Malone Peter , Mitra Anita , Muneer Asif 
Published: March 2017

425 Background: Squamous cell carcinoma (SCC) of the posterior urethra is rare and is associated with sexually transmitted infections, urethritis, chronic strictures or urethral surgery. Unlike anterior urethral SCC, the presentation of posterior urethral SCC is often late and there are currently no standardised treatment protocols. We present our series of posterior urethral SCC treated by radical surgery and bladder preservation by performing a pan-urethrectomy, radical prostatectomy with a bladder neck closure and chemoradiotherapy. Methods: We retrospectively collected data from patients diagnosed with posterior urethral SCC from a penile cancer database. Data including patient age, histological subtypes, surgical management, post-operative complications, chemo-radiotherapy and survival rates were recorded. Results: A total of 10 cases with histologically proven posterior urethral SCC were treated in a single centre. Median follow-up was 19 months (SD±10 months). Mean age at presentation was 49 years (SD±6.44) and usual type SCC (80%) was the most prevalent histological subtype followed by NOS and condylomatous SCC. The majority of cases were poorly differentiated SCC (70%), stage ≥ T3 and required radical surgery with total urethrectomy and radical prostatectomy. Complications included post-operative ileus (30%), wound infection (20%), sepsis (10%), perioperative transfusion was required in one patient. Lymphovascular invasion was present in 90% of cases and local recurrence occurred in 60% of patients. Only one patient was suitable for neo-adjuvant chemo-radiotherapy (cisplatin/5-FU) and a further 5 required adjuvant chemoradiotherapy following surgery. 60% of patients developed metastatic disease and 60% died with a median survival of 9.6 months (SD±5.3) from diagnosis to death. Conclusions: Posterior urethral SCC is rare and the late presentation means that neoadjuvant chemoradiotherapy is often not possible. Radical surgery requires a pan-urethrectomy and urinary diversion. Despite adjuvant chemoradiotherapy, posterior urethral SCC is associated with significant mortality with a median survivial of less than one year.