bluuebunny/crossref_metadata_2025 huggingface dataset:
External beam radiotherapy for small cell carcinoma of the urinary bladder: The Memorial Sloan-Kettering experience.
Authors: Kollmeier Marisa , Kan Chu-Cheng , Bochner Bernard , Dalbagni Guido , Bajorin Dean F. , Zelefsky Michael J.
Published: February 2017

290

Background: To report our experience using definitive external beam radiotherapy for small cell carcinoma of the urinary bladder.

Methods: We reviewed records of 17 patients (14 male, 3 female) with small cell carcinoma of the urinary bladder treated at our institution with external beam radiation therapy (median dose 64.8Gy) for small cell carcinoma of the bladder between January 1994 and June 2011. Median age was 69 years. Sixteen (94.1%) patients received neoadjuvant and/or concurrent platinum-based chemotherapy. All patients underwent pretreatment maximal transurethral resection (visibly complete (n=7); incomplete (n=10). Seven patients had radiographic or pathologic evidence of nodal spread. Patients were followed with cystoscopy and radiographic imaging post-RT. Median followup was 7 months (range, 2-161 mos). Acute (<90days) and late (≥90days) toxicity was recorded using CTCAE v 3.0. Kaplan Meier method was used for survival analysis.

Results: The 2-year overall survival was 62%. Of 17 patients, 3 patients developed local recurrence (LR) with a median time to local recurrence of 19 months. Two of three patients had noninvasive LR managed with transurethral resection and had no evidence of disease at last followup. One patient with invasive LR had both LR and distant metastasis identified <3 months after RT. Four patients developed distant metastases at a median time to progression of 2.5mos in bone (n=2), lung (n=1), and retroperitoneal lymph nodes (n=1). All but one patient with distant metastases had node-positive disease at diagnosis. The 2y distant metastasis-free survival for node (-) and node (+)patients was 90% and 30% (p=0.03). Of 12 patients currently without evidence of disease, 5 have followup ≥30mos. The incidence of grade ≥2 acute and late GU/GI toxicity was 53% and 6% respectively.

Conclusions: Bladder preservation therapy for small cell carcinoma is feasible with encouraging early results. Nodal disease portends a poor prognosis. Brain metastases are uncommon suggesting a limited role for prophylactic cranial irradiation. Radiation therapy with concurrent platinum-based chemotherapy was associated with a low risk of late GU/GI toxicity in our cohort.
Molecular characterization of temsirolimus-induced response in human renal and bladder cancer cell lines.
Authors: Merseburger Axel S. , Kramer Mario W. , Tezval Hossein , Kuczyk Markus , Serth Juergen
Published: February 2017

295

Background: Targeted therapies like mTOR inhibition is a clinically esthablished treatment modality for advanced renal cell cancer (RCC). We hypothesize that common elements of molecular signalling exists in RCC and transitional cell carcinoma of the bladder (TCC) that could provide a rational of the usage of this novel compound in human TCC. Therefore the goal of this investigation was to measure the in vivo and in vitro effect of temsirolimus/CCI-779 on human RCC and TCC cell lines on the molecular level.

Methods: For in vivo experiments 3 RCC (786-O, A498, ACHN) cell lines and 7 TCC (T24, 5637, RT112, EJ-28, CLS-439, HB-CLS-1, HB-CLS-2) cell lines were compared. Effect of temsirolimus/CCI-779 was measured by real time impedance analysis (XCelligence, Roche). Following mRNA isolation microarray based mRNA expression analysis with 45.015 oligoprobes (G4112F, Agilent Technologies) was performed for molecular comparison of RCC and TCC cell lines. Expression patterns of 15 pathways were analyzed using the statistical software R (2.12.0) and the LIMMA package.

Results: RCC and TCC cell lines demonstrated dose dependent inhibition of cellular growth with IC50 values of 10-20nM of temsirolimus/CCI-779 as measured by quantitative real time impedance analysis. Furthermore six out of 15 pathways including the mTOR and VEGF signalling were found with similar expression patterns following treatment with CCI-779 in both tumor entities.

Conclusions: In vivo and in vitro analysis of temsirolimus mTOR inhitibtion on human bladder cancer cell lines support the hypothesis that a common molecular architectur exists in both tumor entities suggesting inhibition of mTOR in TCC as a possible target for further experimental therapeutic studies.
Outcomes of radical cystectomy for micropapillary urothelial carcinoma at the University of Southern California.
Authors: Fairey Adrian Stuart , Daneshmand Siamak , Schuckman Anne , Leiskovsky Gary , Djaladat Hooman , Cai Jie , Miranda Gus , Skinner Eila C.
Published: February 2017

300

Background: The role of micropapillary urothelial carcinoma (MUC) variant histology as an independent prognostic factor for survival after radical cystectomy has not been studied. Our aim was to examine the impact of MUC on survival.

Methods: A retrospective analysis of prospectively collected data from the University of Southern California (USC) Bladder Cancer Database was performed. Between 1985 and 2008, 1681 patients underwent radical cystectomy and extended pelvic lymph node dissection for primary bladder cancer. All surgical specimens underwent central pathologic review by dedicated genitourinary pathologists. Histologic type was categorized according to the WHO/ISUP 1998 classification as urothelial carcinoma (UC; n=1648) or MUC (n=33). The outcomes were overall survival (OS) and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression models were used to analyze survival data.

Results: The median follow-up duration was 10 years (range, 0 to 25 years). Baseline characteristics were similar between histologic types except MUC was associated with advanced clinical (cTanyN1-3: 2% versus 9%, p=0.03) and pathologic (pTanyN1-3: 23% versus 46%, p=0.01) TNM stage, multifocality (37% versus 58%, p=0.02), and high nuclear grade (84% versus 97%, p=0.04). The predicted 5-year OS (59% and 67%, Log rank p=0.79) and RFS (67% and 58%, Log rank p=0.50) rates did not differ between patients with UC and MUC. Multivariable analysis showed that histologic type was not independently associated with OS (HR 0.92, 95% CI 0.56 to 1.50, p=0.73) or RFS (HR 0.92, 95% CI 0.52 to 1.63, p=0.77).

Conclusions: Outcomes of radical cystectomy for patients with MUC are similar to those with UC when controlling for other clinical and pathologic factors.
Temsirolimus in platinum-resistant metastatic urothelial cancer: A phase II trial.
Authors: Gerullis Holger , Eimer Christoph , Georgas Evangelos , Bangner Jens Willem , Otto Thomas
Published: February 2017

302

Background: This investigator initiated phase II trial assessed temsirolimus, an inhibitor of mamalian target of rapamycin (mTOR), as second-line therapy in patients with locally advanced or metastatic TCCU after failure of platinum-containing therapy.

Methods: 15 patients were enrolledin this phase II trial from June/2009 to June/2011. Primary endpoint was overall survival, as secondary endpoints we defined time to disease progression, safety and QoL along treatment. Patients with progressive TCCU after prior platinum-based chemotherapy received 25 mg of temsirolimus for 8 weeks. Evaluation for response was acomlished every 8 weeks according to the RECIST criteria, QoL assessment was done every 4 weeks using the QLC-C30 questionnaire, adverse events (AEs) were recorded and graded using NCI-CTC criteria.

Results: We enrolled 15 patients in this study, of whom 14 (93%) were available for activity and safety assessment. We treated 10 (71%) male and 4 female (29%) patients median age was 64.7 years (45-76). Patients received on average 13 (3-15) infusions of temsirolimus. Median overall survival was 3.5 months (107 days). Median time to disease prgression was 2.5 months. Four patients with transient stable disease were observed. QoL assessment along treatment revealed a reduction of EORTC-QLQ-C30 (Global Health Status-Subscale) from initial 7.86 to 5.00. Temsirolimus was well tolerated, mostly observed were fatigue (Grade 3-4) in 2 patients, pancytopenia (Grade 3-4) in 2 patients, thrombopenia (Grade 3-4) in 2 patients. All other adverse events were grade 1-2 in nature.

Conclusions: The primary endpoint was not met with an overall survival of 3.5 montsh only. Therefore the trial was closed after 14 patients. Temsirolimus seems to have poor activity in patients with progressive metastasized TCCU after platinum-containing first-line therapy.
Neoadjuvant cisplatin/gemcitabine (CG) chemotherapy for muscle-invasive transitional cell carcinoma of the bladder (TCCB): A single-institution experience.
Authors: North Scott A. , El-Gehani Faraj , Venner Peter
Published: February 2017

304

Background: Despite evidence of a survival advantage for neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) for muscle-invasive TCCB, many patients are not treated. While many Canadian centers use CG chemotherapy in this setting, there is little data on pathologic response rate, often considered an important predictor of long term outcome. This retrospective study was undertaken to determine the use of neoadjuvant treatment prior to RC at our institution and assess pathologic response rates at time of RC for patients receiving neoadjuvant CG.

Methods: A retrospective chart review was performed on all patients undergoing RC between January 1, 2007 and June 30, 2011 in Edmonton, Alberta, Canada. Data were collected on patient demographics, pre-treatment clinical stage information, type and amount of chemotherapy administered, and pathologic data from RC specimens.

Results: A total of 251 RC were performed during the study period. Eighty-three RC were performed for non-muscle invasive TCC: 15 non-malignant causes, 27 refractory superficial TCC, 41 non-TCC malignant histology. A total of 168 RC were performed for T2-T4 TCC. Median age at diagnosis was 68 years. Ninety-two (55%) patients received neoadjuvant CG. Seventy-five (45%) patients went straight to RC. Reasons for neoadjuvant GC not being given include: medical contraindication in 43 patients (56%), patient refusal in 9 patients (12%) and lack of referral to Medical Oncologist in 24 patients (32%). Of a possible 116 patients who would have been eligible to receive neoadjuvant chemotherapy, 92/116 (79%) were treated. Of the 92 patients receiving chemotherapy prior to RC, 19 (21%) of the surgical specimens were pathologically free of cancer (pT0) at the time of surgery and 18 (20%) had only superficial disease remaining. By contrast, only three (4%) of the 75 patients who went to immediate RC achieved pT0 status and 5 (7%) had remaining superficial disease.

Conclusions: The use of neoadjuvant chemotherapy prior to RC at our institution is higher than quoted in published literature. The use of neoadjuvant GC improves the chances of eliminating residual cancer in the RC specimen.
Pathologic down-staging and complete pathologic response with gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder.
Authors: Psutka Sarah P. , Olumi Aria F. , Feldman Adam S. , Saylor Philip James , Kaufman Donald S. , Lee Richard J.
Published: February 2017

307

Background: Neoadjuvant chemotherapy (NC) with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) improves survival in muscle invasive urothelial cancer (MI−UC) with patients who achieve pathologic complete response (PCR) following radical cystectomy (RC). Gemcitabine/cisplatin (GC) NC is increasingly employed due to lower toxicity, however, its effectiveness as neoadjuvant therapy is controversial and multiple studies have reported poor utilization of this therapy, despite recent recommendations advocating for broader use. We describe pathologic and clinical outcomes following NC and RC.

Methods: We retrospectively evaluated patients with MI−UC who received NC between 2003 and 2011 (n=38). Those who were treated with neoadjuvant radiation therapy (n= 15) were excluded. We compared initial clinical stage at surgery to final pathological stage and assessed overall−median progression free−survival. Mean follow−up was 25 months (SD 21.6, range 3 –76 months).

Results: Twenty-three patients who received NC were included. Nineteen patients (82.6%) were treated with GC, 3 (13.0%) with MVAC, and 1 (4.3%) with gemcitabine/paclitaxel. The median time from start of NC to RC was 119 days (IQR 98.5−146). 10/19 (52.6%) patients treated with GC achieved PCR (pT0) from clinical stage T2 (n=5), cT3 (n=2) and cT4 (n=3), and 6 (31.2%) were downstaged to pT1 and pTIS from cT2. Two patients treated with MVAC were downstaged to pT1 and one achieved PCR. Median recurrence-free survival was 13 months (IQR 6−19 months) with 8 patients developing recurrent or metastatic UC following RC. At median follow-up of 19 months (IQR 8−31.2 months, Range 1−71 months), 15/23 (65.2%) patients were disease free, all of whom had received GC NC prior to cystectomy.

Conclusions: Neoadjuvant GC for MI−UC was associated with a 52.6% PCR rate at RC and was well tolerated. These data compare favorably with published data on GC and MVAC as NC, and warrant further study.
The impact of preoperative ASA and serum albumin on early complication and survival rate of patients undergoing radical cystectomy for bladder cancer.
Authors: Djaladat Hooman , Fairey Adrian Stuart , Cai Jie , Miranda Gus , Schuckman Anne , Skinner Eila C. , Daneshmand Siamak
Published: February 2017

313

Background: American Society of Anesthesiologist (ASA) score is used to evaluate the physical status of patients before surgery. Serum albumin is also a known marker of nutritional status. We evaluated the impact of preoperative ASA score and serum albumin on early complication and survival of pts who underwent radical cystectomy for bladder cancer.

Methods: 1,964 patients with bladder cancer underwent cystectomy between 1971 and 2008 at the USC. Preoperative serum albumin and ASA score were available in 1471 and 1140 patients respectively. Post cystectomy early complication was defined as any postoperative event leading to lengthening hospital stay or re-admission within 90 days of surgery. Recurrence free survival (RFS) and overall survival (OS) for these cohorts were reviewed.

Results: The demographic data of pts based on their serum albumin and ASA score is presented in table 1. Median follow up was 12.4 years (0 - 36.6 yrs). Low serum albumin (<3.4 g/dL) and high ASA score (3 or 4) were associated with higher early complication rate (43% vs. 33%, p= 0.03 and 40% vs. 28%, p= 0.0001 respectively). In multivariable analysis, low serum albumin was an independent predictor of RFS (HR 1.35, 95% CI 1.00-1.81) and OS (HR 1.62, 95% CI 1.29-2.04). High ASA score was an independent predictor of OS (HR 1.45, 95% CI 1.13-1.85), but not RFS.

Conclusions: Preoperative low serum albumin and high ASA score are independently predictive of post cystectomy decreased overall survival. Low serum albumin is also a risk factor for recurrence after cystectomy. These parameters potentially could be used in nomograms to predict postoperative prognosis in patients undergoing radical cystectomy. Demographic data in 1,471 and 1,140 patients who underwent cystectomy for bladder cancer based on preoperative serum albumin and ASA score, respectively.

[Table: see text]
HPV status in relation to clinicopathologic variables in patients with penile cancer at Los Angeles County-USC Medical Center.
Authors: Schwartz Rachel L. , Jayaratna Isuru Sampath , Mitra Anirban Pradip , Da Silva Diane , Kast W Martin , Chen Moli , Ma Yanling , Quinn David I. , Dorff Tanya B. , Schuckman Anne
Published: February 2017

329

Background: Penile squamous cell carcinoma (PSCC) is a disfiguring and deadly disease. US cancer registry reports a higher incidence in certain minority communities including those over-represented at LAC-USC. Human papilloma virus (HPV) infection is strongly associated with PSCC. This study examined correlations of HPV presence and subtype with PSCC patient clinicopathological variables.

Methods: After IRB approval, a retrospective review of PSCC patients at LAC-USC between 1996-2010 was completed. HPV presence and genotype was detected from primary tumors of 33 patients by DNA amplification followed by reverse line blot hybridization. Associations with patient and tumor characteristics were examined by contingency analyses.

Results: 20 (60.6%) patients were HPV+, and 85% of all HPV+ cases harbored at least one high-risk viral strain (80% of all positive cases had HPV 16, 5% HPV 31, 10% HPV 66). 20% of all positive cases harbored low-risk HPV 11; HPV strains 6 or 35 were not detected in any specimen. 3 patients were positive for multiple strains. Overall median age at diagnosis was 53 (range: 24-77) yrs. Median age was 56 yrs and 49 yrs for HPV+ and HPV- patients, respectively. HPV infection showed a trend towards being more prevalent in patients beyond the fifth decade of life, although this did not reach statistical significance (p=0.10). 22 (66.7%) patients were Hispanic; this ethnicity comprised 60% and 77% of HPV+ and HPV- cases, respectively (p=0.31). This cohort included Stage 0 (n= 1, n= 0), Stage 1 (n= 4, n=2), Stage 2 (n= 4, n= 4), Stage 3 (n=5, n= 1), and Stage 4 (n= 4, n= 5) HPV+ and HPV- patients, respectively. Neither HPV status nor presence of nodal metastasis was significantly associated with stage (p=0.50, p=0.52 respectively). Tumor grade was available for 30 (90.9%) cases; while HPV+ cases tended to have higher proportion of moderately-poorly differentiated tumors than HPV- cases (77.8% vs. 58.3%), this was not statistically significant (p=0.32).

Conclusions: An overwhelming majority of HPV+ cases harbored at least one high-risk viral strain. Several interesting associations of HPV status with age and grade were noted, although the study was underpowered to show significance.
Large retroperitoneal lymph nodes (RPLN) as a predictor for venous thromboembolism (VTE) in patients (pts) with germ cell tumor (GCT) receiving first-line chemotherapy (chemo).
Authors: Tran Ben , Moore Malcolm J. , Amir Eitan , Jewett Michael A , Anson-Cartwright Lynn , Sturgeon Jeremy F. G. , Chung Peter W. M. , Warde Padraig Richard , Bedard Philippe
Published: February 2017

332

Background: VTE causes significant morbidity and mortality in GCT pts. While an existing and validated predictive model identifies VTE risk in chemo pts with any cancer (Khorana model), a predictive model specific to GCT does not exist. Many GCT pts present with bulky RPLN that produce venous stasis in the lower extremities. The objective of this study was to explore the association between large RPLN and VTE in GCT pts receiving chemo and compare large RPLN as a predictor for VTE in GCT pts to the non-GCT specific Khorana model.

Methods: Clinical data from our institutional GCT database was complemented by review of radiology, pharmacy and medical records. All GCT pts receiving 1st line chemo between 1-Jan-00 and 31-Dec-10 were included. Large RPLN were defined as ≥5cm in maximal diameter. Factors used in the Khorana model (baseline BMI, hemoglobin, white cell count and platelets) were collected. We compared the predictive accuracy of large RPLN versus Khorana score ≥3 using receiver operator characteristic (ROC) curve statistical analyses.

Results: The cohort consisted of 260 GCT pts, median age 31.5 years, predominantly testis primary (235, 90%) and good risk (171, 66%). 17 (7%) developed VTE prior to the start of chemo. 19 (7%) were given prophylactic anticoagulation, none of whom developed VTE. Of the remaining 224 pts, 20 (9%) developed VTE during chemo. In a univariate analysis, large RPLN was strongly associated with VTE (OR 7.74, p<0.001), as were Khorana score ≥3 (OR 9.81, p<0.001) and hospital admission during chemo (OR 3.96, p=0.004). ROC curve analyses demonstrated large RPLN was a significant individual predictor for VTE (AUC 0.588, p=0.03), however, Khorana score ≥3 was a better predictor (AUC 0.664, p=0.02). Adding large RPLN to create a modified Khorana score provided marginal gains (AUC 0.682, p=0.02).

Conclusions: Although large RPLN at diagnosis predicts for VTE in GCT pts, the Khorana predictive model is superior. Given the high rate of VTE in GCT pts receiving chemo, we recommend prophylactic anticoagulation for pts at increased risk, including pts with Khorana score ≥3, pts requiring hospital admission or pts with large RPLN.
Effect of preoperative antiangiogenic treatment and subsequent discontinuation on angiogenesis in the primary tumor in patients with RCC.
Authors: Bex Axel , Griffioen Arjan W. , Mans Laurie A. , de Graaf Annemarie M. A. , Nowak-Sliwinska Patrycja , Bosch Steven , de Hoog Celine , de Jong Trees A. M. , Vyth-Dreese Florry , Jonasch Eric
Published: February 2017

350

Background: Angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy has not been previously studied.

Methods: A total of 57 primary tumor samples from various retrospective and prospective studies of presurgical sunitinib or bevacizumab were used. In these studies targeted therapy was given with the primary tumor in situ prior to cytoreductive nephrectomy, to investigate impact of therapy on primary tumors. Primary tumor tissues were assessed for microvessel density (MVD), proliferating endothelial cells, pericyte coverage, apoptosis of tumor or endothelial cells and molecular expression of angiogenesis regulators. Results of tumors pretreated with sunitinib discontinued at different intervals before surgery, were compared to similar analyses of untreated and bevacizumab-pretreated tumors.

Results: Sunitinib and bevacizumab pretreatment resulted in a significant reduction of MVD, as well as an increase in vascular pericyte coverage in the primary tumor (sunitinib samples) consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis were found to be suppressed in sunitinib pretreated tissues, among which VEGFR-1 and -2, angiopoietin-1 and -2 and PDGF-B. Apoptosis was induced both by sunitinib and bevacizumab pretreatment. Interestingly, in sunitinib pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab pretreated and untreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.

Conclusions: This study describes the antiangiogenic response in human primary renal cancers upon treatment with VEGF targeted therapy. Treatment discontinuation of tyrosine kinase inhibitors with short half life leads to accelerated angiogenesis. The results of the current study contribute important data to the ongoing discussion on the discontinuation of treatment with tyrosine kinase inhibitors.
Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy.
Authors: Rini Brian I. , Escudier Bernard J. , Michaelson M Dror , Negrier Sylvie , Gore Martin Eric , Oudard Stephane , Clark Joseph , Tarazi Jamal Christo , Rosbrook Brad , Kim Sinil , Motzer Robert John
Published: February 2017

354

Background: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. In the phase 3 AXIS trial of axitinib vs sorafenib for second-line mRCC, axitinib significantly prolonged median progression-free survival (mPFS) (6.7 vs 4.7 months; hazard ratio 0.665; P<0.0001). Here, we evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy.

Methods: Eligible patients had clear-cell mRCC; measurable RECIST-defined progressive disease after 1 prior first-line systemic therapy; and Eastern Cooperative Oncology performance status (PS) 0/1. Patients were stratified by PS and prior therapy, and randomized 1:1 to either axitinib, at a starting dose of 5 mg twice daily (BID), or sorafenib, 400 mg BID. Patients without toxicity >grade 2 and BP <150/90 mmHg without antihypertensive medication for >2 weeks were eligible to increase axitinib dose to 7 mg BID and then to 10 mg BID.

Results: The mPFS for patients receiving at least one total daily axitinib dose >10 mg (dose-titrated group; n=132) was 6.6 months [95% CI 4.7–8.3] and 8.3 months [95% CI 6.0–10.2] for patients receiving axitinib ≤10 mg (n=227). A total of 194 patients (53.7%) in the axitinib arm and 195 patients (53.9%) in the sorafenib arm had prior sunitinib treatment. The mPFS for patients with duration of prior sunitinib treatment ≥6 months and <6 months were 4.8 months [95% CI 4.5–6.5] and 4.6 months [95% CI 2.8–8.3] for axitinib patients; and 4.6 months [95% CI 2.9–4.9] and 2.9 months [95% CI 2.8–4.6), for sorafenib patients. The mPFS for duration of prior sunitinib ≥9 months and <9 months were 6.3 months [95% CI 4.6–6.7] and 4.5 months [95% CI 2.8–6.4] for axitinib patients; and 4.6 months [95% CI 2.8–4.9] and 2.9 months [95% CI 2.8–4.7]) for sorafenib patients.

Conclusions: Duration of prior sunitinib ≥9 months may be associated with a longer PFS on second-line VEGFR tyrosine kinase inhibitors. Both axitinib dose-increased and non-increased patients had longer PFS compared with the sorafenib arm.
Genomic analysis of translocation renal cell carcinoma: Association of frequent 3p loss and poor outcome.
Authors: Malouf Gabriel , Monzon Federico A. , Couturier Jerome , Molinie Vincent , Escudier Bernard J. , Camparo Philippe , Tamboli Pheroze , Wood Christopher G. , Tannir Nizar M.
Published: February 2017

360

Background: Translocation renal cell carcinoma (RCC) is a rare subtype of kidney cancer that is characterized by translocations involving TFEB or TFE3 genes. We recently reported that adults with translocation RCC have worse prognosis than pediatric and adolescent patients (Malouf et al, J Urol, 2011), however little is known about the genetic and epigenetic differences between these groups.

Methods: Cytogenomic analysis was performed with 250K SNP microarrays (Affymetrix) on 19 tumor specimens of translocation RCC (Age <18 (n=6); Age >=18 (n=13) and 2 established cell lines (UOK109, UOK146). Changes in global DNA methylation levels were measured by using pyrosequencing of highly repetitive LINE-1 sequences on 27 tumor samples. Results were correlated with the patients’ clinical data.

Results: 3p loss was observed in 8 patients (42%) and was associated with other chromosomal alterations frequently seen in clear-cell RCC such as 9p loss. Patients with 3p loss showed poor overall survival (OS) as compared to patients without 3p loss (Median OS 12.7 month vs. not reached) [p=0.03]. There was no association found between 3p loss and clinico-pathological variables such as AJCC stage, age and gender. The UOK146 cell line also showed 3p and 9p loss. Young patients (<18 years) displayed fewer number of genetic abnormalities as compared to older patients (p=0.02). Moreover, Line-1 methylation was found to be lower in adult as compared to young patients (76.7% vs. 71.1%, p=0.02).

Conclusions: Our results show that a subset of translocation RCC is characterized by a genetic profile similar to that of clear-cell RCC and these tumors seem to behave aggressively. Studies to determine the presence of VHL mutation in these tumors are underway. Adult patients display higher genetic abnormalities and lower Line-1 methylation as compared to young patients. These results might explain the different behavior of pediatric and adult translocation RCC.
Updated results of a prospective noninterventional study of everolimus after failure of the first VEGF-targeted therapy.
Authors: Staehler Michael D. , Goebell Peter J. , Kube Ulrich , Kindler Manfred , Koepke Thomas , Janssen Jan , Schmitz Joerg , Weikert Steffen , Kloss Susanne , Steiner Gabriel , Jakob Andreas , Steiner Thomas , Overkamp Friedrich , Bergmann Lothar , Guderian Gernot , Doehn Christian
Published: February 2017

361

Background: Everolimus (EVE, Afinitor) is approved for the treatment of metastatic renal cell cancer (mRCC) after failure of VEGF-targeted therapy. The option to treat mRCC with six approved targeted agents has sparked debate on proper sequencing of these agents. However, data beyond clinical trials is limited. Here, we report prospective non-interventional data on EVE in routine use after failure of the first VEGF-targeted therapy.

Methods: A prospective, single arm, open label, multi center non-interventional study for patients with mRCC was initiated in Germany in 08/2009 to determine effectiveness defined as time between first EVE intake until disease progression due to any cause (TTP) and treatment duration. Targeted enrollment is 400 patients. A first interim analysis was conducted 3 months after 100 patients had been enrolled and was presented previously (Bergmann et al., J Clin Oncol 29: 2011 [suppl; abstr 4552]). Here we present a second interim analysis to corroborate the results of the first interim analysis. Patients were analyzed 14 months after the first 100 patients had been enrolled.

Results: 59 sites included 113 patients between August 2009 and July 2010. At the cut-off date of the first interim analysis (12 November 2011), these patients had been followed for a median of 116 days. The safety population consisted of 99 patients with documented EVE treatment. The median treatment duration had not yet been reached at the time of the first interim analysis. Median time to progression (TTP) was 9.7 months (95% CI: 6 months; n.d.). A total of 230 AEs were reported in 61% of patients including 18 SAEs in 12 patients (12%). These preliminary results are substantiated in this interim analysis with a total observation period of at least 14 months (cut-off date 30 September 2011). Updated data on effectiveness and safety of EVE will be presented.

Conclusions: This non-interventional study on EVE in treatment of mRCC after prior failure of VEGF-targeted therapy provides first evidence on routine use of EVE. Further analysis of this ongoing study affords insight into effectiveness and safety of EVE in routine use after failure of the first VEGF-targeted therapy.
Regulation of SETD2, a histone methyltransferase, in advanced clear cell renal cell carcinoma (ccRCC).
Authors: Ho Thai Huu , Monzon Federico A. , Hoang Anh , Tamboli Pheroze , Furge Kyle A. , Dykema Karl , Petillo David , Teh Bin Tean , Tannir Nizar M. , Hung Mien-Chie , Jonasch Eric
Published: February 2017

368

Background: Although the von Hippel-Lindau (VHL) tumor suppressor gene is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified loss of function mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. However it is unclear whether histone modifications are misregulated in RCC. We hypothesize that loss of SETD2 methyltransferase activity decreases H3K36 trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer phenotype.

Methods: To determine if loss of SETD2 protein expression alters H3K36Me3, SETD2 siRNA oligonucleotides were transfected into HEK293 (human embryonic kidney) cells and H3K36Me3 was analyzed by Western blot. To establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA was isolated from 51 VHL deficient ccRCC specimens and analyzed with Affymetrix GeneChip Mapping 250K Nsp single-nucleotide polymorphism (SNP) arrays. To evaluate alterations of histone modifications in metastatic advanced ccRCC, H3K36Me3 immunohistochemical (IHC) staining was quantitated on tissue microarrays (TMAs) representing 28 paired ccRCC specimens with unaffected kidney parenchyma controls and 40 metastases.

Results: SETD2 siRNA decreases H3K36Me3 (>50%) compared to scrambled controls. Using SNP arrays, LOH at chromosome 3p (location of VHL and SETD2 genes) was detected in >90% of the tested ccRCC tumors. IHC reveals a 27.4% and 52.0% decrease in H3K36Me3 positive nuclei in primary ccRCC and metastases, respectively, when compared to matched adjacent unaffected kidney tissue (P value < 0.0001).

Conclusions: SETD2 siRNA decreases H3K36Me3 indicating that SETD2 is a non-redundant H3K36 methyltransferase. LOH of VHL and SETD2 occurs in >90% of tested ccRCC tumors. H3K36Me3 is decreased in primary ccRCC and even more in metastases, suggesting that SETD2 methyltransferase activity is progressively misregulated in RCC. Loss of SETD2 methyltransferase activity may cooperate with VHL silencing to promote tumorigenesis. Future studies will focus on how SETD2 contributes to tumorigenesis and on determining the prognostic and predictive impact of SETD2 phenotypic changes in patients with ccRCC.
Metabolic evaluation of sporadic papillary kidney cancer.
Authors: Shuch Brian , Ricketts Christopher , Sourbier Carole , Tsutsumi Shinji , Zhang Xiu-ying , Belldegrun Arie S. , Wood Christopher G. , Linehan W. Marston , Neckers Len
Published: February 2017

377

Background: Papillary kidney cancer, which occurs in 15% of patients with kidney cancer, can be aggressive and there is currently no effective form of therapy for this disease. To evaluate the metabolic characteristics of sporadic papillary kidney cancer, we have evaluated metabolic parameters of several papillary kidney cancer cell lines and available gene expression profiles.

Methods: Established cell lines derived from patients with sporadic papillary kidney cancer (LABAZ, MDACC-55, HRC-86T2) and from a hereditary form of fumarate hydratase-deficient kidney cancer (UOK262) were evaluated. All sporadic lines were initially sequenced for fumarate hydratase (FH). All cell lines were metabolically profiled using the Seahorse Extracellular Flux Analyzer and further evaluated for reactive oxygen species (ROS), mitochondrial membrane potential, and glucose dependence. Finally gene expression profiles of publically available datasets of papillary and HLRCC tumors were downloaded, normalized, and analyzed.

Results: Sporadic lines had no alterations in FH and metabolic analysis demonstrated normal oxygen consumption and minimal lactate production, in contrast to highly glycolytic UOK262. Also unlike UOK262, the sporadic papillary kidney cancer lines were not sensitive to glucose withdrawal, had low levels of ROS, and had normal mitochondria membrane potential. Principal component analysis (PCA) demonstrated that HLRCC tumor specimens are very different from sporadic papillary tumors at the molecular level.

Conclusions: Our study of established sporadic papillary RCC and fumarate hydratase-deficient HLRCC cell line together with analysis of available gene expression profiles demonstrates that these sporadic papillary kidney cancer cell lines appear to have a distinct metabolic profile from those in the fumarate hydratase deficient kidney cancer cell line. Understanding the metabolic basis of papillary kidney cancer could provide the foundation for the development of targeted approaches to therapy for patients with this disease.
Effect of bisphosphonates (Bis) combined with sunitinib (Su) on the response rate (RR), progression-free survival (PFS), and overall survival (OS) of patients (pts) with bone metastases (mets) from renal cell carcinoma (RCC).
Authors: Keizman Daniel , Ish-Shalom Maya , Taksey Jason David , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Boursi Ben , Berger Raanan , Maimon Natalie , Gottfried Maya , Hayat Henry , Peer Avivit , Kovel Svetlana , Sella Avishay , Carducci Michael Anthony
Published: February 2017

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Background: Bis are used to prevent skeletal events of bone mets, and may exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a RR, PFS, and OS benefit to pts with bone mets from RCC that are treated with Su.

Methods: We performed a multicentre retrospective study of pts with bone mets from RCC who were treated with Su. Pts were divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on RR, PFS and OS, was tested with adjustment for known prognostic factors using a chisquare test from contingency table and partial likelihood test from Cox regression model.

Results: Between 2004–2011, 209 pts with metastatic RCC were treated with Su. 76 pts had bone mets, 35 group 1 and 41 group 2. The groups were balanced regarding the following known prognostic factors: past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to sunitinib treatment (tx), the presence of > 2 mets sites, the presence of lung/liver mets, ECOG performance status, anemia, calcium level >10 mg/dL, elevated alkaline phosphatase, platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, sunitinib induced HTN, and the use of angiotensin system inhibitors. They were also balanced with regard to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective response was partial response/stable disease 86% (n=30) vs 71% (n=29), and progressive disease 14% (n=5) vs 29% (n=12) (p=0.125, OR 2.48) in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 2.6, p < 0.0001), and median OS 21 vs 13 months (HR 2.1, p=0.029), in favor of group 1. In multivariate analysis of the entire pt cohort (n=76), factors associated with PFS were Bis use (HR 2.2, p=0.035) and pre-tx NLR >3 (HR 0.38, p=0.009). Factors associated with OS were Bis use (HR 2.8, p=0.008), elevated alkaline phosphatase level (HR 0.287, p=0.0003), and Su induced HTN (HR 5.57, p < 0.0001).

Conclusions: Bis may improve the outcome of Su tx in RCC with bone mets. Whether this is generalizable to other TKIs is not known. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Population-based analysis of cancer control of partial nephrectomy for high-risk localized renal cell carcinoma.
Authors: O'Malley Rebecca Leigh , Hayn Matthew H. , Wilding Greg , Schwaab Thomas
Published: February 2017

385

Background: Partial nephrectomy (PN) has reported equivalent oncologic outcomes with superior renal function outcomes when compared to radical nephrectomy (RN) for treatment of localized renal cell carcinoma (RCC). Whether PN provides adequate cancer control in high risk disease is unclear. To clarify, survival outcomes were compared between those who underwent RN and PN for high risk RCC.

Methods: Using the Surveillance, Epidemiology, and End Results database patients with RCC who underwent PN or RN for a localized tumor ≤ 7cm were identified. Cancer-specific (CSS) and overall survival (OS) were compared between those with high risk disease (defined as poorly or undifferentiated grade and/or pathologic stage T3) who underwent PN or RN.

Results: Of 51,183 patients with localized RCC ≤ 7cm, 24.9% had high risk disease, 85.2% and 14.8% of which underwent RN and PN, respectively. Five-year CSS was superior in the PN group vs. the RN group (93.3% vs. 86.0%, p<0.001). On multivariable analysis undergoing RN was no longer predictive of CSS (HR 1.23, p=0.08). Similarly, 5-year OS was superior in the PN versus RN group (79.5% vs. 70.1%, p<0.001). RN remained independently associated with poor OS on multivariable analysis (HR 1.16, p=0.031). Propensity analysis accounting for factors affecting selection for type of nephrectomy produced similar results. RN did not influence CSS but portended a 20% increased risk of death from all causes (p=0.008).

Conclusions: In patients with high risk RCC, partial nephrectomy is associated with improved OS and does not compromise cancer control as compared to radical nephrectomy.
Development of a molecular profiling assay for circulating tumor cells (CTCs) utilizing automated multiplexed in situ hybridization for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Nagy Dea , Crespo Mateus , Attard Gerhardt , Miranda Susana , Garsha Karl , Sathyanarayana Ubaradka G. , Yun Steve , Otter Michael , Miller Phillip , Pestano Gary , De Bono Johann Sebastian , Dittamore Ryan
Published: February 2017

39

Background: ERG gene rearrangements lead to overexpression of the ERG oncogene in 50% of localized and metastatic prostate cancers. Recent studies have indicated that this gene fusion correlates with androgen sensitivity in prostate cancer patients and an association with increased DNA Repair activity (PARP1). The PTEN tumor suppressor has also been shown to regulate the AKT pathway, and related to increased PARP1 activity. We hypothesized that future PARP1 inhibitors and other targeted therapies for mCRPC will likely require the development of a companion diagnostic assay for measuring ERG rearrangement and PTEN deletion status in CTCs.

Methods: We isolated CTCs utilizing the CellSearch system from mCRPC patients for enumeration. Following enumeration, the cells were transferred to glass slides and interrogated utilizing the automated Benchmark staining platform with multiplexed Quantum Dot FISH inclusive of probes for 5’ERG, 3’ERG, PTEN, and Cen 10. FISH signals were visualized utilizing spectral imaging.

Results: Successful transfer of the CTCs from the CellSearch to a glass slide were achieved In model cell line systems, in cultured cells (LnCaP and VCaP) either directly or after spiking to PBL and five out of 6 times we were able to successfully demonstrate simultaneous single copy 5’ and 3’ ERG and PTEN/Cen 10 labeled probes. Studies are in progress to extend the clinical utility of this assay to isolated CTC from cases with metastatic prostate cancer.

Conclusions: CTCs are likely to be utilized clinically for monitoring disease progression mCRPC patients as measures for therapeutic efficacy. As more therapeutics are approved for use in mCRPC patients, the ability for oncologists to molecularly characterize the type of CTCs driving tumor burden is likely to play a significant role in optimizing patient management by determining the type and the sequence of future targeted therapies. We have for the first time demonstrated a platform to molecularly characterize patient CTCs on an automated platform that is amenable to standard clinical use.
Prostate-specific antigen testing among primary care physicians and urologists: Patterns of care and impact of professional society guidelines.
Authors: Prasad Sandip M. , Alexander G. Caleb , Eggener Scott E.
Published: February 2017

40

Background: During the past decade, the incidence of prostate cancer in the United States has declined. We hypothesized this was related to lower rates of prostate-specific antigen (PSA) testing and sought to evaluate PSA testing rates nationally.

Methods: Using the National Ambulatory Medical Care Survey, a nationally representative sample of outpatient visits in the United States, we analyzed rates of PSA testing in men age 40 years or older who visited PCPs or urologists from 1997 to 2008.

Results: An estimated 26.6 million (95% CI: 24.8-28.4 million) PSA tests were ordered during 94.5 million (95% CI: 90.9-98.1 million) office visits to urologists and 95 million (95% CI: 87.5-102.8 million) tests were ordered during 1.17 billion (95% CI: 1.15-1.18 billion) visits to PCPs, with an annual increase of 3.4% and 6.0%, respectively (P=0.055 and P<0.001 for trend). After adjusting for year, race, ethnicity, region, insurance and provider type, testing by PCPs was more likely among older men and highest among men aged 60 to 69 years (reference: 40-49 years; OR 2.32, 95% CI: 1.88-2.85). Compared to men without a chronic medical condition, those with one chronic condition had greater odds of receiving a PSA test (OR 1.28, 95% CI: 1.08-1.52).

Conclusions: Prostate cancer incidence has declined over the past decade despite increasing rates of office-based PSA testing by PCPs and urologists during the period. Increasing rates of PSA testing merit scrutiny, especially in men with limited life expectancies who are unlikely to benefit from screening.
Everolimus (E) and temsirolimus (T) associated pneumonitis (P) in patients with metastatic renal cell cancer (mRCC): A single-center experience.
Authors: Cauley Diana H. , Atkinson Bradley J. , Ng Chaan S. , Wang Xuemei , Xiao Lianchun , Corn Paul G. , Jonasch Eric , Tannir Nizar M.
Published: February 2017

401

Background: P is a known adverse effect (AE) of mammalian target-of-rapamycin inhibitors, with a literature reported incidence of 25-45%. The goal of this review was to characterize the incidence, timing, management, and overall survival (OS) of pts treated at our center.

Methods: Retrospective review of 332 patients (pts) with complete, evaluable records, who received E and/or T between 6/1/2007 and 10/1/2010. Clinical correlation was made in conjunction with serial radiologic imaging studies.

Results: P occurred in 25.2 of E and 8.1 % of T pts. 10.7 of E and 11.1 % of T pts reported no symptoms (sx). 60.7 and 72.2 % reported cough, 67.9 and 61.1 % dyspnea, 17.9 and 5.6 % fever, and 67.9 and 88.9 % fatigue, with E and T, respectively. The median # of sx/pt was 2 and 3; 42.9 and 50 % received steroids, 35.7 and 22.2 % received antibiotics, 21.4 and 27.8 % had a pulmonary consult, and 10.7 and 16.7 % received oxygen, with E and T, respectively. Providers discontinued tx in 75 and 38.9%, continued tx in 17.9 and 27.8%, continued at reduced dose in 0 and 5.6%, held and later dose reduced in 7.1 and 16.7%, and held then resumed at same dose in 0 and 11.1% of pts, with E and T, respectively. The median NCI-CTC P grade was 2 (range 1–3) in both groups. No patients died from P.

Conclusions: A higher incidence of P was observed in pts treated with E than T. The finding of improved OS in pts who develop P with E is intriguing and should be further investigated.

[Table: see text]
Incidence of syn- and metachronous adrenal metastasis following tumor nephrectomy: A retrospective bicenter analysis.
Authors: Peters Inga , Herrmann Thomas R. W. , von Klot Christoph , Wegener Gerd , Stransky Petr , Hes Ondrej , Hora Milan , Kuczyk Markus , Merseburger Axel S.
Published: February 2017

417

Background: Metastases of adrenal gland occur in approximately 1.2 - 10% in kidney cancer patients. Synchronous adrenalectomy has become dispensable since studies have demonstrated no clinical benefit. The aim of this large bi-institutional study was to determine the appearance of syn- and metachronous metastasis to the adrenal gland as detected by CT, PET-CT or MRI imaging with consecutively surgically removal of suspicious lesions.

Methods: We retrospectively reviewed the clinical and pathological records of 2308 patients (1200 pts. from Medical School Hanover until 2009 and 1108 pts. from University Hospital Plzeň until 2010) who underwent radical/partial nephrectomy. Synchronous adrenalectomy was carried out in 222 of all cases (10.4%). Metachronous adrenalectomy was performed in 11 cases including 8 ipsilateral and 3 contralateral adrenalectomies due to suspicious imaging among follow-up. In cases of metachronous metastasis pre-operative imaging, surgical and histopathological results were correlated.

Results: Metastatic spread in patients with synchronous adrenalectomy was found in 17/222 cases (7.6%), as suspected. In metachronous procedures positive pathological results was found in 10 of 11 (91%) cases. In one case it was a benign pathological result. In all positive cases a metastasis from the former clear cell carcinoma was pathologically confirmed. 27% of all cases were detected in the contralateral adrenal gland.

Conclusions: Synchronous adrenalectomy is not routinely recommended with nephrectomy. In case of preoperative suspicious imaging an intraoperative frozen section should be performed. Radiological investigations are of high diagnostic value for detecting metachronous tumor growth within the adrenal gland. Surgery in this scenario should be recommended due to the here reported malignancy rate of 91%.