bluuebunny/crossref_metadata_2025 huggingface dataset:
Postchemotherapy consolidative surgery for metastatic urothelial carcinoma.
Authors: Ercole Cesar Emilio , Campbell Steven C. , Dreicer Robert , Garcia Jorge A. , Gong Michael C. , Krishnamurthi Venkatesh , Stephenson Andrew J.
Published: February 2017

362

Background: The role of post-chemotherapy consolidative surgery for metastatic urothelial carcinoma (UC) is controversial and supported by small, single-center series in select patients. We sought to assess our experience with post-chemo retroperitoneal lymph node (RPLN) dissection for primary metastatic or relapsed UC to the retroperitoneum (with or without concomitant cystectomy and/or nephroureterectomy). Methods: Since 2008, 15 patients with metastatic or relapsed UC of the bladder or upper tracts (UT) and associated RPLN metastases were considered for post-chemo consolidative surgery. Records were reviewed for response to therapy, final pathology, and impact of surgery on overall survival (OS). Chemo agents used were provider dependent with 9 patients treated with gemcitabine/cisplatin, 3 with gem/carboplatin, and 2 with methotrexate, vinblastine, doxorubicin, cisplatin (1 received a combination due to intolerance). A median of 3.5 cycles were given in the adjuvant (n=5) and induction (n=10) setting. Seven patients presented with UT disease, of those 3 with relapse; median follow-up was 31.6 months (mos, IQR 14, 72), with 1 patient deceased. Nine patients had a bladder primary, 5 had induction chemo (median follow-up: 22 mos, IQR 16, 40), with 1 alive, 4 dead of disease, and 2 of other causes. To date, 13 patients have undergone surgery. Overall median follow-up is 23 mos. Results: Five patients (3 bladder, 2 UT) were noted to have radiographic complete response (CR) with induction and a median survival of 21.5 mos, with one patient alive at 7 years. All but one patient in the UT group are alive. Two patients had pathological CR, both were in the bladder cohort and died at 8 and 23 mos post-op. For all other patients, final pathology noted a median of 2 LN positive for malignancy (average 3.6). Neither chemo nor timing of administration showed a difference in OS. Conclusions: There is a role for post-chemo consolidative surgery in selected patients with metastatic UC. Compared to patients with the primary tumor in the UT, those with a primary bladder tumor and RPLN fared worse with a shorter overall survival time. More studies are necessary to better define the role of surgery in this setting.
Prevalence of atypical urine cytology in patients treated with gemcitabine-cisplatin (GC) for urothelial carcinoma (UC).
Authors: Kruczek Kimberly R. , Wang Lu , Barkan Guliz , Henry Elizabeth
Published: February 2017

363

Background: The prevalence of atypical urothelial cells (AUC) in the general population is estimated to range between 2-23% with known variability between individual pathologists’ use of this diagnosis. At our institution, the AUC rate for all urinary tract cytology (UTC) is 6.1%. Increased rates of urothelial atypia have been described in pts receiving certain systemic and intravesical therapies for UC. This may confound the use of UTC for post-therapy surveillance. Our objective is to describe the prevalence of urothelial atypia in pts treated with GC, as it is currently unknown. Methods: Patients who received at least one cycle of GC for UC at a single institution from 1/1/2007-9/30/2014 were identified. Demographics, clinical characteristics, treatment setting, number of cycles, and specimen type were recorded. Urine cytology reports were reviewed and tabulated. Results: Seventy-four pts treated with GC were identified. Median age at treatment was 65 (range 42-80); 58 (78%) were male. Median number of cycles was 4 (range 1-9). Treatment settings were: 15 (20%) neoadjuvant, 38 (51%) adjuvant, and 21 (28%) metastatic. Ten (14%) pts were previously treated with intravesical therapy (9 BCG, 1 mitomycin). Thirty-six (49%) pts had urine cytology available. Twenty-seven (75%) pts had at least 1 urine cytology within 12 months post-chemotherapy, with 44 total specimens. Nine (25%) pts had cytology performed >1-year post treatment. Cytology specimens within 12 months post-chemotherapy were reviewed. Two out of 44 specimens had AUC (5%), with all other cases negative. The pts with AUC were male, received adjuvant therapy, had prior radical cystectomy with orthotopic neobladder reconstruction, and had no intravesical therapy. Conclusions: The prevalence of AUC in pts treated with GC was similar to the general population. Chemotherapy with GC does not appear to morphologically affect urothelial cells. If atypical UTC is seen in this population, the cause should be investigated, as GC does not appear to influence urothelial changes. Additional study is needed to characterize the impact of systemic therapy on urothelial atypia and to guide the use of urine cytology for post-therapy surveillance.
A single-arm, multicenter, open-label phase II trial of cabazitaxel as second-line treatment for patients with locally advanced or metastatic transitional cell carcinoma (TCC).
Authors: Peer Avivit , Neumann Avivit , Keizman Daniel , Frank Stephen Jay , Berger Raanan , Leitzin Larisa , Pinto Ester , Neiman Victoria , Rosenbaum Eli
Published: February 2017

372

Background: For patients with advanced TCC who have progressed on a platinum-based regimen, no widely accepted standard second line therapy currently exists. A 2-stage phase II study was conducted to assess the activity and toxicity profile of the microtubule inhibitor cabazitaxel (Jevtana; FDA-approved in hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen) in patients with metastatic TCC after failure of prior platinum-based chemotherapy. ClinicalTrials.gov NCT01600339. Methods: Patients with one prior platinum based systemic therapy for metastatic TCC received cabazitaxel at a dose of 25 mg\m2every 21 days with prophylactic GCSF support, until disease progression or unacceptable toxicity. The primary endpoint was objective tumor response rate (ORR). Secondary endpoints included safety, time to progression (TTP), and overall survival (OS). Results: Twenty-three patients were enrolled to the study, 19 of whom received treatment. Male\female ratio was 15\4 and the median age was 67 (range, 56-81) years. Partial response (PR) was observed in 1 patient (5.3%), 10 patients (52.6%) achieved stable disease (SD), including 8 (42.1%) that had prolonged SD (≥16 weeks).Furthermore, the disease control rate (PR or prolonged SD) was 47.4%. The median TTP and OS were 4.2 (95% CI, 2.0-6.0) months and 9.9 (95% CI 5.6-13.2) months, respectively. The median number of treatment cycles was 5 (range 1-10). One patient experienced Grade 5 toxicity. Neutropenic fever occurred in 10.6% of patients. Most common toxicities were anemia and diarrhea. Conclusions: Cabazitaxel had modest efficacy in the treatment of advanced TCC, and there was no evidence of a significant response. Toxicity profile was considerable. The role of Cabazitaxel in urothelial carcinoma may need further evaluation in rational combination strategies, but not as a single agent. Clinical trial information: NCT01600339.
Split-dose cisplatin as an alternative to every-3-week dosing when using cisplatin/gemcitabine to treat advanced urothelial cancer.
Authors: Gonzalez Cinthia Marie , Jordan Emmet , Zabor Emily C. , Kania Brooke Elizabeth , Regazzi Ashley Marie , Ostrovnaya Irina , Iyer Gopa , Bajorin Dean F. , Bambury Richard Martin , Rosenberg Jonathan E.
Published: February 2017

373

Background: Cisplatin-based chemotherapy is the standard of care first-line therapy for locally advanced or metastatic urothelial cancer (mUC) with reported response rates (ORR) of 50%, median progression free survival (mPFS) 7 months and median overall survival (mOS) 14 months in phase III trials using cisplatin 70 mg/m2 every 3 weeks (q3wk). Many patients cannot receive cisplatin due to impaired performance status, renal dysfunction, or other co-morbidities. Carboplatin is an alternative but is associated with lower response rates and shorter survival. Administering cisplatin 35 mg/m2 day 1+8 (i.e., split dose) every 3 weeks may be associated with lower toxicity and allow more patients receive the drug. In this retrospective analysis we examined the safety and efficacy of cisplatin/gemcitabine using split dose cisplatin. Methods: Patients who received split dose cisplatin/gemcitabine between 2007-2013 were identified. We recorded baseline demographics, clinical characteristics, and number of cycles administered. Responses were determined retrospectively using RECIST v1.1; OS and PFS were assessed using the Kaplan-Meier method. Results: 50 patients were identified and baseline characteristics are outlined in Table 1. The median number of cycles administered was 4 (range 1-7). 25 patients (50%) discontinued therapy due to completion of planned course, 14 (28%) due to progressive disease and 11 (22%) due to toxicity. ORR was 54%, mPFS was 5.4 months (95% CI: 4.2 – 8.8) and mOS was 13.3 months (95% CI: 9.6 – 21.9). Conclusions: In this analysis, split-dose cisplatin was administered safely in patients who were deemed ineligible for the q3wk regimen and efficacy did not appear to be compromised. The split-dose regimen may allow more patients tolerate cisplatin, the most active FDA-approved drug in this disease. [Table: see text]
Frailty as a marker of adverse outcomes during cystectomy for urothelial cancer.
Authors: Kates Max , Patel Hiten , Sopko Nikolai , Liu Jen-Jane , Pierorazio Phillip M , Bivalacqua Trinity
Published: February 2017

374

Background: Frailty has been identified as a marker of physiologic reserve, and a more accurate predictor of adverse postoperative outcomes compared with age. Although many definitions of frailty exist, recently a clinical predictive rule, the “modified frailty index”(mFI), has been developed utilizing administrative data to predict adverse outcomes in the lung cancer population undergoing lobectomy. Our goal was to validate this clinical rule among patients with bladder cancer undergoing cystectomy. Methods: Patients undergoing cystectomy were identified from the National Surgical Quality Improvement Program (NSQIP) participant use files (2006-2011). The mFI was defined as in prior studies with 11 variables based on mapping the Canadian Study of Health and Aging Frailty Index to NSQIP comorbidities and activities of daily living (ADL)s. These 11 variables each received 1 point, and the sum was divided by 11 for a fraction between 0 and 1. Univariate χ2, independent sample t-test, and logistic regression analyses were performed where appropriate. Results: Of the 1,302 cystectomy patients identified, 30% had mFI of 0, 40% had mFI of 0.09, 21% had mFI of 0.18, and 9% had mFI ≥0.27. Overall, 56% of patients experienced a Clavien complication. Patients with mFI ≥0.27 were older ( 72 vs 64 yrs)and more likely to be smokers (54%) compared with mFI of 0 (30%, p<0.01). Mean operative times (342-349 minutes) were similar across mFI indices. Reoperation (5% vs 8.5%) and readmission (20.5% vs 25%) were higher when mFI =0 compared with mFI≥0.27 (P<0.01). Clavien 4 and above complications occurred in 9.1% (36/396), 10.1% (53/526), 12.9 % (35/270) and 13.6% (15/110) among patients with an mFI of 0, 0.09, 0.18, and ≥0.27, respectively (p=0.05). Similarly, the overall mortality rate increased from 2.5% in the lowest frailty index group to 5.4% in the highest. Conclusions: Among patients undergoing cystectomy, the modified frailty index can identify those patients at greater risk for severe complications, readmissions, and mortality. Given that bladder cancer is increasing in prevalence particularly among the elderly, pre-operative risk stratification is crucial to inform decision-making.
Management and outcomes of clinical stage II a/b seminoma: Results from the National Cancer Database.
Authors: Paly Jonathan J. , Gray Phillip John , Lin Chun Chieh , Sineshaw Helmneh , Jemal Ahmedin , Efstathiou Jason Alexander
Published: February 2017

378

Background: Testicular seminoma is the most common solid tumor seen in patients aged 15-35 and disease specific survival approaches 100% in controlled studies, even for those with node-positive disease. We sought to describe modern practice patterns as well as survival outcomes and factors associated with receipt of adjuvant therapy for patients presenting with initial clinical stage (CS) IIA/B disease. Methods: Data on patients diagnosed with CS IIA/B testicular seminoma from 1998-2011 were extracted from the National Cancer Data Base. Demographic, clinical, treatment, payer characteristics were evaluated using multivariate logistic regression to identify factors associated with receipt of chemotherapy or adjuvant radiation therapy (ART) within 6 months of orchiectomy. Five-year Kaplan-Meier overall survival (OS) by CS and treatment was calculated. Results: In total, 2,185 patients with CS II A/B were included. Management included orchiectomy alone (11.35%), adjuvant chemotherapy (27.46%), or ART (52.72%). In multivariate analysis, receipt of orchiectomy plus ART rather than adjuvant chemotherapy was more likely with CS IIA status (OR 2.4, p < 0.01), treatment outside of teaching or NCI network institution (OR 1.9-2.8, p < 0.02), or tumor size ≥4cm (OR 1.6, p < 0.01). Receipt of ART was less likely in Hispanic patients (OR 0.6, p=0.03) or in those diagnosed from 2006-2011 (OR 0.5, p < 0.01). Five-year OS for all patients was 97.2% for orchiectomy + ART, and 93.9% for orchiectomy + chemotherapy (log-rank p = 0.01). For CS IIA patients, 5-year OS was 98.3% for orchiectomy + ART versus 93.6% for orchiectomy + chemotherapy (log-rank p < 0.01). Differences in OS for CS IIB treated with chemotherapy or ART were not statistically significant. Conclusions: Consistent with national guideline recommendations, our analysis suggest that compared to chemotherapy, ART is associated with a survival advantage for CS IIA patients. Chemotherapy or ART showed no significant difference in effectiveness in patients with CS IIB. Disease bulk, race, treatment center type, and time period are associated with choice of adjuvant therapy. Longer follow-up and validation of these results is needed to account for late effects of treatment.
Frequent expression of PD-L1 in testicular germ cell tumors.
Authors: Fankhauser Christian Daniel , Curioni Fontecedro Alessandra , Beyer Joerg , Tischler Verena , Sulser Tullio , Moch Holger , Bode Peter Karl
Published: February 2017

379

Background: Testicular germ-cell cancer is curable even in the presence of metastatic disease. Yet, about 10-15% of patients become cisplatin-refractory and will eventually die of their disease. Moreover, short- and long-term side effects of cisplatin make the search for less toxic treatment strategies worthwile. Programmed Death Receptor 1 (PD-1, CD279) is one member of the extended family of T cell regulators expressed on the surface of activated T cells, B cells, and macrophages. Its ligand, PD-L1 (B7-H1, CD274), is expressed on tumor cells, T cells and other tissues. The interaction of these two molecules negatively regulates immune responses. Of major interest is that inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate clinical antitumor activity . The aim of this study was to analyze the expression of PD-L1 in testicular germ-cell tumors to evaluate its potential as predictive marker for further therapeutic strategies. Methods: Immunohistochemistry was performed in 486 Formalin Fixed Paraffin Embedded (FFPE) specimens using a monoclonal rabbit antibody (E1L3N, Cell Signaling Technology, Inc. (CST) of Danvers, MA, USA). Results: PD-L1 expression was found in 171 out of 248 (69%) seminomas, 19 out of 48 (40%) yolk sac tumors, 7 out of 46 (15%) teratomas, 2 out of 10 (20%) choriocarcinomas and 53 out of 87 (61%) embryonal carcinomas. In 20 out of 20 Intratubular germ-cell neoplasia unclassified (IGCNU) and also in 20 out of 20 normal tissue specimens no single case exhibited PD-L1 expression. Conclusions: Our study describes for the first time the frequent expression of PD-L1 in a large series of human testicular germ-cell tumors, but not on normal testis tissue or IGCNU. Based on our results, checkpoint inhibition with anti-PD1 and anti-PDL1 antibodies might represent an attractive approach in germ-cell cancer, where new active agents are urgently needed.
A panel of dynamic micromechanical biomarkers in the detection and differentiation of prostate cancer.
Authors: Good Daniel W. , Hammer Steven , Scanlan Paul , Stewart Grant , Reuben Robert L , McNeill Alan S
Published: February 2017

38

Background: Elasticity devices enable quantitative measurements and can reduce the need for operator interpretation. Our dynamic assessment enables micromechanical markers to be identified: amplitude ratio [AR], phase lag [PL] and mean ratio [MR], at specific frequencies. Aim: To assess the efficacy of a panel of dynamic micromechanical biomarkers for the detection of prostate cancer (Primary endpoint) (and differentiation of significant from insignificant disease (secondary endpoint)) in ex-vivo prostates and in patients, using a direct elasticity assessment probe (E-finger). Methods: Patients undergoing surgery for prostate cancer were enrolled into a prospective clinical study; exclusion criteria (previous TURP, 5ARI). Ex-vivo prostates were systematically assessed at multiple points on posterior surface. In-vivo testing was done using the probe attached to the index finger and assessing the prostate via DRE using 12 -16 different areas. Measurement points were marked and noted on final pathology to allow correlation with final histology. CART was used to create a model of the micromechanical markers and regression analysis used to identify histopathological parameter associations. Results: 22 patients were recruited to the study to date, mean age was 64 (55 – 73), median PSA 7.5 (5.5 – 10), over 50% were cT1c, median weight 51g (44 – 68) and over 50% were pT3 on final pathology. Over 600 measurement points were assessed. The in-vivo marker panel was made up of: 10HzARA, 10HzPLA, 1HzPLC, 15HzMRB and 1HzARA. Sensitivity was 89%, specificity 87%, PPV 86%, NPV 88% for cancer detection in-vivo. That for the ex-vivo tests were Sen 71%, Spec 81%, PPV 80%, NPV 72% (primary outcome). For differentiation of clinically significant from insignificant areas sensitivity and specificity were 81% and 75% respectively (secondary outcome). Correlation of the marker panel with underlying tumour volume was strong (R2 = 0.75). Conclusions: These results show the promise of micromechanical biomarkers in the detection of prostate cancer and in the differentiation of significant from insignificant disease. This study shows that these markers maintain their accuracy from the ex-vivo into the in-vivo environment.
Interim [18f] fluorodeoxyglucose positron emission tomography (PET) for early metabolic assessment of response to PEB chemotherapy for metastatic seminoma: Preliminary findings.
Authors: Giannatempo Patrizia , Alessi Alessandra , Raggi Daniele , Farè Elena , Tana Silvia , Nicolai Nicola , Serafini Gianluca , Padovano Barbara , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Maffezzini Massimo , Gianni Alessandro M. , Mariani Luigi , Crippa Flavio , Salvioni Roberto , Necchi Andrea
Published: February 2017

381

Background: A risk-adapted strategy for metastatic seminoma may further refine the necessary burden of chemotherapy while sparing futile treatment. The objective of this study was to evaluate the association of the early metabolic response to cisplatin, etoposide, and bleomycin (PEB) and dimensional response. Methods: Patients (pts) with newly-diagnosed seminoma and who were candidate to PEB were staged at baseline by computed tomography (CT), PET and serum tumor markers (STM). Then, restaging with PET after 2 cycles of PEB (PET2), and with CT after treatment (3-4 cycles [CT3-4]) were provided. One (greatest) target lesion was chosen to evaluate metabolic/dimensional changes. Wilcoxon rank sum test was used to analyze the association between PET response and either the shrinkage of target lesion (primary endpoint) or baseline, or final dimensions. Results: In the time-frame 02/2009-11/2013, 37 pts have been enrolled. Two pts had CSIIA, 13 CSIIB, 13 CSIIC, and 9 CSIII. 3 had an intermediate prognosis because of liver (n=1) and bone (n=2) disease. The latter were recognized by PET while having a bone-negative CT scan. 4 had a retroperitoneal and 1 a mediastinal primary. All pts had a PET-positive target disease. After 2 cycles of PEB, 27 pts (72.9%) had a metabolic complete response (CR), 10 a partial response (PR). 12 pts had a CR at CT3-4. Median follow up was 18 months (IQR: 13-23). A significant association was found between PET2 response and baseline (p=0.003), final diameter (p<0.001), and % of tumor shrinkage (p=0.014). Pts with PET2 CR had a median residual diameter of 1.2 cm (IQR: 1-1.9) while pts with PET2 PR 3.75 cm (IQR: 2.6-6.1, p=0.002). 6 Pts received RT after PEB. 2/10 pts with PET2 PR had a relapse (0/27 CR). Conclusions: A significant association was found between PET2 response and tumor shrinkage in pts with metastatic seminoma. PET2 CR pts could be predicted not to need additional re-imaging or treatment after PEB, and simplifying the follow up should be an endpoint. PET2 PR category includes pts yielding a difficult-to-treat disease. A detailed cost-efficacy analysis of the strategy will be required further.
Complicated postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in advanced testicular germ cell tumours: Is it worth the efforts?
Authors: Heidenreich Axel , Porres Daniel , Pfister David J. K. P.
Published: February 2017

382

Background: PC-RPLND is performed in patients with residual masses following chemotherapy for advanced testicular cancer. Complicated PC-RPLND is defined by redo, salvage or desperation procedures including the necessity to resect major adjacent vascular, skeletal or intestinal structures. We report on our single centre experience of complicated (group A) versus uncomplicated PC-RPLND (group B). Methods: A total of 138 patients underwent PC-RPLND and 24 (14.8%) patients underwent complicated RPLND: resection of major retroperitoneal vessels n=15 (9.3%), skeletal and pancreaticoduodenal structures in 5 (3.1%) and 4 (2.5%) patients, respectively. We performed a retrospective analysis of treatment-associated complications (Clavien-Dindo classification). Progression-free, cancer-specific and overall survival was calculated. Results: There were significant differences between group A and B concerning tumour diameter (5.9 vs 18.6cm, p = 0.03), intermediate/poor IGCCCG risk (39.9% vs 83.4%, p=0.02), seminomatous primary (7.9% vs 20.8%, p=0.03). Pathohistology of the residual masses was significantly different between group A and B: vital cancer was identified in 6 (4.3%) and 8/24 (33.3%, p=0.02) pts, resp., whereas teratoma was identified in 37 (26.8%) and 14/24 (58.3%, p=0.01), resp. In addition 3 pts in group B demonstrated malignant somatic transformation. After a median follow-up of 32 months for group B, 3 patients with MTS experienced recurrences, 1 patient died of the disease. The remainder survived event-free. In group A, median follow-up was 37 months and DOD was observed in 2 pts, 8 pts (5.8%) experienced recurrences. Frequency of complications grade I-IIIb did not differ significantly between group A and B with vascular or skeletal surgery (6.2 vs 13.3%), however, it increased significantly to 65% in pancreatic surgery (p < 0.001). Conclusions: Few patients with advanced NS need complex surgery in an interdisciplinary setting with good functional and oncological outcome. Despite an increased risk of short-term complications complicated PC-RPLND results in long-term survival > 90% and it is justified if performed at specialized centres.
Multiplatform comprehensive kinase analysis of penile squamous cell carcinoma (PSCC) to identify drivers and potentially actionable therapeutic targets.
Authors: Mehta Amitkumar N. , Yang Eddy Shih-Hsin , Willey Christopher Douglas , Crowley Michael , Chen Dongquan , Anderson Joshua , Naik Gurudatta , Cooper Tiffiny , Sonpavde Guru
Published: February 2017

389

Background: PSCC is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers of disease and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor tissue and adjacent normal tissue. Methods: We collected fresh frozen tumors from 10 patients with PSCC, of whom 3 had adjacent normal tissue available. After macrodissection to demarcate tumor from normal tissue, the samples underwent analysis of kinases using platforms to assess DNA, RNA and kinase activity. Next Generation Sequencing of 515 kinase genes was performed using the Agilent Kinome capture and run on the Illumina HiSeq2500 at PE100bp. The Nanostring nCounter platform analyzed the expression (RNA) of 519 kinase genes. Global kinase activity of tissue lysates was measured using Pamstation@12 high-content phospho-peptide substrate microarray system (PamGene International). Upstream kinase prediction was performed and network mapping was done with GeneGo MetaCore. Ingenuity pathway analysis data was performed to integrate over-expression at the activity and gene expression level with coexisting missense mutations at DNA level. Results: Top pathways observed to be upregulated in both the kinase activity and gene expression platforms were PTEN Signaling, STAT3 Pathway, GNRH Signaling, IL8 Signaling and B Cell Receptor Signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH Signaling, NF-kB Signaling, and STAT3 pathways. ERBB2, ERBB3 and SYK were altered on gene sequencing and also showed elevated kinase activity. Kinases previously implicated in prostate cancer (PAK4, TNK2), breast cancer (ERBB2) and genital dysplasia (ROR2) also demonstrated mutations. Conclusions: Multiplatform comprehensive analysis of kinases at the DNA, RNA and protein activity levels discovered several potential drivers of PSCC and actionable therapeutic targets. Further validation in preclinical and translational trials is warranted to make advances in this rare malignancy with substantial unmet needs.
Bilateral testicular germ cell tumors.
Authors: Curreri Stephanie A. , Markt Sarah C. , Miller Rowan , O'Donnell Elizabeth , Bernard Brandon David , Kamran Sophia C. , Albiges Laurence , Wright Alexi A. , Sweeney Christopher , Beard Clair
Published: February 2017

392

Background: Germ cell tumors (GCTs), both seminomatous and non-seminomatous, account for greater than 90% of testicular cancers. While bilateral testicular GCTs are rare, the incidence of bilateral tumors has increased over time. Methods: 668 cases of bilateral and 38,593 cases of unilateral testicular GCTs were reported between 1973 and 2011 by the SEER database. Patient characteristics and tumor features were analyzed. Results: The incidence of bilateral GCTs among men with testicular GCTs was 1.7% (668 of 39,261 total cases). Among the 668 men with bilateral GCTs, 53% (n=353) of second GCTs occurred within three years after the first cancer. 29% (n=196) of bilateral tumors occurred synchronously. Among patients with bilateral GCTs, 378 first GCTs and 466 second GCTs were seminomatous. 43% of bilateral cases were concordant seminomatous GCTs, 16% were concordant non-seminomas, and 41% were discordant histologies. 68% of unilateral GCTs, 70% of first GCTs, and 82% of second GCTs were staged as Localized disease. Testicular cancer was the cause of death for 4% (n=1,630) of men with a unilateral GCT and 1% (n=8) of men with bilateral GCTs. A second malignant neoplasm (SMN) was the cause of death for 2% (n=736) of men with a unilateral GCT and 2% (n=16) of men with bilateral GCTs. Conclusions: Among men with bilateral testicular GCTs, 59% had concordant histological diagnoses between their first and second tumor. Most (53%) second cancers among men with bilateral tumors occurred within three years after diagnosis of first cancers. Men who experience bilateral testicular GCTs do not appear to have an increased risk of death due to testicular cancer or a subsequent non-germ cell malignant neoplasm compared to men with a unilateral testicular GCT. [Table: see text]
Programmed death ligand-1 (PD-L1) expression in penile squamous cell carcinoma.
Authors: Wang Jennifer , Rodriguez Jaime , Rao Priya , Pettaway Curtis Alvin , Pagliaro Lance C.
Published: February 2017

393

Background: PD-1 protein is a co-inhibitory receptor expressed on B cells, T cell, and NK cells. Its ligand PD-L1 (B7-H1) leads to inhibition of T cell proliferation and cytokine production and is not expressed on normal tissues other than macrophages, but is expressed on various human carcinomas. Expression of PD-L1 in the HPV-associated disease penile carcinoma is unknown. Methods: Formalin-fixed paraffin-embedded tumor specimens were obtained from 19 patients. PD-L1 staining was done with an E1L3N rabbit monoclonal antibody with the summary of a positive score using H-score membrane staining, which considers both intensity and percentage of cells, with >5% score as a positive. HPV status was also evaluated using FISH or p16 immunohistochemical staining to evaluate for correlation with PD-L1. Results: 23 samples between primaries and lymph nodes were collected from the 19 patients with 5/23 samples (22%) positive for anti-PDL1 staining. 6 samples (26%) were positive for HPV by at least one method of testing with 2/6 (33%) HPV positive patients having positive PD-L1 membrane staining. In both of these samples, there was equivocal peritumoral inflammatory infiltration of PD-L1 cells. Conclusions: This analysis shows that PD-L1 is expressed in penile squamous cell carcinomas and may indicate a role for future anti-PD-L1/PD-1 drugs as therapeutic options. Further analyses of correlated clinical features, survival, and separate PD-L1 staining in peritumoral inflammatory cells are underway.
Rates of retroperitoneal lymph node dissection for stage I non-seminomatous germ cell tumors: Results from the National Cancer Database.
Authors: Haseebuddin Mohammed , Handorf Elizabeth , Kutikov Alexander , Waingankar Nikhil , Plimack Elizabeth R. , Uzzo Robert G. , Smaldone Marc C.
Published: February 2017

395

Background: Per existing best practice guidelines, careful observation with serial imaging (active surveillance) or primary chemotherapy have supplanted primary retroperitoneal lymph node dissection (RPLND) for stage I non-seminomatous germ cell tumors (NSGCT). Hypothesizing that rates of primary RPLND have declined over the past decade, our objective was to assess temporal trends in primary treatment for stage I NSGCT using a large national cancer registry. Methods: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I NSGCT from 1998-2011. Temporal trends for receipt of primary RPLND, chemotherapy, or observation (defined as no treatment) were assessed. Adjusting for patient, demographics (age, ethnicity, race, insurance status, education, income, geographic location), and clinicopathologic characteristics (stage), multivariable logistic models were used to examine the association between available covariates and receipt of primary RPLND. Results: Of 15,822 patients identified over the study period, 9,001 (56.9%), 2,937 (18.6%), and 3,884 (24.5%) underwent observation, RPLND, and chemotherapy respectively. While rates of observation minimally changed over time (56.3 to 55.0%, p=0.85), a significant decrease in utilization of RPLND (23.0 to 12.4%, p<0.001) was matched by a significant increase in receipt of primary chemotherapy (20.7 to 32.5%, p<0.001). Rates of RPLND declined across all age groups—age < 30 (24.3% to 12.1%, P<0.0001), age 30-39 (21.6% to 13.8%, p <0.0001), age 40-49 (23.1% to 11.4%, p<0.0001), age>50 (20.0% to 11.7%, p = 0.02). Following adjustment, stage T2 (OR 0.79 [CI 0.72-0.87]) and T3 (OR 0.33 [CI 0.24-0.96]), and age categories 40-49 years (OR 0.83 [CI 0.72-0.94]) and ≥50 years (OR 0.66 [CI 0.52-0.82]) were associated with decreased utilization of RPLND. Conclusions: In hospitals reporting to the NCDB, utilization of primary RPLND for stage I NSGCT has significantly decreased over the last decade, while receipt of primary chemotherapy has increased over the same period. While employed in more than 50% of patients, rates of observation remain unchanged.
Risk-stratified treatment of patients with metastatic germ cell tumor with progression after first-line therapy.
Authors: Gunnarsson Orvar , Hwang Wei-Ting , Squillante Christian Michael , Nathanson Katherine L. , Stadtmauer Edward A. , Vaughn David J.
Published: February 2017

398

Background: The optimal management of patients with metastatic germ cell tumor (GCT) who experience progression after first-line (FL) therapy is controversial. A risk-stratified approach was introduced in 2005. Favorable risk patients received 4 cycles of paclitaxel, ifosfamide, cisplatin (TIP); unfavorable risk patients received 2 cycles of TIP followed by 2 cycles of high-dose chemotherapy [(HDCT); carboplatin and etoposide with autologous stem cell support]. Favorable risk was generally defined as gonadal primary and relapse > 6 months after CR or marker negative PR to FL therapy; all others were unfavorable risk. The aim of this study is to present survival outcome of this risk-stratified approach at a single institution. Methods: A chart-based retrospective review was conducted on all patients with metastatic GCT who experienced progression after FL therapy from 2005 to 2013. Data were collected on baseline demographics and disease characteristics. Progression-free survival (PFS) and overall survival (OS) were calculated for favorable and unfavorable risk patients. Results: 37 patients were identified and included for analysis. Patients characteristics: Caucasian 92%; median age 27 years; gonadal primary 84%; non-seminoma, 81%. 16 (43%) favorable risk patients received TIP x 4; 21 (57%) unfavorable risk patients received TIP x 2 followed by HDCT x 2. The median time for follow-up was 16 months. Favorable risk patients: 2- and 4-year PFS of 60% and 45%; 2- and 4-year OS of 74%. Unfavorable risk patients: 2- and 4-year PFS of 41% and 27%; 2- and 4-year OS of 55% and 34%. Both IGCCCG risk classification at initial diagnosis and IPFSG risk classification at relapse had prognostic validity for OS (log rank p ≤ 0.05) but not PFS (log rank p = 0.065–0.080). Conclusions: Risk-stratified treatment of patients with metastatic GCT with progression after FL therapy may result in the best risk/benefit ratio. However, the optimal management of these patients is still not known and prospective randomized comparisons are needed.
Retrospective analysis of chemotherapy for the patients with advanced bladder adenocarcinoma.
Authors: Oh Sung Yong , Kim Young Sam , Lee Ji Hyun , Kim Moonjin , Choi Young Jin , Soel Yong Mi , Park Min Jae , Kim Ki Hyang , Park Lee Chun , Kang Jung Hun , Hwang In-Gyu , Kim Hyo Song , Lim Seung Taek , Rha Sun Young , Lee Soonil
Published: February 2017

399

Background: By definition, primary adenocarcinoma of the bladder (PAB) is a malignant neoplasm derived from urothelium of the bladder showing histologically pure glandular differentiation. Because of its rarity, role of chemotherapy for metastatic adenocarcinoma of bladder is still questionable. Therefore, we performed a retrospective analysis of the clinical features and chemotherapy outcomes of metastatic PAB to evaluate the clinical findings at presentation, overall survival (OS) and progression-free survival (PFS) and prognostic factors. Methods: Eligible patients for this retrospective analysis were initially diagnosed with adenocarcinoma and presented with a clinically no other primary site of origin. The collected data included age, gender, performance status, stage, hemoglobin, albumin, initial date of diagnosis, treatment modality utilized, response to treatment, presence of relapse, last status of patient, and last date of follow-up. Results: We retrospectively reviewed 29 patients who treated with chemotherapy as metastatic PAB at 10 Korean medical institutions from 2004 to 2014.The median age of patients was 58 years (range, 17 to 78 years) and 51.7% of the patients were female. Fifteen patients were urachal adenocarcinoma. Of 27 symptomatic patients, 22 experienced gross hematuria. Ten patients had two or more metastatic sites of the lungs (51.7%), peritoneum (41.4%), and ovary (20.7%), as the most common sites. Twelve patients were treated with 5-FU based chemotherapy, 5 were gemcitabine based, 3 were taxane and adriamycin based, and others. 13 of them achieved CR (10.3%) or PR (34.5%). Median PFS and OS for all patients were 10.6 months (95% confidence interval [CI], 9.5 to 11.6 months) and 24.5 months (95% CI, 1.2 to 47.8 months), respectively. In the prognostic factor analysis, the cases of urachal adenocarcinoma had worse tendency in PFS and OS (p=0.024 and P=0.046, respectively). Conclusions: Metastatic Despite most of chemotherapy, PFS and OS were short especially in urachal carcinoma, however, there were some long-term survivors, therefore, additional research on the predictive markers of several clinical, pathological differences and their treatments will be needed.
Prognostic factor for overall survival in the "difficult-to-treat" germ cell tumor patients.
Authors: Nakamura Terukazu , Oishi Masakatsu , Ueda Takashi , Shiraishi Takumi , Nakanishi Hiroyuki , Naya Yoshio , Hongo Fumiya , Okihara Koji , Miki Tsuneharu
Published: February 2017

402

Background: Our previous observation showed germ cell tumor (GCT) patients who finished at first-, second- or third-line chemotherapy obtained good overall survival. On the other hand, patients with 4th line-or-after chemotherapy showed much poorer outcome. The aim of this study was to investigate the prognostic factor for overall survival in the patients with 4th-line-or-after chemotherapy. Methods: Between August 1998 and December 2013, seventy-four GCT patients had 4th line-or-after chemotherapy at our institution. These patients were defined as ‘difficult-to-treat’ GCT patients in this study. We retrospectively assessed clinical and therapeutic parameters. Median age was 33 y.o.(range;19-55). Nonseminoma was found in 86.5%. Good, intermediate and poor prognosis by IGCCC was 23, 17 and 26 cases, respectively. With regard to IGCCC at salvage, very low, low, intermediate, high and very high was 2, 7, 10, 18 and 6 cases, respectively. Results: Fiver-year overall survival was 55.6%. Choice of 2nd line or 3rd line chemotherapy did not influence overall survival, for example, VeIP (vinblastine, ifosfamide, cisplatin) or VIP (etoposide, ifosfamide, cisplatin) versus other chemotherapy as 2nd line therapy (5-y OS; 55.2% and 56.3%, log-rank, p=0.78). The identical result was observed in paclitaxel-containing therapy such as TIP versus other chemotherapy (paclitaxel, ifosfamide, cisplatin) (5-y OS; 52.8% and 57.1%, log-rank, p=0.90). In the choice of 4th line chemotherapy, gemcitabine-containing regimen was not superior to other chemotherapy (5-y OS; 57.0% and 55.3%, log-rank, p=0.98). Statistical significant parameters were primary site, IGCCC at salvage, required chemotherapy line and serum tumor marker (STM) normalization by univariate analysis. Multivariate analysis showed independent prognostic factor for overall survival was normalization of serum tumor marker during chemotherapy (Hazard Ratio;0.12, 95% Confidence Interval;0.02-0.62, p=0.01). Conclusions: STM normalization is thought to be mandatory for overall survival in the management of ‘difficult-to-treat’ advanced GCT patients.
Renal nephrometry score and predictors of pathologic upstaging in patients undergoing partial and radical nephrectomies.
Authors: Pruthi Deepak Kumar , Chhibba Ruchi , Drachenberg Darrel E , McGregor Thomas
Published: February 2017

412

Background: To examine the predictive capability of pre-operative anatomic imagining characterization of the R.E.N.A.L. Nephrometry Score (RNS) in assessing pathologic upstaging of clinical T1 (cT1) lesions to pathologic T3 (pT3) in partial and radical nephrectomy specimens. Methods: We conducted a retrospective review of all patients undergoing radical and partial nephrectomies between January 1, 2011 and May 31, 2014 for cT1 renal masses. All pre-operative imaging scans were reviewed and the R.E.N.AL. Nephrometry score (radius for tumor size as maximal diameter, exophytic/endophytic tumor properties, nearness of deepest portion of tumor to collecting system or sinus, anterior/posterior descriptor and location relative to polar line) was applied to each scan. Chi-square, Fisher exact test, and Student t test were utilized to examine associations. Results: Of the 229 patients who underwent partial or radical nephrectomy for cT1, 124 (54%) underwent partial nephrectomy. On pathologic evaluation 195 (85%) patients had malignancy. Of all tumors 26 (13%) were pathologically upstaged to pT3 with the majority attributable to renal sinus/fat (35%) or perinephric fat (31%) involvement. High RNS (>10) was significant in predicting pathologic T3 upstaging (p=0.039) but did not predict high grade (Furhman grade 3-4) disease (p=0.803). While a high nephrometry score trended toward predicting malignancy vs benign disease (p=0.086), a higher mean nephrometry score (7.81 vs. 6.84) significantly predicted malignancy (p=0.015). When controlled for cT1a lesions, tumor location relative to polar lines (L=3 vs. L1+2) was predictive of pT3 upstaging (24 vs. 6%, p=0.03). Age >65 was significantly associated with upstaging (26 vs. 7%, p=0.0001). Conclusions: Surveillance of small renal masses is common but high RNS and age >65 significantly predicted pathologic upstaging. Mean nephrometry score was also useful in predicting malignancy. Nephrometry score may aid in deciding on early surgical intervention.
Overall survival (OS) in Swedish RCC patients treated 2000–2012: Update of the RENCOMP study.
Authors: Lindskog Magnus , Wahlgren Thomas , Sandin Rickard , Kowalski Jan , Jakobsson Maria , Lundstam Sven , Ljungberg Börje , Harmenberg Ulrika
Published: February 2017

413

Background: The RENal COMParison (RENCOMP) study showed a significant improvement in OS for Swedish patients diagnosed with renal cell carcinoma (RCC) and metastatic (m)RCC in the first years following the introduction of targeted agents (TAs) in 2006 (Br J Cancer 2013;108:1541). Here we investigated whether a further improvement in OS can be detected in the more recent years of the TA era. Methods: Using data from the Swedish Cancer Register (diagnosis and death records), National Patient Register (in-/out-patient visit records), and Swedish Prescribed Drug Register (prescribed/dispensed drug records), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2012 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TAs, and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimates of adjusted HR. The regression model included the covariates age, gender, geographical region, institution size, nephrectomy status, diagnosis period, and TA prescription. Results: In total, 3,980, 2,956, and 5,225 RCC patients were identified from 2009–2012, 2006–2008, and 2000–2005, respectively. From 2002–2012, 4,217 patients met the criteria for mRCC diagnosis. RCC patients diagnosed 2009–2012 and 2006–2008 had a significant improvement in OS compared with patients diagnosed 2000–2005 (median OS: not reached and 86 vs. 48 months, respectively; both P<0.001 [log-rank]). Likewise, mRCC patients diagnosed 2009–2012 and 2006–2008 had a significant improvement in OS compared with patients diagnosed 2002–2005 (median OS: 18.0 and 13.0 vs. 10.0 months, respectively; both P<0.001 [log rank]; with adjusted HR [95% CI] of 0.76 [0.69–0.83] and 0.97 [0.89–1.06], respectively). Factors significantly associated with longer OS in mRCC were (HR, 95% CI): female gender (0.88, 0.82–0.94), lower age (0.97, 0.97–0.98), prior nephrectomy (0.57, 0.53–0.61), and a TA prescription (0.84, 0.77–0.91). Conclusions: A continued significant improvement in OS for RCC and mRCC patients was shown, reflecting intensified medical and surgical treatment, more available TAs, and increased clinical experience.
The association between obesity and incidence of total and fatal renal cell carcinoma in two prospective cohorts.
Authors: Wilson Kathryn M , Cheng Jed-Sian , Sanchez Alejandro , Graff Rebecca , Rodriguez Dayron , Feldman Adam S. , Barrisford Glenn , Bechis Seth , Blute Michael , Stampfer Meir J. , Chang Steven L. , Giovannucci Edward L. , Albiges Laurence K. , Choueiri Toni K. , Cho Eunyoung , Preston Mark A
Published: February 2017

414

Background: Recent studies suggest an “obesity paradox” in renal cell carcinoma (RCC), in which obese people are more likely to be diagnosed with RCC, but are less likely to die of the disease. We studied the association of body mass index (BMI) with risk of both total and fatal RCC in two large prospective cohorts. Methods: The Nurses’ Health Study (NHS) consists of 117,097 women followed since 1976, and the Health Professionals Follow-up Study (HPFS) consists of 48,268 men followed since 1986. Height and weight were reported at baseline and updated biennially through 2008, with disease follow-up through 2010. We used multivariable Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of both total and fatal pathology-confirmed RCC by BMI immediately prior to diagnosis. Models were adjusted for diabetes, hypertension, smoking, alcohol intake, NSAID use, physical activity, and parity in women. Results: We confirmed 349 cases of RCC, including 103 fatal cases, in NHS, and 226 cases in HPFS, with 46 fatal cases. Compared to women with normal BMI (18.5-24.9 kg/m2) immediately prior to diagnosis, obese women (BMI≥30) had an increased risk of RCC (HR 1.38, 95% CI: 1.03-1.84, p-trend=0.004), adjusting for possible confounders. The HR for fatal RCC was similar but not statistically significant (HR 1.35, 95% CI: 0.79-2.29, p-trend=0.22). Obese men had a non-significantly increased risk of RCC (HR 1.45, 95% CI: 0.96-2.21, p-trend=0.05), with a significantly increased risk of fatal RCC (HR 2.56, 95% CI: 1.11-5.90, p-trend=0.13). Among women, the associations with baseline BMI (1976) were somewhat stronger (HR 1.88, 95% CI: 1.36-2.61, p-trend<0.0001 for total; HR 1.98, 95% CI: 1.07-3.66, p-trend=0.002 for fatal). For men the association with baseline BMI (1986) was weaker for fatal RCC (HR 1.34, 95% CI: 0.50-3.58, p-trend=0.27). Conclusions: Our results support that obesity is a risk factor for RCC incidence and also suggest that it is adversely associated with fatal RCC. These results are stronger for women than for men, though this may be due to the lower number of cases among men.