bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of urothelial carcinoma with seminal vesicle involvement in locally advanced bladder cancer.
Authors: Salami Simpa Samuel , Udager Aaron , Miller Brady Garland , Palapattu Ganesh S. , Tomlins Scott , Chinnaiyan Arul M. , Spratt Daniel Eidelberg , Feng Felix Yi-Chung , Kunju Lakshmi Priya , Wu Angela J. , Morgan Todd Matthew , Weizer Alon Z. , Montgomery Jeffrey Scott , Lee Cheryl T. , Mehra Rohit
Published: February 2017

440

Background: Muscle-invasive bladder cancer is associated with poor clinical outcomes, especially in locally advanced (pT4) disease. There is a paucity of data, however, regarding the clinical impact of seminal vesicle (SV) involvement. Therefore, we sought to characterize clinicopathologic features of patients with urothelial carcinoma involving seminal vesicles, and evaluate clinical outcomes in patients with locally advanced (pT4) bladder cancer with or without SV involvement. Methods: After institutional review board (IRB) approval, we retrospectively identified all men with pT4 (per the 7th edition of the AJCC Cancer Staging Manual) bladder cancer who underwent radical cystectomy between 2002 and 2013 at a single large academic institution. Clinicopathologic and follow-up data for all patients were obtained from the electronic medical record. The presence or absence of divergent differentiation, including aggressive forms (plasmacytoid, nested, micropapillary, and sarcomatoid), was recorded. Estimates of overall survival (OS) were compared by plotting Kaplan-Meier curves and using log-rank test. Results: A total of 62 patients were eligible for analysis. The median age and follow-up duration were 72 (range: 46 – 87) years and 12 (range: 0 – 141) months respectively. SV involvement was present in 17.7% (11/62) of patients. The frequency of divergent differentiation (including aggressive forms), angiolymphatic invasion, nodal disease (pN1-3), and positive soft tissue margins was relatively higher among those with SV involvement (not significant, all p >0.05). The 1 and 2-year OS for patients with SV involvement were 32.7% and 0% respectively, compared with 51.0 % and 24.9% respectively for patients without SV involvement. There was no statistically significant difference between the median OS of men with and without SV involvement (9 vs. 13 months, respectively; p = 0.19). Conclusions: In this relatively limited sample size cohort, we did not observe any difference in the overall survival of locally advanced bladder cancer patients with and without SV involvement.
The expression and clinical significance of PD-L1 in patients with upper tract urothelial carcinoma.
Authors: Sheng Xinan , He Zhisong , Kong Yan , Chi Zhihong , Si Lu , Cui Chuanliang , Tang Bixia , Mao Li Li , Wang Xuan , Lian Bin , Yan Xieqiao , Li Si Ming , Dai Jie , Guo Jun
Published: February 2017

444

Background: Primary upper tract urothelial carcinoma (UTUC) is rare. In China UTUCs are more common than in Western populations and account for 20–30% of all TCCs.An antibody that targets programmed death ligand-1 (PD-L1) pathway has been shown to be active towards various types of cancer including bladder urothelial carcinoma. In this study, we investigated the PD-L1 expression and prognostic significance in UTUC. Methods: Formalin-fixed paraffin-embedded tumor samples from 78 patients with upper tract urothelial carcinoma from Peking University Cancer Hospital and Peking Universiy First Hospital were retrieved. PD-L1 expression was evaluated by immunohistochemistry using rabbit monoclonal anti-PD-L1 antibody. PD-L1 positivity on tumor cell membrane was defined as ≥ 1% of tumor cell membrane staining.The clinical data of patients were retrospective collected. The multivariate analysis was used to assess the association of PD-L1 expressionwith tumor staging, pathological N classification, whether firstly diagnosed with metastasis, disease free survival(DFS) and overall survival (OS) in patients. Results: The positive rates of PD-L1 expression were 42.3% (33/78) for upper tract urothelial carcinoma. Sex,location, pathological tumor staging, pathological N classification, whether firstly diagnosed with metastasis did not correlate with PD-L1 expression. In patients with upper tract UC, PD-L1 expression was not associated with DFS and OS on univariate analyses. Conclusions: To our knowledge, this is first study about PD-L1 expression in UTUC patients. In this study, We found the PD-L1 expression in UTUC was higher than in the bladder urothelial carcinoma. It means anti-PD-L1 treatment may be better for advanced UTUC. There was no correlation between PD-L1 expression and outcome.
Autophagy inhibition (AI) as a novel treatment strategy in bladder cancer (BC).
Authors: Grivas Petros , Visconte Valeria , Day Mark L. , Day Kathleen C. , Liebert Monica , Palmbos Phillip Lee , Tomlins Scott A. , Carew Jennifer
Published: February 2017

449

Background: BC response to chemotherapy has reached a plateau; novel treatment targets are needed. Autophagy is an important protein degradation mechanism that may be involved in chemotherapy response/resistance. AI was shown to overcome drug resistance in preclinical studies, but has not been well studied in BC. We conducted comprehensive gene expression analysis in BC cell lines to define their autophagy pathway expression signatures. We then investigated the anti-tumor activity and pharmacodynamics (PD) of our novel autophagy inhibitor ROC-325 (superior to hydroxychloroquine) in preclinical BC models with high baseline autophagy levels. Methods: Baseline expression of autophagy-related genes was evaluated by RNASeq in 21 BC cell lines. Gene and protein expression of selected autophagy-related genes was confirmed by qRT-PCR and immunoblot. PD effects of ROC-325 on lysosomal protease cathepsin D (CTSD) were assessed in 2 selected BC cell lines: UM-UC-3 (mesenchymal), UM-UC-6 (epithelial). The ability of ROC-325 (72 hour treatment) to augment gemcitabine (G) and cisplatin (C) activity in the 2 cell lines was evaluated by MTT assay and combination index analyses, t- test with 2-sided comparison was used, experiments were in triplicate. Results: RNASeq showed significant heterogeneity in baseline expression of early and late autophagy-related genes among BC cell lines; elevated expression of multiple autophagy-related genes was a prevalent phenomenon. CTSD level was elevated in multiple cell lines. PD analysis showed dose-dependent increase of CTSD expression in UM-UC-3 cells after ROC-325 (1-10uM) treatment correlating with reduced cell viability. The activity of G and C was greater in UM-UC-6 vs UM-UC-3 cells. Both cell lines were sensitive to ROC-325. The addition of ROC-325 to G or C yielded additive benefit in both cell lines. In UM-UC-6, ROC-325 addition significantly increased the activity of GC combination vs GC alone (p = 0.0049). Conclusions: AI merits further investigation as new treatment strategy in BC. Evaluation of in vitro and in vivo efficacy/safety of ROC-325 with/without other agents, and assessment of putative predictive biomarkers is being pursued in BC models with genomic and transcriptomic annotation.
Urachal versus nonurachal adenocarcinomas of the bladder: A population-based report.
Authors: Sun Maxine , de Velasco Guillermo , Meyer Christian P , Bellmunt Joaquim , Nguyen Paul L. , Trinh Quoc-Dien , Choueiri Toni K.
Published: February 2017

450

Background: Previous studies are inconclusive on whether urachal vs. non-urachal adenocarcinomas of the urinary bladder have different prognoses. Our objective was to assess survival differences between urachal vs. non-urachal adenocarcinomas in light of evolving treatment strategies over the past years. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with a diagnosis of adenocarcinoma of the urinary bladder between years 1988 and 2012. The variable of interest was urachal vs. non-urachal adenocarcinomas. Kaplan-Meier curves and log-rank tests were performed to assess the univariable effect of urachal vs. non-urachal adenocarcinomas on survival. Multivariable Cox regression analyses were performed for prediction of cancer-specific mortality (CSM) and overall mortality. Sub-analyses comprised of competing-risks regression models. Results: Overall, 2345 (89%) and 301 (11%) non-urachal and urachal adenocarcinoma patients were identified, respectively. The 5-year CSM-free survival rates for urachal vs. non-urachal adenocarcinomas were 63% vs. 50% (P< 0.001). For the same groups, the 5-year overall survival rates were 50% vs. 32%, respectively (P< 0.001). In multivariable Cox regression analyses, no difference was recorded between urachal vs. non-urachal adenocarcinomas for CSM (hazard ratio [HR]: 0.86, P= 0.2) or any mortality (HR: 0.84, P= 0.07). Important prognosticators of CSM and survival were surgery, lymph node dissection, disease stage and grade. Conclusions: No survival difference was recorded in the current study between urachal vs. non-urachal adenocarcinoma of the bladder. However, surgery and lymph node dissection constitute important factors for both tumor types.
Renal function in bladder cancer patients after trimodality therapy: Long-term results of a large institutional experience.
Authors: Roberts Hannah J. , Drumm Michael , Niemierko Andrzej , Goldberg Saveli , Clayman Rebecca Helen , Heney Niall M. , Feldman Adam S. , Wszolek Matthew F , Michaelson M Dror , Lee Richard J. , Saylor Philip James , Zietman Anthony L. , Shipley William U. , Efstathiou Jason A.
Published: February 2017

453

Background: Maintenance of renal function following treatment of bladder cancer presents an ongoing challenge. The decline following radical cystectomy is well documented. However, in patients undergoing trimodality bladder-sparing therapy consisting of transurethral resection (TURBT) and concurrent chemoradiation followed by adjuvant chemotherapy, renal function is poorly understood. Methods: We performed a retrospective review of 178 patients with muscle-invasive bladder cancer who underwent bladder-sparing therapy between 2001 and 2013 and collected nadir creatinine values in the month preceding TURBT and at 1, 3, 5, 7, and 9 years post treatment initiation. Wilcoxon signed-rank test and mixed effects analysis were performed to compare the pre-treatment and post-treatment levels of creatinine and EGFR and to analyze their temporal change. Results: Median follow-up was 48 months (range: 1 to 162 months). The mean pre-treatment creatinine and EGFR were 1.12 mg/dl and 71 mg/dl, respectively. Cr increased to 1.21 mg/dl and EGFR decreased to 65 mg/dl at 1 year following treatment initiation (p = 0.001, p = 0.002). All post-treatment values were also significantly different from pre-treatment values (all p values < 0.002), but there was no significant difference between the post-treatment values over time. Conclusions: Following bladder-sparing therapy for muscle invasive bladder cancer, renal function was generally well preserved in the long term. Although there was a modest yet statistically significant decrease in renal function that occurred during the first year, there was no further decline up to 9 years. While this initial decrease in function is of unknown clinical significance, the lack of further decline after 1 year is different from similar studies following cystectomy.
Amplification of chromosome 3q21-25 in urothelial carcinoma with squamous differentiation.
Authors: Sanford Thomas , Meng Maxwell V. , Porten Sima P.
Published: February 2017

457

Background: Squamous differentiation is found in up to 60% of patients with urothelial carcinoma of the bladder. There is conflicting evidence regarding clinical relevance of aberrant urothelial differentiation as both population-based and retrospective studies have supported and refuted its correlation with poor prognosis and advanced stage in multivariate models. The biology of these tumors is poorly understood but some suggest that extensive squamous differentiation may resemble pure squamous tumors with similar responses to chemotherapy, radiation, and higher rate of local recurrence. Our aim was to compare tumors with squamous differentiation with those of pure urothelial histology at the genomic level to better elucidate targetable differences. Methods: We reviewed pathology reports for 412 patients with urothelial carcinoma from TCGA to identify patients with any amount squamous differentiation. Copy number alteration data obtained via the GISTC algorithm was downloaded from cbioportal.com. Chi square analysis was used to compare chromosomal amplifications in samples with squamous differentiation compared with samples that had no amount of variant histology. Results: 50 patients (12%) had some squamous differentiation, of which 15 commented on the percent of involvement – on average, 17% of the sample had squamous differentiation. A total of 257 (62%) of patients had no variant histology. Multiple specific sites in the 3q21-26 chromosomal region were noted to be amplified in squamous histology compared with pure urothelial carcinoma. Specific genes found to be amplified included SOX2 and PIK3. Conclusions: Amplifications of chromosome 3q21-25 were enriched in patients with squamous differentiation compared to those with pure urothelial carcinoma of the bladder. Amplification of this region has been reported in squamous transformation in multiple sites, including lung cancer. This study shows that, similar to other cancers, SOX2 may be necessary for squamous transformation. Furthermore, squamous cancer, which has traditionally though to be chemo-resistant, may respond to agents that target amplifications of genes found on the long arm of chromosome 3 including the PIK3-Akt pathway.
Characterization of mutational load in patients with advanced urothelial cancer.
Authors: Pal Sumanta K. , Ali Siraj Mahamed , Ennis Riley , Elvin Julia Andrea , Vergilio JoAnn , Suh James , Yelensky Roman , Ross Jeffrey S. , Miller Vincent A. , Joshi Monika , Choueiri Toni K. , Stephens Philip J. , Frampton Garrett Michael
Published: February 2017

460

Background: The efficacy of novel immunotherapeutic agents (e.g., PD-1/PD-L1 and CTLA4 inhibitors) in advanced cancer is linked to tumor mutational load. We assessed mutational load via comprehensive genomic profiling (CGP) performed in the course of clinical care for patients with advanced urothelial cancer (UC). Methods: DNA was extracted from 40 microns of FFPE sections from 760 consecutive patients with relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for at least 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Mutational load was characterized as the number of such SUBs or INDELs per megabase (Mb) after filtering to remove known somatic and deleterious mutations, given that these are selected for with hybrid capture. Results: The median age of the patients was 66 years old with a 3:1 male:female ratio. Mean mutations per megabase were assessed as a range of 0 to 79, and the 25th, median, and 75th quartile thresholds were 3.2, 5.5, and 8.8. MSH6 alterations in 0.8% cases had a median of 15.2 mutations per megabase. However, the ten most frequently altered genes in this series- TERT (64%), TP53 (54%), CDKN2A (35%), CDKN2B (28%), KDM6A (24%), ARID1A (23%), MLL2 (22%), PIK3CA (21%), RB1 (21%) and FGFR3 (19%) - were not associated with differences in mutational load. Conclusions: A highly variable mutational load was seen in patients with advanced UC. A subpopulation of MSH6-altered UC had very high mutational loads relative to other UCs. Further correlation to clinical outcomes will be investigated to assess the correlation between mutational load and response to immunotherapy.
Latent class analysis of bladder urothelial carcinoma to reveal sub-classes defined by alterations to chromatin and signal transduction networks.
Authors: Fichtenholtz Alex , Khan Alyna , Ross Jeffrey S. , Ali Siraj Mahamed , Miller Vincent A. , Stephens Philip J , Neumann Eric
Published: February 2017

469

Background: 70,000 new cases of bladder urothelial carcinoma are diagnosed in the United States each year. Previous studies of this disease suggest two divergent pathways of carcinogenesis, with ~70% of cases being driven by alterations in signal transduction pathways (FGFR3, HRAS) and the remainder featuring alterations in cell cycle genes (TP53, RB1). Other studies focus on the high prevalence of alterations in chromatin remodeling genes (ARID1A, CREBBP, EP300) in this tumor type. The relationship between chromatin modifier alterations and the two bladder TCC sub-classes is not yet understood. Methods: Comprehensive genomic profiling (CGP) on 638 clinically confirmed cases of advanced bladder urothelial carcinoma was performed using the FoundationOne platform. The coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer were sequenced and analyzed for base substitutions, insertions, deletions, copy number alterations and select gene fusions. The resultant alteration profiles were analyzed for their information content with an entropy-based approach and the profiles were subjected to hierarchical latent class analysis (LCA). Results: CGP of 488 male and 150 female UCs of median age 66 (min: 29, max: 87) resulted in 3241 detected alterations across 302 unique genes, for a mean of ~5.1 known or likely somatic alterations per sample. The most commonly altered genes were TP53, CDKN2A/B, ARID1A, KDM6A, and MLL2. Information was concentrated in the 33 most frequently altered genes. Multiple high level clusters were defined by combinatorial patterns of alterations in TP53, CDKN2A/B, RB1, and FGFR3. Sub-classes were defined by mutually exclusive alterations in the chromatin modifiers KDM6A, MLL2, and ARID1A. Conclusions: We present a global picture of UC sub-classes that encompasses previously identified local relationships including the mutual exclusivities between FGFR3 and TP53, RB1 and CDKN2A/B, and KDM6A and MLL2. In the context of clinically relevant genomic alterations that auger response to targeted therapies, identification of sub-classes of UC may further delineate response to therapy.
Conditional survival of patients with metastatic testicular germ-cell tumors (MT-GCT) treated with first-line curative therapy.
Authors: Ko Jenny J. , Bernard Brandon David , Tran Ben , Li Haocheng , Asif Tehmina , Stukalin Igor , Lee Margaret , Day Daphne , Alimohamed Nimira S. , Sweeney Christopher , Bedard Philippe L. , Heng Daniel Yick Chin
Published: February 2017

472

Background: The IGCCCG risk stratification prognosticates survival outcomes in metastatic testicular germ cell tumour (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment (conditional survival) is unknown. We evaluated conditional survival in patients with MT-GCT who were eligible for first-line therapy. Methods: We included patients who were eligible for first-line therapy for MT- GCT at 5 tertiary cancer centres from 1990 to 2012. We assessed 2-year (Y) conditional overall (COS) and disease-free survival (CDFS) at a given timepoint, defined as the probability of surviving, or surviving and disease-free, respectively, for an additional 2Y at a given timepoint since the start of first-line treatment. Outcomes were stratified by IGCCCG risk criteria, pathology and age. Results: For all patients (n = 942, favourable 63%/intermediate 19%/poor 16%), median follow-up was 99 months (m) (IQR 56-141); 2YCOS increased from 92% (95% CI 91%–94%) at baseline to 98% (95% CI 97%–99%) at 24m, and 2Y CDFS increased from 83% (95% CI: 81%-86%) at baseline to 98% (95% CI 97%-99%) at 24m after diagnosis. 2YCOS changed little in the IGCCCG favourable and intermediate groups, but in the poor-risk group, improved from 71% (95% CI 64%–78%) at 0m to 93% (95% CI 89%-98%) at 24m. 2Y CDFS for favourable risk group improved significantly at 12m (91% baseline vs. 95% at 18m); intermediate, at 12m (84% baseline vs. 95% at 12m); poor, at 12 m (55% baseline vs. 85% at 12m). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to > 2Y post therapy. No significant differences in COS and CDFS were noted between seminoma and non-seminoma, while older patients ( > = 40) had inferior 2Y COS from 0-18m but no differences were noted after 18m. Conclusions: Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. A poor-risk patient, after 2Y of survival, had the same probability of relapse and survival as a favourable/intermediate risk patient.
Cyclin-dependent kinase 4/6 inhibition for the treatment of mature teratoma germ cell tumor: Long-term follow-up of a phase II study.
Authors: Narayan Vivek , Hwang Wei-Ting , Lal Priti , Rosen Mark Alan , Gallagher Maryann , O'Dwyer Peter J. , Vaughn David J.
Published: February 2017

474

Background: We have previously reported the results of a phase II clinical trial evaluating the safety and efficacy of palbociclib for the treatment of patients with unresectable germ cell tumors, including mature teratoma, teratoma with malignant transformation, and non-teratomatous tumors. In an effort to better assess the efficacy of palbociclib, we now report long-term follow-up of a more homogeneous population of patients with unresectable mature teratoma treated on the phase II clinical trial, with an emphasis on clinically-relevant endpoints for this incurable patient population. Methods: This was a retrospective analysis with long-term follow-up of the patient cohort with mature teratoma treated on the phase II study of palbociclib for the treatment of retinoblastoma protein-expressing germ cell tumors. Patient clinical data was obtained from the medical records and from communication with the enrolled patients and referring medical providers. Major medical events for the treatment of germ cell tumor, including before, during, and after study treatment, were recorded. Clinical events of interest included the initiation of systemic therapy, radiation therapy, surgical debulking, or other invasive procedures. Study endpoints included pre-study and post-study clinical event rates, event-free survival, and radiographic progression-free survival. Results: Long-term follow-up was obtained for 12 patients with mature teratoma. The median pre-study follow-up time was 19.7 months, and the median post-study follow-up time was 38.0 months. The median number of palbociclib treatment cycles was 11. The pre-study clinical event rate was 2.27 events/year (95% CI 1.66 – 3.13), and the post-study event rate was 0.62 events/year (95% CI 0.36 – 1.09). The median progression-free survival was 5.3 months (95% CI 1.8 – 22.6), and the median event-free survival was 16.2 months (95% CI 3.0 – 24.3). Conclusions: The initiation of palbociclib resulted in a clinically-meaningful delay in disease-related major clinical events and radiographic progression. These findings lend further support to the therapeutic activity of CDK4/6 inhibition in this incurable patient population.
Quantifying decreased radiation exposure from modern CT scan surveillance programs of germ cell tumors.
Authors: Howard Stephanie Anne Holler , Rosenthal Michael , Qin Lei , Bernard Brandon David , Beard Clair , Sweeney Christopher
Published: February 2017

478

Background: Active surveillance (AS) is increasingly used to manage clinical stage I testicular cancer (CS1TC,) but has the risk of radiation exposure from CT scans. Modern CT scanners with iterative reconstruction techniques (IRT) produce equivalent image quality with less radiation dose compared with traditional filtered back projection (FBP). Data examining timing of CS1TC relapses on AS have suggested it is safe to decrease CT scanning of abdomen and pelvis from the NCCN 2009 guideline of approximately 16 scans over 5 years to 7 scans. We examine the impact of the CT upgrade and decreased scans on radiation dose and associated risks. Methods: This IRB-approved study enrolled 24 CS1TC patients who had CT scans on the same Toshiba Aquilion 64 CT before and after IRT software installation. Dose-length product and CT dose index volume were recorded. A medical physicist calculated effective doses. Radiation doses were compared using the Wilcoxon signed rank test. Median effective dose per scan was multiplied by scan number based on 16 and 7 scan 5 year AS protocols to calculate an estimated cumulative dose (ECD). Lifetime attributable risk (LAR) of dying of a radiation-associated solid tumor was estimated for a single exposure at age 35 using the excess absolute risk transport model from the Biological Effects of Ionizing Radiation VII analysis of long-term atomic bomb survivors. Results: Median pre and post upgrade doses were 12.5 mSv and 7.7 mSv respectively (p < 0.0001). A linear regression model with a constrained zero intercept fit to the data found that IRT dose was best estimated as 61% of FBP dose (95% CI 0.56 – 0.66). Table 1 lists ECD and LAR data for both AS regimens pre and post upgrade. Conclusions: IRT, as part of an integrated approach to optimize patient outcome, should reduce CT-related risks by about 39%. This reduction, combined with the scan reduction of newer AS regimens, further significantly lowers the already small potential mortality of imaging associated cancers. [Table: see text]
Impact of bleomycin (BLM) administration on the development of pulmonary toxicity in advanced germ cell tumors (GCT) receiving first-line chemotherapy (CT): A meta-analysis of randomized studies.
Authors: Oualla Karima , Miceli Rosalba , Sonpavde Guru , Nicolai Nicola , Raggi Daniele , Giannatempo Patrizia , Boffi Roberto , Busia Alessandra , Mariani Luigi , Salvioni Roberto , Necchi Andrea
Published: February 2017

482

Background: Little is known about the impact of BLM administration on the development of pulmonary toxicity (PT) in patients (pts) with advanced GCT. This information is critical to further enhance the successful delivery of effective and safe CT in these pts. Methods: Literature was searched for randomized trials of 1st-line CT ( ≥ 3 cycles) for GCT. Descriptive statistics were used to summarize data, dichotomized by BLM-containing vs non containing CT. Univariable and multivariable analyses by random effect models evaluated the predictive role of BLM administration on the development of all grade and G3-4 PT, adjusted for the length of follow-up (FUP, continuous), time-frame of treatment ( ≤ 1997 versus > 1997) % of pts with lung metastases (LM), % of primary mediastinal GCT (PMGCT), IGCCCG risk group. Results: 53 arms of 26 phase II and III trials totalling 6,498 pts were selected: 40 with BLM (n = 5,093) and 13 without BLM (n = 1,405). Median % of pts with LM was 44% (range 22-84%) and 31% (19-79%) in BLM-containing and non containing arms (Wilcoxon test p = 0.505). Median % of PMGCT was 15% (range 0-48%) and 2% (0-13%), respectively (p = 0.146). Median BLM total dose and No. of administrations were 360mg (range 120-375) and 12 (2-24). Median FUP was 52 and 53 months, respectively. The pooled probability of all grade PT was 11.7% (95% CI: 8.4-16.0%) and 1.7% (95% CI: 0.7-4.2%) in BLM-containing and non containing arms. Univariably, BLM administration was associated with the incidence of both all grade (odds ratio [OR]: 7.57, 95%CI: 2.84-20.18, Wald test p < 0.001) and G3-4 PT (OR: 5.19, 95%CI: 1.57-17.16, p = 0.007). Multivariably, BLM administration was significantly associated with the incidence of all grade PT (OR: 4.14, 95%CI: 1.36-12.59, p = 0.012) and trended to significance for G3-4 toxicity (OR: 2.24, 95%CI: 0.91-5.51, p = 0.080). Conclusions: In this meta-analysis, BLM administration was significantly associated with the development of PT in pts with GCT. The quantification of the magnitude of incidence of PT provided here might be useful to optimize the delivery of non-PEB CT in the 1st-line setting.
Pan-HER tyrosine-kinase inhibitors (TKI) dacomitinib and afatinib in penile squamous cell carcinoma (PSCC): Results from an ongoing open-label, single-group, phase 2 trial of dacomitinib in chemonaive patients (pts).
Authors: Raggi Daniele , Necchi Andrea , Giannatempo Patrizia , Nicolai Nicola , Colecchia Maurizio , Calareso Giuseppina , Togliardi Elena , Crippa Flavio , Mariani Luigi , Perrone Federica , Pelosi Giuseppe , Salvioni Roberto , Sonpavde Guru
Published: February 2017

483

Background: Prognosis of pts with advanced/metastatic PSCC is poor and chemotherapy exerts a low efficacy. Targeting HER pathway is rational and promising in PSCC. Two companion trials are enrolling in the 1st-line/neoadjuvant setting (Dacomitinib, NCT01728233) and salvage setting (Afatinib, NCT02541903). Here we present the ongoing results of the former study. Dacomitinib is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: 37 pts with clinical N2-3 or M1 disease receive oral Dacomitinib 45 mg daily until surgery or disease progression (PD)/unacceptable toxicity. No prior systemic therapy is allowed. Computed tomography and PET scan are repeated q2 months. Simon’s Optimal 2-stage design is applied. The primary endpoint is the objective response-rate (ORR = CR/PR according to RECIST v1.1: H0 ≤ 5%, H1 ≥ 20%, α and β = 10%). Next generation sequencing (NGS) with “Hot-spot cancer panel” (Ion Torrent, Life Technologies) is being performed for all enrolled pts. Results: From 06/13 to 05/15, 14 pts were treated. Median age was 57 yrs (IQR: 54-72). 4 had received inguinal/pelvic lymphadenectomy, 4 had inguinal+pelvic nodes, 10 bilateral disease, and 4 distant mets. Two pts achieved a PR (ORR: 14.3%), 8 a SD, 4 a PD. 8 pts (57.1%) had a metabolic PR. 9 pts underwent post-Dacomitinib lymphadenectomy: > 90% necrosis was seen in one patient. After a median follow-up of 6.97 months, 6 pts (42.8%) were progression-free (median PFS was 4.47 months). Median OS was 11.9 months, 1-year OS was 50% (95%CI: 8.05-82.63). Skin toxicity was observed in 7 pts (6 G1, 1 G3), G2 diarrhea in two, and bleeding of cutaneous mets in one. Tissue from one PR pt harbored missense mutations in FBXW7 (R505S), PTEN (A3T), and TP53 (R273H, loss of function mutation) genes. Conclusions: Dacomitinib is endowed with antitumor activity in PSCC. Results are pending confirmation in the whole sample size. Dacomitinib and Afatinib trials will provide insights into the targeting of HER pathway in PSCC based on prior chemotherapy administration. Preliminary data on molecular alterations linked to clinical benefit are being observed. Clinical trial information: NCT01728233.
Programmed death-ligand 1 (PD-L1) expression in cured and not cured testicular and other germ cell tumors (GCT).
Authors: Bernard Brandon David , Albiges Laurence , Signoretti Sabina , Novak Jesse , Hirsch Michelle S. , Massard Christophe , Loriot Yohann , Fadel Elie , Chartier Suzanne , de Montpreville Vincent , Fizazi Karim , Sweeney Christopher , Adam Julien
Published: February 2017

485

Background: PD-L1 is involved in immune regulation and is prognostic in many tumor types. The aim of this study was to assess PD-L1 expression in orchiectomy and metastases (mets) from GCT and to assess for an association with outcome. Methods: Immunohistochemistry (IHC) on whole sections from archival formalin-fixed paraffin-embedded tissue from Dana-Farber Cancer Institute (DFCI) and Gustave Roussy (IGR) was performed using anti-PD-L1 antibody E1L3N. Stained slides were scored semi-quantitatively and assessed independently. At DFCI, PD-L1 was scored as percent of positive tumor cells (TC) and extent of positive immune cell (IC) infiltrate; at IGR, a cut-off of 5% defined positive TC and IC. PD-L1 status was assessed by site, histology and chemotherapy (CT) status. PD-L1 status was correlated with clinical outcome. Most samples at DFCI were pre-CT (74.2%) whereas most at IGR were post-CT (85.4%). Results: IHC from 171 patients with GCT (89 DFCI, 82 IGR) from 1987-2014 was reviewed. The DFCI cohort included 69 orchiectomy, 15 mets and 5 unknown origin with 28 total deaths; the IGR cohort included 26 lung mets, 36 mediastinal or retroperitoneal lymph node mets and 20 primary mediastinal tumors. DFCI had 38 seminoma (S), 50 nonseminoma (NS) and 1 unknown; at IGR, 13 S and 69 NS. In both cohorts, PD-L1 staining in IC was higher in S (DFCI 33/38 moderate (mod)-high (86.8%); IGR 12/13 positive (92.3%)) vs. NS (DFCI 26/50 mod-high (52.0%); IGR 35/68 positive (51.5%)) (DFCI p = 0.003; IGR p = 0.006). At DFCI, 5 samples had PD-L1 positive TC (2 mixed GCT, 2 pure choriocarcinomas (CC) and 1 S); at IGR, 14 had positive TC (all NS, including 11 pure CC). More PD-L1 positive TC were CC than other GCT types (DFCI p = 0.003; IGR p < 0.001). In 36 S orchiectomy samples at DFCI, 0/4 that scored none-mild died and 2/31 (6.5%) that scored mod-high died (p = 1.00); in 30 NS orchiectomy samples, 4/9 (44.4%) that scored none-mild died and 2/16 (12.5%) that scored mod-high died (p = 0.14). Conclusions: Higher PD-L1 status in orchiectomy is not associated with GCT survival. PD-L1 positive TC may serve as a histological marker for CC among NS. Higher PD-L1 expression on IC in S and on TC in CC may point to immunotherapy as a therapeutic option in these tumors.
Role of cytoreductive nephrectomy in renal cell cancer (RCC) with venous tumor thrombus.
Authors: Abel Edwin Jason , Zargar Kamran , Margulis Vitaly , Mann Michael , Spiess Philippe E. , Ashouri Kenan , Borregales Leonardo Daniel , Haddad Ahmed , Rew Charles , Chen Gong , Shi Fangfang , Matin Surena F. , Wood Christopher G. , Karam Jose A.
Published: February 2017

496

Background: RCC with tumor thrombus may require complex surgery to remove the primary tumor. Some patients with tumor venous thrombus and metastatic RCC are unlikely to benefit from cytoreductive nephrectomy. The purpose of this study was to identify risk factors for poor overall survival in metastatic RCC patients with tumor thrombus. Methods: Patient data was collected from 4 centers for patients with mRCC and venous thrombus at presentation treated surgically from 2000-2014. Kaplan Meier analysis was used to estimate OS using two prognostic classification systems (MSKCC, IMDC) assessed at time of surgery. MDACC criteria (Cancer 2010) were calculated to estimate potential benefit from cytoreductive nephrectomy. Univariate and multivariate Cox proportional hazard models were used to evaluate the association of individual variables with OS. Results: A total of 293 patients were evaluated and median OS (IQR) was 17.2 (6.4-41.0) months for the entire cohort. Venous thrombus level (Neves classification) was 0,1,2,3, and 4 for 77, 38, 104, 45, and 29 patients respectively. Median OS (IQR) was worse (p = 0.03) for patients with IVC thrombus above the diaphragm 6.8 (2.2-19.1) months compared to renal vein only thrombus 18.8(8.1-37.8) months or IVC thrombus below the diaphragm 18.9 (6.7-44.5) months. Using MSKCC criteria, patients were classified as favorable (21), intermediate (213) or poor risk (59). MSKCC risk grouping was not predictive of OS (p = 0.14). Using IMDC criteria, patients were classified as favorable (24), intermediate (176) or poor risk (93). IMDC risk grouping was not predictive of OS (p = 0.99). Using MDACC criteria, patients were divided into favorable (258) and unfavorable (35) groups. Median OS was higher (p = 0.008) in favorable risk patients, 18.8 (7.2-43.7) vs. 8.2 (2.3-28.2) months. Preoperative variables that were independent predictors of OS included: body mass index, IVC thrombus above diaphragm, lactate dehydrogenase > ULN, and retroperitoneal lymphadenopathy. Conclusions: Metastatic RCC patients with IVC thrombus above the diaphragm or patients classified as unfavorable using MDACC criteria have poor OS and may not benefit from cytoreductive nephrectomy in the presence of venous tumor thrombus.
Predicting adherent perinephric fat with preoperative clinical and radiological factors in partial nephrectomy: Development and validation of a risk score.
Authors: Borregales Leonardo Daniel , Adibi Mehrad , Thomas Arun Z. , Reis Rodolfo B. , Chery Lisly J , Devine Catherine E , Wang Xuemei , Potretzke Aaron M. , Potretzke Theodora , Figenshau Robert S. , Bauman Tyler M. , Matin Surena F. , Karam Jose A. , Wood Christopher G.
Published: February 2017

497

Background: The decision to perform a partial nephrectomy (PN) relies largely upon the complexity of the renal mass and its surrounding anatomy. An often encountered intraoperative challenge in PN is the adherent perinephric fat (APF). The anticipation of this feature may improve preoperative risk assessment and aid in decision-making for the surgical approach. We sought to develop and externally validate a score that predicts for APF based on preoperative clinical and radiological prognostic factors. Methods: We retrospectively analyzed 495 consecutive patients that underwent open or minimally invasive PN. APF was defined as the presence of “dense”, “adherent”, or “sticky” perinephric fat at time of dissection by the surgeon and this did not required subcapsular dissection for tumor isolation. A score model was developed using multivariate logistic regression analysis. This score was further validated using an external data set with 285 patients. Discrimination and calibration were assessed by calculating the area under the receiver operating characteristic curve (AUC) and the Hosmer–Lemeshow statistic, respectively. Results: Among the 495 patients, 95 (19%) patients presented with APF. On multivariate analyses, diabetes mellitus (p = 0.009), perinephric fat thickness (p < 0.001) and perinephric stranding (p < 0.001) were predictors of encountering APF in PN. A risk score ranging from 0 to 4, was developed based on these three variables to predict for APF. Among the 285 patients in the validation cohort, 41(14.3%) presented with APF. The score demonstrated good discrimination of 0.82 and 0.84 for the development and validation cohort, respectively. The model did not show a statistically significant lack of calibration (p-values = 0.98, 0.35). Moreover, predicted probabilities of APF based on a 0.5 threshold yielded a specificity of 92.3 and 92.2 in the development and validation cohorts, respectively. Conclusions: The score can accurately predict the presence of APF in patients with small renal mass planning to undergo PN. This score could aid current algorithms of preoperative risk assessment and impact surgical approach.
Trough blood levels of sunitinib for Asian (Japanese) patients with metastatic renal cell carcinoma and therapeutic drug monitoring.
Authors: Kawasaki Yoshihide , Takasaki Shinnya , Ito Akihiro , Mitsuzuka Koji , Yamashita Shinichi , Kawamorita Naoki , Izumi Hideaki , Adachi Hisanobu , Kaiho Yasuhiro , Tanaka Masaki , Kikuchi Masafumi , Yamaguchi Hiroaki , Mano Nariyasu , Arai Yoichi
Published: February 2017

508

Background: The optimal blood concentration of total Sunitinib (SU) (SU + its active metabolite) is reportedly 50-100 ng/ml at trough levels according to the product literature. This is, however, based on models optimally calculated for Caucasians; hence, the desirable blood concentration for Asian patients, including Japanese, is unclear. We examined trough SU levels in Japanese patients with metastatic renal cell carcinomas (mRCC), to determine the preferred concentration of total SU and its doses. We also evaluated the efficacy and dependability of therapeutic drug monitoring (TDM) through the duration of therapy. Methods: Patients with mRCC scheduled for targeted therapy were prospectively recruited between November 2011 and August 2015. TDM of trough levels for patients treated with SU was performed on a regular basis. For this, blood samples were obtained immediately before administering SU on day 8 and day 15 after the initial administration day. Pre-therapeutic characteristics and post-therapeutic outcomes were evaluated. Relationships between pre-therapeutic characteristics, the dose of SU administered, adverse events (AEs) and total SU concentration at trough levels were determined. Results: Twenty of a total of 31 eligible patients were analyzed. Median patient age was 64 years (52-82), median BMI was 23.58 kg/m2 (17.7-32.78), and the average duration of SU therapy was 5 months (1-40). Seventeen patients were treated with SU as first-line therapy and 3 patients as second-line therapy after interferons. Patients with trough SU levels of over 80 ng/ml following the first course needed to discontinue SU due to AEs. All of the patients who obtained long-term stable disease (SD) or partial response (PR) without any AE > grade 2 were those with trough SU levels of 40-60 ng/ml. Conclusions: Our study suggests that trough total SU levels of 50-100 ng/ml are too high for Japanese people. And 40-80 ng/ml seems to be the preferable trough blood concentration of total SU after the first course of SU therapy in Japanese patients. TDM appears to be effective for the management of patients, to obtain optimal benefits of SU without AEs during therapy.
Epidemiological trends in metastatic renal cell carcinoma in the era of targeted therapies: An analysis of the SEER registry.
Authors: Rao Arpit , Wiggins Charles , Lauer Richard C.
Published: February 2017

516

Background: Clear cell RCC (ccRCC) accounts for 70-75% of all kidney and renal pelvis cancers with approximately 16% of patients presenting with distant (metastatic) disease. Five year overall survival (OS) remains dismal at 11.2% for patients with distant disease. Several tyrosine kinase inhibitors (TKI) were approved by US Food and Drug Administration for use in metastatic RCC between 2005 and 2012. While these therapies have been shown to improve outcomes in metastatic ccRCC, the long term impact remains unknown. Methods: The Surveillance, Epidemiology and End-Results (SEER) database was queried for patients aged 18 years and older diagnosed with distant stage (metastatic) ccRCC between 2001 and 2012 in the nine core SEER registries. Analyses were restricted to histologically confirmed cases. Study period was divided into 3-year intervals: 2001-03 (pre-TKI era); 2004-06 (TKI trials era); 2007-09 (early TKI era); and 2010-12 (sequential TKI era). Patients were stratified by age at diagnosis: 18-60 years, 60-69 years, and 70+ years. One, two, and three year, and median cause-specific survival were calculated by Kaplan-Meier method. Differences in cause-specific survival by time period were assessed with the Log-Rank test. Results: A total of 3,747 eligible patients were included in the analysis. For all ages combined, cause-specific survival at three years post-diagnosis was 18.8% for those diagnosed during the period 2001-03 (median 8 months), 22.7% in 2004-06 (median 10 months), 23.2% in 2007-09 (median 9 months), and 28.9% in 2010-12 (median 11.0 months) (p= 0.0004). No statistically significant improvement in survival was observed in patients aged 70 years and above (p= 0.1302). Conclusions: Our analysis quantifies the improvement in survival outcomes in metastatic ccRCC that correlate with TKI use in this setting. While there is evidence that all age groups may have benefitted from these therapies, the impact is least pronounced in patients aged 70 years and above. A SEER-Medicare analysis is planned to evaluate disparities in TKI use in this age group.
Comparing surgical tissue versus biopsy tissue in the development of a clear cell renal cell carcinoma xenograft model.
Authors: Dong Yiyu , Manley Brandon , Hakimi A. Ari , Coleman Jonathan A. , Russo Paul , Hsieh James
Published: February 2017

519

Background: The use of xenograft tumor models is considered the ideal platform to investigate the effects and toxicities of novel drugs in primary human tumors. The establishment of a personalized xenograft model using preoperative or pretherapy biopsy for patients with metastatic or high risk disease could improve selection of targeted therapy. We report on our xenograft model using various tissue sources including biopsies and correlation with patient’s clinical features. Methods: 56 specimens from primary and metastatic ccRCC from 48 patients were collected. After surgery (n=35) or biopsy (n=21) the specimen was transplanted either subcutaneously or after cell culture to immunodeficient mice. Tumor engraftment was followed for up to 4 months. Successfully engrafted patient-derived tumors were passaged to further mice. Conformation of xenograft tumors with formalin-fixed, paraffin-embedded and Hematoxylin and eosin stained tumor sections was done to assure morphological concordance with the patients tumor. We used a two-tailed two proportion z-test to compare the number of successful xenografts harvested from surgical tissue or biopsy tissue. Results: Overall 25 of the 56 specimens were successful in growing tumor in our immunodeficient mice. The frequency of success based on the type and site of tissue harvest may be seen in Table 1. We found biopsy tissue to be significantly more successful compared to surgical tissue, 61.9% compared to 34.2% (p-value=0.044). Conclusions: We believe our xenograft model, using biopsy tissue, demonstrates the feasibility of a real time personalized in vivo model to aid in the selection of targeted treatments for systemic therapy in ccRCC patients. [Table: see text]
Brachytherapy boost and cancer-specific mortality in favorable high-risk and other high-risk prostate cancer.
Authors: Muralidhar Vinayak , Xiang MIchael H. , Orio Peter F. , Martin Neil E. , Beard Clair , Feng Felix Yi-Chung , Hoffman Karen E. , Nguyen Paul L.
Published: February 2017

52

Background: A randomized trial has recently reported improved 5-year biochemical recurrence-free survival with brachytherapy (BT) boost compared with external beam radiation therapy (EBRT) boost in intermediate- to high-risk prostate cancer. Recent retrospective data suggest that BT boost may also confer a cancer-specific survival benefit in the high-risk subgroup. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4+4 = 8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL). Methods: We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with EBRT or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT+BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results: BT boost was not associated with an improvement in 5-year PCSM compared with EBRT alone among patients with favorable high-risk disease (1.6% vs 1.9%; adjusted hazard ratio [AHR] 0.56; 95% confidence interval [CI], 0.21 to 1.52, P = 0.258) and intermediate-risk disease (0.7% vs 0.9%; AHR 0.83; 95% CI, 0.59 to 1.16; P = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with BT boost compared with EBRT alone (3.9% vs 5.0%; AHR 0.73; 95% CI, 0.55 to 0.95; P = 0.022). Conclusions: Brachytherapy boost is associated with a decreased rate of PCSM in men with high-risk prostate cancer, but this benefit was not seen among patients with favorable high-risk disease. This suggests that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high risk disease.