bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

352 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

359 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

362 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.