bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of (18F) FDG-PET-CT for preoperative lymph-node staging of bladder cancer.
Authors: van Essen Julius , Grosse Joachim , Pfister David J. K. P. , Epplen Robin , Heidenreich Axel
Published: February 2017

275

Background: Radical cystectomy with extended pelvic lymphadenectomy (EPLA) is the treatment of choice for muscle-invasive bladder cancer. For preoperative staging computed tomography and magnetic resonance imaging of the abdomen and the small pelvis are most commonly used in daily routine.Since the aforementioned methods, have a low sensitivity to detect local lymph node metastasis (LNM) we have prospectively evaluated the role of FDG – PET/CT for locoregional staging.

Methods: In 27 patients (n = 27) with known invasive urothelial carcinoma or squamous cell carcinoma of the bladder a staging FDG – PET - CT was performed 1-2 days prior to radical cystectomy with EPLA. Subsequently, the results of the histopathological work-up of lymph node specimens and their anatomical localisations were correlated to the FDG-PET/CT findings. Total of 452 lymph nodes were removed, on average ≈ 16.7 per patient.

Results: In 3/27 (11.1%) patients LNM were detected in histopathology. 2 patients showed one positive lymph node, 1 patient had two LNM. In two of these patients, the FDG-PET/CT showed an increased enrichment of FDG in projection to the corresponding histologically positive LN. One false negative and one false positive result of FDG-PET/CT were found. Calculated based on the patient population, the following statistics were calculated: Sensitivity (SENS) 66%, specificity (SPEC) 95.8%, positive predictive value (PPV) 66%, negative predictive value (NPV) 95.8%. Related to the absolute number of LN (n = 452), the following numbers were calculated: SENS 75% SPEC 98.7, PPV 37.5%, NPV 99.7%.

Conclusions: To date, few studies have been conducted with regard to FDG-PET/CT and its role in locoregional staging. The reported specificity and NPV was between 86% and 100%, sensitivity and PPV were between 50% and 100%. Our results demonstrate specificity and NPV values of larger than 90% and make FDG-PET/CT a valuable staging tool to potentially identify patients with negative nodes in whom EPLA could be safely ommitted. Curently, routine use of PET CT scans can not be recommended and it is currently tested in a prospective multicenter study including a larger patient cohort.
Alterations in the PI3K/Akt signaling pathway and association with outcome in invasive high-grade urothelial cancer (UC).
Authors: Balar Arjun Vasant , Iyer Gopa , Al-Ahmadie Hikmat , Janakiraman Manickam , Ostrovnaya Irina , Regazzi Ashley Marie , Garcia-Grossman Ilana Rebecca , Pendse Deepa , Bochner Bernard , Bajorin Dean F. , Milowsky Matthew I. , Solit David B.
Published: February 2017

277

Background: Activating mutations in PIK3CA have been associated with improved outcomes in patients (pts) with breast cancer (Kalinsky, Clin Cancer Res 2009). Molecular profiling of invasive high-grade UC demonstrates that PI3K/Akt pathway alterations occur in up to 15% of cases. The prognostic value of PI3K/Akt pathway alterations in invasive UC is unknown.

Methods: Clinically annotated archival frozen surgical specimens from 95 pts (94 cystectomies, 1 nephroureterectomy) with high-grade invasive UC were genotyped for mutations in all coding exons of PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms using high-throughput Sanger sequencing. Copy number alterations were examined using an Agilent 1M oligonucleotide array. Clinical variables including time to recurrence (TTR) and overall survival (OS) were correlated with the presence of mutations or copy number events in PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms.

Results: Specimens from 95 pts (71 M; 24 F) with a median age of 71 years (41-88) were evaluated. 34 (36%) received neoadjuvant chemotherapy and 75 (79%) were prior smokers. 4 pts (4%) had Stage 0, 11 (12%) had Stage I, 15 (16%) had Stage II, 33 (35%) had Stage III and 32 (34%) had Stage IV disease at surgery. The median follow-up was 31.5 months. Alterations (mutations or copy number gains/losses) in PI3K/Akt signaling pathway genes were identified in 26 (27%) specimens and were associated with a trend toward longer TTR, hazard ratio 0.53 (95%CI 0.24, 1.14) (p=0.08).

Conclusions: Alterations in PI3K/Akt signaling in pts with invasive UC may be associated with an improvement in outcome similar to that observed in breast cancer. Further analysis in a large independent tumor set is ongoing.
Prognostic value of extranodal extension and other lymph node parameters in patients with upper tract urothelial carcinoma.
Authors: Cha Eugene K. , Fajkovic Harun , Jeldres Claudio , Chromecki Thomas F. , Rink Michael , Margulis Vitaly , Novara Giacomo , Lotan Yair , Raman Jay D. , Kassouf Wassim , Bensalah Karim , Weizer Alon Z. , Roscigno Marco , Pycha Armin , Ficarra Vincenzo , Montorsi Francesco , Scherr Douglas , Shariat Shahrokh F.
Published: February 2017

281

Background: The aim of the current study was to assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters in a large multicenter cohort of patients with LN metastasis (LNM) following radical nephroureterectomy (RNU).

Methods: Retrospective analysis of 222 patients with LNM treated with RNU for upper tract urothelial carcinoma (UTUC) without neoadjuvant therapy. Microscopically, each LN metastasis was evaluated for presence of ENE.

Results: The median number of LNs removed, number of positive LNs, and LN density were 4 (IQR: 8), 2 (IQR: 2), and 51.3% (IQR: 71.7%), respectively. Overall, 110 patients (49.5%) had ENE. Presence of ENE was associated with more advanced pT stage (p=0.026). In multivariable analyses, ENE was associated with disease recurrence (p=0.01) and cancer-specific mortality (p=0.013). LN density, when stratified by 30% cutoff, was associated with disease recurrence and cancer-specific mortality (p=0.048 and p=0.049) in univariable, but not in multivariable analyses. Addition of ENE to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p<0.001). Addition of ENE to a multivariable model including age, pT stage, and tumor architecture improved predictive accuracy for cancer-specific mortality from 70.6% to 74.4% (p<0.001).

Conclusions: ENE is a powerful predictor of clinical outcomes in UTUC patients with LNM. While other LN parameters seem to have limited clinical value, ENE could help risk stratify UTUC patients with LNM for better counseling and clinical trial design.
Prognostic impact of expression Notch-1 in invasive bladder transitional cell carcinoma.
Authors: Yousif Nasser Ghaly , Deb Abdallah Ali , Al-Matwari Majid , Mousa Husham J.
Published: February 2017

299

Background: Notch signal pathway plays a fundamental role in mediator of tumorigenesis, either as a tumor promoter or suppressor, depending on cellular context and expression levels; we investigated the prognosis of invasive bladder transitional cell carcinoma patients with over-expression of Notch-1.

Methods: Tumor tissue samples from 78 resected patients with invasive bladder transitional cell carcinoma were obtained, and immunohistochemistry was used to evaluate the expression of the molecular markers Notch-1 and Jagged-1. To further confirm the immunohistochemical results tissue samples were subjected to RT-PCR and Western blot analysis, staining evaluation results were analyzed statistically in relation to various clinicopathological characters. Kaplan–Meier and Cox proportional hazards regression methods were used to assess associations of Notch-1 expression with invasive bladder transitional cell carcinoma survival.

Results: Survival time in patients with high expression of Notch-1 and Jagged-1 was significantly shorter than that in patients with low expression p=0.009 and more recurrence p=0.01, in multivariate analysis, Notch1 expression was proved to be an independent predictor of prognosis; (hazard ratio Notch-1 was 1.93 (95% CI, 1.02-3.03; P =0.014), expression was not related to patient sex or age.

Conclusions: Notch-1 expression is associated with tumor progression, indicating that Notch-1 may be involved in the carcinogenesis and progression of invasive bladder transitional cell carcinoma. These findings also suggest that Notch-1 may be a potential diagnostic marker and therapeutic target in patients.
Comparative effectiveness of intensity modulated radiation therapy (IMRT), proton therapy (PT), and conformal radiation therapy (CRT) in the treatment of localized prostate cancer.
Authors: Sheets Nathan Christopher , Goldin Gregg , Meyer Anne-Marie , Wu Yang , Chang YunKyung , Sturmer Til , Holmes Jordan A , Reeve Bryce B. , Godley Paul Alphonso , Carpenter William Ruffin , Chen Ronald C.
Published: February 2017

3

Background: Comparative effectiveness research is urgently needed in prostate cancer because of the rapid adoption of newer and costlier radiation treatments such as IMRT and PT despite limited demonstrated benefit compared to prior technologies. We compared the morbidity and disease control outcomes of IMRT, PT and the older CRT for primary prostate cancer treatment.

Methods: Population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2000 through 2009 for patients with non-metastatic prostate cancer. Propensity score adjustment was used to balance demographic, disease and institutional characteristics. Rates of morbidity (gastrointestinal, urinary, erectile dysfunction, hip fractures) and additional cancer therapy (surrogate for recurrence) were calculated.

Results: IMRT use increased from 0.15% in 2000 to 95.9% in 2008. In propensity score-adjusted analyses, men who received IMRT vs. CRT were less likely to be diagnosed with GI morbidity (13.4 vs. 14.7 per 100 person-years, p<0.001) and hip fractures (0.8 vs. 1.0, p=0.006), but more likely to be diagnosed with erectile dysfunction (5.9 vs. 5.3, p=0.006). IMRT patients were less likely to receive additional cancer therapy (2.5 vs. 3.1, p<0.001). In a propensity-score matched comparison between PT and IMRT, PT patients had a higher rate of GI morbidity (17.8 vs. 12.2 per 100 person-years, p<.001). No significant differences in rates of other morbidities or additional therapies between PT and IMRT.

Conclusions: IMRT vs. CRT was associated with less GI morbidity and hip fractures, more erectile dysfunction, and less need for additional cancer therapy. This large-scale population-based study is the first to suggest a simultaneous reduction in disease recurrence and morbidity in patients treated with IMRT vs. CRT for localized prostate cancer. Proton therapy did not significantly improve outcomes compared to IMRT, but had increased GI morbidity. These results provide new and long-needed information to decision-makers regarding the currently available evidence on the comparative effectiveness of different RT techniques.
Pooled analysis of phase II trials evaluating weekly or conventional cisplatin as first-line therapy for advanced urothelial carcinoma (UC).
Authors: Agarwal Neeraj , Boucher Kenneth M. , Maughan Benjamin , Hussain Syed A. , Kaufman Donald S. , Lorusso Vito , Moore Malcolm J. , Galsky Matt D. , Sonpavde Guru ,   SWOG
Published: February 2017

308

Background: Weekly gemcitabine with day 1 cisplatin 70 mg/m2 every 3-4 weeks (GC) is considered a conventional first line chemotherapy for advanced UC. Weekly split-dose cisplatin (delivering a similar cumulative dose per cycle) with concurrent weekly gemcitabine (wGC) may be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC and wGC to compare efficacy and safety.

Methods: Two trials of wGC (n=74) patients and 3 trials of GC (n=131) were identified. A Cr Cl ≥60 ml/minute was required, except one trial of wGC that enrolled 19 patients with Cr Cl 40-60 ml/minute. Since the data were not derived from randomized trials, GC and wGC were not formally compared, and exact 95% quasi-binomial confidence intervals (CI), which allows for heterogeneity between studies in the same grouping, for response rates and grade ≥3 toxicities were calculated. Long-term outcomes were not uniformly reported and hence inevaluable.

Results: The 95% CI overlapped, suggesting agreement between wGC and GC (Table). After accounting for random variability, no clear difference in the CR, PR, SD and grade ≥3 toxicities between GC and wGC were observed. Limitations of a retrospective study apply.

Conclusions: GC and wGC yielded similar responses and grade ≥3 toxicities in advanced UC. These results are hypothesis-generating and in the absence of randomized trials, wGC should not be routinely substituted for GC in cisplatin-eligible patients.

[Table: see text]
Association between cancer stem-like cell gene expression and clinical outcome in localized prostate cancer: A nested case-control study.
Authors: Fairey Adrian Stuart , Yang Dongyun , Groshen Susan G. , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Stephens Craig , Cooc Janine , Goldkorn Amir
Published: February 2017

31

Background: New biomarkers are needed to better predict outcome after radical prostatectomy for clinically localized prostate cancer. Recent data suggest that subpopulations of cancer stem-like cells (CSC) are present in prostate cancer, and the CSC phenotype has been associated with high tumorigenicity, drug resistance, and disease progression. We sought to determine whether the expression of genes associated with the CSC phenotype are associated with disease recurrence.

Methods: A nested case-control study was performed. Cases were men who underwent radical prostatectomy and had disease recurrence (n=147). Controls were men who underwent radical prostatectomy and did not have disease recurrence (n=59). Cases and controls were matched based on D’Amico risk stratification group. Laser capture microdissection with mRNA extraction and quantitative RT-PCR were used to measure the expression of 9 novel candidate CSC-associated genes (Axin2, Bmi1, CD133, CD44a, CTNNB1, ITGA2, Nkx3-1, Notch1, TACSTD2) in formalin-fixed, paraffin-embedded radical prostatectomy specimens. The Wilcoxon test was used to examine the association between CSC-associated gene expression and D’Amico risk stratification group. The optimal chi-square approach and recursive partitioning analysis were used to determine the association between CSC-associated gene expression and disease recurrence.

Results: Complete gene expression data were evaluable for 206 out of 261 patients (79%). The median age was 64 years (range, 42-78 years). High expression of TACSTD2 (p=0.04) and CD44a (p=0.05) were associated with D’Amico low risk group. The optimal chi-square approach showed that Axin2 was associated with disease recurrence (recurrence rate: Axin2 ≤ 3.83 = 80% versus Axin2 > 3.83 = 43%, p=0.0015). Recursive partitioning analysis confirmed an association between Axin2 and disease recurrence.

Conclusions: A novel finding of the current study was that a low gene expression level of Axin2 was associated with disease recurrence. High gene expression levels of TACSTD2 and CD44a were associated with D’Amico low risk group. Further analysis of the Wnt/beta-catenin pathway is ongoing in this cohort.
Trends in the adoption of robotic technology for radical cystectomy: A population-based analysis.
Authors: Chang Steven Lee , Jiang Wei , Chung Benjamin I.
Published: February 2017

311

Background: The adoption of the da Vinci Surgical System (Intuitive Surgical, Inc.) for robotic surgery requires a substantial financial investment by hospitals, acquisition of new surgical skills by surgeons, and demand from patients. Although the benefits of this technology have been previously described, the prevalence and adoption rate for robotics in the management of bladder cancer is not currently known. We performed a population-based analysis to determine how the introduction of robotic technology has altered the surgical management of bladder cancer.

Methods: We analyzed patient-level data from the Prospective Rx Comparative Database (Premier, Inc., Charlotte, NC), which collects data from over 600 non-federal hospitals throughout the United States. We captured all patients who underwent a radical cystectomy with a diagnosis of bladder cancer between January 1, 2003, and December 31, 2010, based on codes from the International Classification of Disease, 9th edition. Radical cystectomies utilizing the da Vinci Surgical System were identified by a detailed review of the hospital charge data.

Results: There was an increase in an overall adoption of robotic radical cystectomy from <2% in 2003 to 23% in 2010. Since 2005, teaching hospitals had a relative increased utilization of robotic radical cystectomy by approximately 40% each year compared to non-teaching hospitals. Hospitals in the West had the highest odds (odds ratio [OR] 3.1, p<0.001 [vs Midwest]) of utilizing robotic surgery for radical cystectomy while larger hospitals (>200 beds) were more likely to adopt robotic technology for radical cystectomy (OR 1.78, p<0.0001).

Conclusions: There has been a relatively rapid adoption of the da Vinci Surgical System in the performance of radical cystectomy. This increased utilization is potentially secondary to the acquisition of robotic surgical skills and familiarity with transperitoneal pelvic anatomy following the widespread use of robotic technology for radical prostatectomy during the same time period.
Small cell carcinoma of the genitourinary tract: A 10-year single institution experience.
Authors: El-Gehani Faraj , Dechaphunkul Arunee , Kamal Muna , Pertschy Danielle , Joseph Kurian , North Scott A. , Venner Peter , Pervez Nadeem
Published: February 2017

312

Background: Small cell carcinoma (SCC) of the genitourinary (GU) tract is rare and there is no standard treatment strategy for managing these patients. The objective of this study is to report the clinical experience and management of patients with SCC of the GU tract, treated in the Cross Cancer Institute, Edmonton, AB, Canada from 1999 to 2009.

Methods: A retrospective chart review of all patients diagnosed with SCC of the GU tract between 1999 to 2009 was undertaken. Data was collected on demographics, clinical and pathological characteristics, and patient outcomes.

Results: Fifty-eight patients were identified with primary sites as follows: urinary bladder (UB) 35 (60%), prostate 17 (29%) and upper urinary tract (UUT) 6 (11%). Mean age for the entire group was 68 years; 12/58 were female and 46/58 were male. Sixty-six percent (37/58) had pure SCC; the rest had mixed histology. Seventy percent (41/58) were positive for at least one neuroendocrine marker. Overall, 27/58 had limited stage disease, 25/58 had extensive disease and six were unknown. Treatment of limited stage patients was 10/27 (37%) concurrent chemotherapy with radiation, 5/27 (19%) surgery +/- adjuvant chemotherapy, 5/27 (19%) chemotherapy alone, 2/27 (7%) radiation alone and 5/27 (19%) supportive care only. For extensive stage patients, 5/25 (20%) received chemotherapy alone, 3/25 (12%) received radiation alone, 4/25 (16%) received RT and chemotherapy, 4/25 (16%) surgery alone and 9/25 (36%) supportive care only. One patient with limited stage disease received prophylactic cranial irradiation. Despite this, only one patient in the entire cohort presented with brain metastases as the site of initial relapse. Median survival for the entire cohort was 24 months (28 months for limited stage disease and 7 months for extensive). Prostate patients tended to do worse, with a survival of only eight months.

Conclusions: SCC of the GU tract is aggressive with an overall poor prognosis. As there is no standard of care for these patients, they are treated according to local protocols. Further efforts should be made to develop more effective treatments and the role of PCI should be investigated in the setting of a clinical trial, in conjunction with other extrapulmonary SCCs.
Could a salvage lymphadenectomy after chemotherapy have clinical impact on cancer survival in patients with metastatic urothelial carcinoma?
Authors: Saika Takashi , Bekku Kensuke , Kishimoto Ryo , Ebara Shin , Edamura Kohei , Kurose Kyohei , Nasu Yasutomo , Kumon Hiromi ,   Okayama Urological Research Group
Published: February 2017

321

Background: A clinical impact of salvage lymphadenectomy after chemotherapy in urothelial carcinoma patients with metastatic lymphnodes swelling is controversial. We verified a clinical role of salvage lymphadenectomy with analyzing long-term outcome after salvage surgery in the patients treated with cisplatin/gemcitabine-based chemotherapy.

Methods: From 2003 to 2011, 20 of 28 (71%) urothelial carcinoma patients with metastatic lymphnodes showed objective responses (CR in 2, PR in 18) after multiple courses of the chemotherapy. Thirteen of the PR patients underwent salvage lymphadenectomy after the chemotherapy (9 male and 4 female, median 64.0 years old). Seven of the patients underwent radical surgeries for primary lesions as well. Remaining 5 patients denied salvage surgery. Progression free survival and overall survival of the patients were analyzed retrospectively in comparison with those of patients without salvage surgery.

Results: All 13 patients could achieve surgical CR. Pathological findings showed pathological CR in 9 patients. In median follow-up 26.9 months (range: 4.5-74.6), progression free survival and cause specific survival in patients with salvage lymphadenectomy showed better trends in comparison with those in 5 PR patients without the surgery (63.5% vs 20.0%, and 85.7% vs 40.0% at 2 years, p=0.0907 and 0.0229; log-rank test).

Conclusions: Although this study was retrospective and nonrandomized, salvage lymphadenectomy in patients with residual tumor after GCP chemotherapy could have an impact on cancer survival. Surgical CR should be achieved in an affordable patient who is responder of GCP therapy.
Immunohistochemical expression of cancer stem cell markers OCT3/4, NANOG, DPPA4, and CCND2 in testicular germ cell tumors.
Authors: Moniz Ravendra Ryan , Costa Walter Henriques , Fanni Victor Soares , Cunha Isabela Werneck , Rocha Rafael Malagoli , Guimaraes Gustavo Cardoso , Zequi Stenio C.
Published: February 2017

333

Background: The purpose of this study was to examine the immunohistochemical expression of OCT3/4, CCND2, DPPA4 and NANOG in primary non-seminomatous germ cell testicular tumors that might be associated with different entities of germ cell tumors. OCT3/4, NANOG, DPPA4 and CCND2 have been identified as key regulators of pluripotency in mammalian embryonic and induced stem cells.

Methods: Tissue samples of non seminoma testicular germ cell tumors including carcinoma in situ (CIS, n=10), seminoma component (n=5), embryonic carcinoma (n=20), mature teratoma (n= 7), immature teratoma (n=7), yolk sac tumor (n=5) and choriocarcinoma (n=3) were first analyzed by histological evaluation followed by selection of the appropriate tissue sections prepared from paraffin embedded testicular tissue blocks fixed with buffered formalin. To investigate immunohistochemical expression, of cancer stem cell markers samples tissues were analyzed under central pathological evaluation.

Results: In CIS cells all markers were detected with a strong immunohistochemical expression suggesting that CIS cells maintain characteristics of embryonic stem cells. The invasive tumor samples, in comparison, showed a more heterogeneous expression pattern of OCT3/4, NANOG, DPPA4 and CCND2. There was an abundant expression in seminomas and embryonic carcinomas compared to a marked reduction expression in choriocarcinoma and teratomas. The expression of the markers was related to tumoral tissue differentiation. The seminomatous component and the embryonic carcinoma and undifferentiated tissues such as intratubular neoplasia presented elevated expressions. Specialized tissues such as teratoma and choriocarcinoma present low expression levels or absence of studied markers. The teratomatous subtypes do not express NANOG. The sub-type coriocarcinoma tumors do not express CCND2 and NANOG.

Conclusions: The immunohistochemical expression of stem cell markers OCT3/4, NANOG, DPPA4 and CCND2 follow a specific pattern that is related to tumoral differentiation and consequent loss of pluripotency characteristics.
Consolidative high-dose chemotherapy (HDCT) after conventional-dose chemotherapy (CDCT) as first salvage treatment for male patients (pts) with metastatic germ cell tumors (mGCTs).
Authors: Beausoleil Michel S , Potvin Kylea R. , Howson-Jan Kang , Ernst D. Scott , Stitt Larry , Winquist Eric
Published: February 2017

336

Background: Some men with mGCTs progressing after response to initial cisplatin-based combination chemotherapy are cured with CDCT as 1st salvage, however, many are not. Prognosis has recently been better defined by the IPFSG prognostic factors. HDCT with autologous stem cell rescue has been routinely offered after CR/PRm- remission with CDCT at our institution over the past two decades. We retrospectively reviewed our data to assess the validity of the IPFSG prognostic factors and evaluate the potential value of this approach.

Methods: Eligible men with mGCTs progressing after at least 3 cycles of cisplatin-based chemotherapy received after 01 Jan 1990 and treated with cisplatin-based CDCT+/−HDCT (etoposide + carboplatin) were identified and data collected. Pts were classified into risk groups using IPFSG factors, PFS and OS were analyzed and results for CDCT+/−HDCT compared.

Results: 38 eligible 1st salvage pts had received a median of 4 cycles (range, 1–7) of CDCT. 20 pts received CDCT alone & 18 pts received CDCT+HDCT. Overall median PFS was 24.6 months (95%CI, 7.3–28.7) and overall median OS was 34.6 months (95%CI, 17.2–51.3). Distribution by IPFSG category, 2-year PFS and 3-year OS rates within each risk category were very similar to IPFSG results. Two toxic deaths occurred with CDCT. Pts treated with CDCT+HDCT more often had better responses to 1st-line chemotherapy and pure seminoma histology. Overall pts treated with CDCT+HDCT had improved PFS (HR: 0.18; 95%CI, 0.07–0.51; p=0.001) and OS (HR: 0.25; 95%CI, 0.10–0.65; p=0.004) compared to CDCT alone. Examination by IPFSG risk category showed that the 2-year PFS and 3-year OS rates for CDCT+HDCT was higher in all prognostic groups except for the very high risk which did not have any HDCT pts.

Conclusions: The IPFSG prognostic factors were valid in our 1st salvage mGCT pts. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved PFS and OS outcomes, consistent with observations of Lorch et al (JCO 2011). Ideally the value of optimal CDCT+HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic GCT in a randomized trial.
Testicular germ cell tumors with bony metastases: Diagnosis, management, and outcomes (a case series).
Authors: Karpathakis Anna , Jamal-Hanjani Mariam , Kwan Amy , Mazhar Danish , Rudman Sarah Maria , Powles Thomas , Shamash Jonathan , Chowdhury Simon
Published: February 2017

343

Background: Metastasis of testicular germ cell tumour (GCT) to bone is a rare event and there is little evidence on optimal curative management.

Methods: A retrospective review of case records of germ cell tumour patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 14/03/2011 was conducted.

Results: 2,550 cases of testicular germ cell tumour were reviewed and 19 patients with bone metastases were identified, median age 38yrs. Average duration of follow-up was 21.7 months. Most were NSGCT (11/19), or seminoma (3/19). Five patients were treated on the basis of markers alone. Bone metastases present at diagnosis 12/19, and diagnosed at relapse/progression in 6/19 cases. Bony metastases were most commonly found in the vertebrae (15/19), pelvis (5/19) and ribs (3/19). In 10 cases a single bone metastasis was found, in 9 cases multiple areas of bone metastasis occurred. The imaging modality diagnostic of bone metastases was most frequently CT scan (11/19), FDG-PET (4/19) or MRI (3/19). The majority of these cases received only one line of chemotherapy (13/19), others received up to a maximum of seven line of systemic treatment (Table). Six patients (31.6%) died during follow up after an average of 17.5months and 3.3 lines of systemic treatment.

Conclusions: Bone metastasis in GCT is rare, and is believed to confer poor prognosis. This series of patient outcomes following standard first-line platinum based chemotherapy is small but appears to support this conclusion.

[Table: see text]
Association of GSTP1, COMT, and TPMT with testicular cancer (TC) treatment outcome after cisplatin-based chemotherapy (CBCT).
Authors: Fung Chunkit , Vaughn David J. , Mitra Nandita , Ciosek Stephanie L. , Vardhanabhuti Saran , Nathanson Katherine L. , Kanetsky Peter A.
Published: February 2017

344

Background: Genetic variation in GSTP1, COMT, and TPMT, which are genes important to the metabolism of cisplatin, may affect TC treatment outcome. We hypothesized that single nucleotide polymorphisms (SNPs) of these genes causing increased cisplatin metabolism may be associated with worse treatment outcome.

Methods: TC patients who had CBCT, ≥ 1 year of follow-up since initiation of CBCT, and genotyping completed as part of a genome-wide association study were included. After excluding markers with genotyping call rates of < 90%, we analyzed 3, 43, and 44 SNPs each for GSTP1, COMT, and TPMT respectively. We evaluated three endpoints: refractory disease (RD) as defined by radiographic or serologic evidence of TC after initial CBCT; progression-free survival (PFS); and overall survival (OS). We studied SNP association with these endpoints assuming additive, recessive, and dominant genetic models and adjusted p-values for false discovery rate to account for multiple comparisons.

Results: 137 patients (82.5% white, median age of 31 years) were recruited. Among them, 81.7% had non-seminoma and 68.6%, 8.0% and 22.6% were in good, intermediate, and poor IGCCC prognostic group respectively. 33.6%, 62.0%, 0.7%, and 2.9% had EP, BEP, TIP, and VIP respectively as initial CBCT with a mean total cisplatin dose of 345.3 mg/m2. After initial CBCT, 8.0% developed RD; among the remaining 92.0%, 23.8% had recurrent TC after a mean follow-up of 46.8 months. We found no statistically significant associations of our SNPs with PFS or OS. However, the COMT rs2073743 G allele conferred a higher risk of RF. It was present in 40.9% of patients with RD versus 21.1% of those without. Assuming recessive inheritance, patients with rs2073743 GG had over 20-fold increased odds (odds ratio = 22.69, (95% CI 3.3 – 155.8) ) of RD compared to those who carry at least one C allele. After adjusting for race, IGCCC, primary site of disease, type of CBCT, and total cisplatin dose, this association was no longer statistically significant.

Conclusions: COMT rs2073743 may be associated with RD, but replication and validation studies will be imperative to confirm this finding.
Clinical outcome of extragonadal germ cell tumors: Retrospective analysis at a single institution in Japan.
Authors: Kakimoto Ken-Ichi , Takeda Ken , Nakata Wataru , Nakayama Masashi , Arai Yasuyuki , Nishimura Kazuo
Published: February 2017

345

Background: Extragonadal germ cell tumors (EGGCT) are very rare and account for only 2% to 5% of all malignant germ cell neoplasms. Although multimodality treatment, including cisplatin-based chemotherapy and postchemotherapy surgery, has improved the prognosis of patients with EGGCT, few findings are available for these tumors. We therefore performed a retrospective analysis of Japanese patients with EGGCT.

Methods: We performed a retrospective review of the medical records of 34 male patients ranging in age from 18 to 62 years (median age, 30 years) treated at our institution between 1982 and 2010. Fifteen patients (44%) had primary mediastinal EGGCT, 16 patients (47%) had primary retroperitoneal EGGCT, and three patients (9%) had primary mediastinal and retroperitoneal EGGCT.

Results: Twenty-six patients (76%) had nonseminomatous EGGCT, and eight patients (24%) had seminomatous histology. Surgical procedures were performed in five patients (15%) as induction treatment. Three of them had seminomatous histology and were continuously disease-free after adjuvant chemotherapy. Twenty-nine patients (85%) had received cisplatin-containing regimen as induction therapy. Twenty-three patients underwent post–chemotherapy surgery, and 14 of them (60%) had residual viable malignant cells. On univariate analysis, nonseminomatous EGGCT (P<0.01) and resistance to cisplatin (lack of achievement of CR/PRm- by induction chemotherapy; P<0.01) were identified as negative prognostic factors for survival. Twenty of 34 patients (59%) were alive without disease, and 13 patients with nonseminomatous histology died of disease progression. The overall 10-year survival rate for all patients was 53%.

Conclusions: Patients with seminomatous EGGCT have a very good prognosis, while nonseminomatous histology and resistance to cisplatin were found to be negative prognostic factors.
Phase II study combining personalized dendritic cell (DC)-based therapy, AGS-003, with sunitinib in metastatic renal cell carcinoma (mRCC).
Authors: Figlin Robert A. , Amin Asim , Dudek Arkadiusz , Logan Theodore , Lance Raymond S. , Holzbeierlein Jeffrey M. , Master Viraj A. , Pal Sumanta Kumar , Gamble Alicia H. , DeBenedette Mark , Tcherepanova Irina Y. , Williams W. Lee , Plessinger Doug , Miesowicz Fred , Nicolette Charles A. ,   AGS-003-006 Study Group
Published: February 2017

348

Background: AGS-003 is a personalized immunotherapy that employs autologous DCs co-electroporated with the subject’s amplified tumor mRNA and synthetic CD40L RNA. Based on previous results with single agent AGS‐003 and acceptance of TKIs as the standard of care for mRCC, AGS-003 was evaluated in combination with sunitinib as initial treatment for advanced RCC. Progression free survival (PFS) results for the combination have been previously presented and show improvement compared to historical data in unfavorable risk patients treated with sunitinib alone.

Methods: AGS-003-006 is an open label phase II study that included subjects with newly diagnosed, metastatic clear cell RCC. Tumor was harvested by nephrectomy or metastasectomy for mRNA. Autologous monocytes were collected by leukapheresis for the production of DCs. Subjects subsequently received sunitinib (4wks on, 2wks off) combined with AGS-003 (every 3wks X 5 doses, then every 12wks) until progression. AGS-003 doses consisted of 1 X 107 cells administered by intradermal injection to a single lymph node basin. Response was evaluated per RECIST and subjects followed for PFS and OS. Immune responses were assessed at baseline and after five AGS-003 doses using multiparametric flow cytometry.

Results: 25 subjects were enrolled; 21 received treatment. The median PFS from registration for subjects receiving at least one dose of AGS-003 was 11.9 months. For subjects with 1–2 MSKCC risk factors (intermediate risk), PFS = 14.9 months and for subjects with 3–4 MSKCC risk factors (poor risk), PFS = 6.0 months. Median OS from registration has not been reached. Median OS for poor risk subjects = 7.9 months. Median OS for intermediate risk subjects has yet to be reached, but will exceed 28.3+ months.

Conclusions: AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Interim data indicate that AGS-003 in combination with sunitinib yields a median OS higher than that reported for sunitinib alone in unfavorable risk subjects. Updated OS and immune response correlates will be presented. These results support the ongoing, randomized phase III ADAPT study.
Carbonic anhydrase IX (CAIX) as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma (mccRCC) in patients (pts) receiving sorafenib: Analysis of a randomized controlled trial (TARGET).
Authors: Qu Angela Q. , Cheng SuChun , Atkins Michael B. , Signoretti Sabina , Choueiri Toni K.
Published: February 2017

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Background: No biomarkers have been routinely utilized to provide guidance for treatment in mccRCC. Retrospective data analyses have suggested that CAIX may have a predictive role in pts receiving immunotherapy or vascular endothelial growth factor (VEGF)-targeted therapy (Atkins Clin Cancer Res. 2005, Choueiri BJU Int 2010). We examined the predictive value of CAIX as a biomarker in estimating treatment outcome in pts receiving sorafenib vs. placebo as part of a large randomized trial (RCT).

Methods: Paraffin embedded tumor tissue was collected from 133 participants with independently reviewed disease-progression status in the TARGET study (N=903), which randomized pts to receive either sorafenib or placebo following progression on cytokine based therapy. Tumor tissue sections were immunostained for CAIX using the M75 antibody. The percentage of CAIX-positive tumor cells was assessed for each tumor by a single pathologist. The impact of CAIX expression on progression free survival (PFS, primary endpoint), and tumor shrinkage (TS) was analyzed for both sorafenib and placebo treated pts.

Results: Overall, 51% of pts were intermediate and 49% low risk per MSKCC criteria. 68% had high CAIX expression (>85% cell staining). Clinical characteristics were similarly distributed between pts with low vs. high CAIX staining, as well as pts with CAIX data vs. not. Median PFS for pts with high CAIX vs. low CAIX was 5.5 months and 5.4 months respectively on the sorafenib arm (p = 0.97), and 1.5 months and 1.7 months on the placebo arm (p = 0.76). Median TS for pts with high CAIX status was −14.9% vs. −12.6% in pts with low CAIX status (p = 0.63) on the sorafenib arm, and +1.3% (high CAIX) vs. +4.8% (low CAIX) in pts on the placebo arm (p=0.60).

Conclusions: Despite suggestive retrospective evidence, data from the TARGET study did not find CAIX expression status to be of predictive or prognostic value for treatment with sorafenib in pts with mccRCC following cytokine failure.
A pharmacogenomic scoring system predicting median time to progression (mTTP) on sunitinib (SUN) as first-line treatment in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Beuselinck Benoit , Karadimou Alexandra , Couchy Gabrielle , Claes Bart , Lambrechts Diether , Berkers Joost , Paridaens Robert , Schoffski Patrick , Van Poppel Hendrik , Wolter Pascal , Arnaud Mejean , Lerut Evelyne , Laguerre Brigitte , Theodore Christine , Linassier Claude , Delva Remy , Sevin Emmanuel , Goldwasser Francois , Zucman-Rossi Jessica , Oudard Stephane
Published: February 2017

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Background: There are no established biomarkers predicting outcome of SUN treatment in mRCC.

Methods: We assessed 30 single nucleotide polymorphisms (SNPs) in 10 genes on fresh frozen clear cell RCC nephrectomy specimens originating from pts who developed metastatic disease.

Results: We processed 79 samples. In 49 pts, normal kidney tissue adjacent to the tumor was used, in 30 pts only tumoral tissue was available. After nephrectomy and in presence of synchronous or metachronous metastasis, all pts received SUN as 1st line treatment. We observed associations between several SNPs and mTTP: In the promotor region of the gene encoding for IL-8 (proangiogenic growth factor): rs4073: TT or TA versus (vs) AA variant: mTTP 12 mo vs not reached (NR) (p=0.02). In ABCB1 (involved in drug transport): rs2032582: TA or TT vs GT/GA or GG: 9 vs 16 mo (p=0.03). rs1128503: TT vs CT or CC: 9 vs 16 mo (p=0.02). In VEGFR3 (a target of SUN): rs307826 : GA vs AA: 9.3 vs 18 mo (p=0.01). rs307821 : GT vs GG: 10 vs 16 mo (p=0.08). rs448012 : CC/CG vs GG: 12 mo vs NR (p=0.02). In NR1/2 (promotor leading to increased CYP3A4 expression): rs3814055: TT vs CC/CT: 13 vs 18 mo (p=0.02). rs1054190: CC vs CT: 14 vs 20 mo (p=0.14). In PDGFR-alpha (another SUN target): rs1800812: TT vs GG/GT: 3.5 vs 16 mo (p<0.0001). A scoring system combining 7 non-overlapping SNPs was build and pts were classified in a favorable, intermediate and unfavorable SNP profile group. A link with mTTP and response rate was found, but not with established clinical prognostic scores (MSKCC).

Conclusions: SNPs in genes linked to the pharmacokinetics and -dynamics of SUN can probably predict outcome of SUN treatment in mRCC. Our results confirm in part previous observations made by other groups in pazopanib or SUN (in IL-8, VEGFR3 and NR1/2) and highlight the potential role of other SNPs (in ABCB1, NR1/2 and PDGFR). Extension of the series and univariate/multivariate validation are ongoing.

[Table: see text]
Serum calcium and incident and fatal prostate cancer in the Swedish AMORIS study.
Authors: Van Hemelrijck Mieke , Hermans Ruben , Michaelsson Karl , Garmo Hans , Hammar Niklas , Jungner Ingmar , Walldius Goran , Lambe Mats , Holmberg Lars
Published: February 2017

36

Background: Many observational studies have shown a positive association between intake of dairy products and prostate cancer (PCa) risk. From a biological point of view it is of interest to study this association as bone was recently shown to be a positive regulator of male fertility which suggests that regulation of bone remodeling and reproduction are linked. Since androgens promote cell proliferation and inhibit prostate cell death, it is possible that calcium (Ca) is linked to PCa risk via its link with the reproductive system. We studied the association between serum Ca and PCa while also accounting for levels of albumin, a protein to which Ca is bound.

Methods: A cohort based on 192,183 men with baseline information on Ca (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Age-stratified multivariable Cox proportional hazard models were used to analyze associations between Ca and incident and fatal PCa risk. All models were adjusted for fasting status, glucose levels, socio-economic status, season at time of Ca measurement, Charlson comorbidity index, and history of fractures.

Results: A 6,202 men were diagnosed with PCa and 672 died of PCa during mean follow-up of 12 years. A weak negative association was found between PCa risk and Ca (HR per SD: 0.97 (95%CI: 0.95-1.00)). A similar association was also found between albumin-corrected Ca and PCa risk (HR: 0.96 (0.89-1.03), 0.94 (0.87-1.01), and 0.92 (0.86-0.99) for the 2nd, 3rd, and 4th quartile compared to the 1st; P for trend: 0.02). No association was found with fatal PCa, nor was there effect-modification by overweight. A strong positive association between Ca and death was observed when censoring for PCa (HR per SD: 1.13 (95%CI: 1.12-1.15)).

Conclusions: Serum levels of Ca were weakly negatively associated with PCa risk in our study when adjusted for age and history of comorbidities and fractures. A negative association between Ca and PCa risk is likely explained by the strong relation between Ca and non-PCa death. These competing risks need to be handled in order to define whether Ca is causally involved in PCa aetiology or whether it only acts a marker of other metabolic events in the causal pathway.
124I-cG250 PET scan for early detection of response to sunitinib in patients (Pts) with metastatic clear cell renal cell carcinoma (MccRCC).
Authors: Larson Steven M. , Motzer Robert John , Pandit-Taskar Neeta , Bartz Roman , Feldman Darren Richard
Published: February 2017

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Background: Mutation and/or methylation of the von Hippel-Lindau gene leading to overexpression of hypoxia-inducible factor-1 alpha (HIF1α) has been implicated as a driving event in the pathogenesis of ccRCC. Downstream effectors of HIF1α such as VEGF have become key targets of novel therapies for MccRCC (eg, sunitinib (S)). Carbonic anhydrase-IX (CAIX) transcription is also regulated by HIF1α and is overexpressed in ~95% of ccRCC. Linkage of cG250 (Girentuximab), a chimeric antibody to CAIX, to radioactive iodine (124I), has resulted in a radiotracer specific for ccRCC; 124I-cG250 (124I-Girentuximab) PET/CT demonstrated a sensitivity of 86% and a specificity of 87% for detecting primary ccRCC (Uzzo AUA 2010). Since responses to targeted therapies likely occur on a molecular level before they are detectable with standard imaging, we hypothesize that 124I-cG250 PET/CT could allow earlier recognition of response or progression to S than CT in pts with MccRCC.

Methods: This is a pilot study of 124I-cG250 PET/CT in 25 pts with MccRCC planned to begin treatment (Tx) with S. 124I-cG250 PET/CT will be assessed for its ability to predict Tx response during (days 25–28) and at completion (days 39-42) of the first cycle of therapy, in comparison to standard CT imaging at routine intervals. PET/CT and CT will each be interpreted by 1 nuclear medicine physician, who will be blinded to the results of the comparator imaging modality, but aware of the clinical history of the pts. Eligibility include age ≥18, ECOG PS < 2, histologically confirmed MccRCC, Tx planned with S, and radiographic evidence of unidimensionally measurable disease with at least one lesion ≥2 cm in diameter on 16-slice multi-detector CT. Key exclusion criteria include uncontrolled/unstable hyperthyroidism or Grave’s Disease, unstable cardiac disease and uncontrolled seizure disorder or history of CVA or TIA within the past 12 months.

Results: NA.

Conclusions: This is the first clinical trial to prospectively evaluate the use of a histologically specific imaging modality to measure early changes in ccRCC CAIX protein expression as a predictor of response to biologically targeted Tx. Enrollment will commence in November 2011.
Activity of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Pal Sumanta Kumar , McDermott David F. , Ramies David A. , Morrissey Stephanie , Lee Yihua , Miles Dale , Holland Jaymes S. , Dutcher Janice P.
Published: February 2017

364

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC.

Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST.

Results: Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 – 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached.

Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).