bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic factors for response to systemic treatments carried out in patients with advanced renal carcinoma.
Authors: Muriel C. , Esteban E. , Martinez-Camblor P. , Astudillo A. , Crespo G. , Pardo P. , Izquierdo M. , Berros J. , Gutierrez E. , Lacave A. J. 
Published: February 2017

369 Background: The analysis of predictive factors of response could help to select those patients with advanced renal cell carcinoma (RCC) who would be good candidates for systemic treatments Methods: The expression of several biomarkers was retrospectively analysed by immunohistochemistry (IHC), as well as 2 analytical variables: thrombocytosis and neutrophilia, in 135 patients with advanced RCC treated with cytokines (CK) and/or biological agents and was correlated to the response. Results: 67 patients were treated only with biological agents and 68 with CK (23 treated also with biological agents). Univariate statistical analysis: HIF-1alpha did not correlate significantly with the response to these drugs. The overexpression of ACIX was associated to a larger response (%) to biological agents such as sunitinib (65.9 vs. 16.7 p<0.001) or sorafenib (61.9 vs 0 p=0.007), and CK (22.6 vs. 0 p=0.038). PTEN showed a predictive value for response (%) to sunitinib (70.8 vs. 34.1 with PTEN negative p=0.005). p21 was associated to a lower response (%) with sunitinib (35.9 vs. 65.4 with p=0.025). Thrombocytosis was not significantly associated with the response (%) to biological agents, although it was associated to CK (0 vs. 20 without thrombocytosis p=0.017). Neutrophilia correlated with a smaller response to biological agents (29.6 vs. 57.5 without neutrophilia, p=0.045), although it did not associate with a response to CK. In the multivariate analysis, overexpression of ACIX was an independent predictor of a larger response to biological agents and CK with an OR of 8,773 (p<0.001). Conclusions: Our findings prove the usefulness of ACIX to select patients with advanced RCC candidates to receive systemic treatment. PTEN and p21 could be important in the prediction of response to sunitinib. Thrombocytosis and neutrophilia appear to relate to the response to CK and biological agents respectively. No significant financial relationships to disclose.
Evaluation of tumor-associated macrophages as a prognostic indicator in patients with papillary renal cell carcinoma.
Authors: Hutterer G. C. , Chromecki T. F. , Zigeuner R. , Klatte T. , Kampel-Kettner K. , Pummer K. , Remzi M. , Mannweiler S. 
Published: February 2017

372 Background: Prognostic indicators in papillary renal cell carcinoma (PRCC) are not well defined. We evaluated the prognostic relevance of tumor-associated macrophages (TAM) in patients with PRCC. Methods: PRCC specimens were re-evaluated by one blinded pathologist (SM), with respect to pT-classification (TNM 2002), nodal status, Fuhrman grade (I-IV), tumor size, subtype (type 1 or 2), tumor necrosis, and presence of TAM. Presence of TAM was associated with pathological parameters (chi-square and fisher's exact tests). Impact of TAM on cancer-specific survival (CSS) was assessed (Kaplan-Meier method and log-rank test). A multivariate regression analysis including pT-stage, grade, vascular invasion, necrosis, tumor size, papillary subtype and TAM was performed with respect to CSS. Results: 177 patients operated for PRCC from 1984 to 2006, were evaluated. Presence of TAM was noted in 112/177 (63%) tumors and was significantly associated with favorable pathological parameters: low pT-classification (pT1a/b: 71/90, 79%; pT2: 14/31, 45%; pT3a/b: 27/56, 48%; p<0.001), node negative tumors (Nx/pN0: 111/170, 65% vs. pN1/2: 1/7, 14%; p=0.01), low grade (G1: 35/45, 78%; G2: 67/110, 61%; G3: 10/22, 45%; p=0.025), absence of vascular invasion (V0: 106/153, 69% vs. V1/2: 6/24, 25%; p<0.001), and papillary subtype (type 1: 64/87, 74% vs. 48/89, 54%; p=0.007), respectively. Median follow-up was 68.3 months. Five-year CSS probabilities for patients with TAM-positive tumors were 93.5%, compared with 72.5% in patients with TAM-negative tumors (p<0.001). Median survival was not reached in both groups. Multivariate analysis revealed node positive tumors (HR=2.4, 95%CI=1.1-5.0; p=0.025), distant metastases (HR=8.7, 95%CI=2.6-29.3; p<0.001), and tumor size (HR=1.2, 95%CI=1.0-1.3; p=0.03) as independent predictors of death from PRCC, whereas presence of TAM was independently associated with favorable outcome (HR=0.3, 95%CI=0.1-0.9, p=0.026). Conclusions: Presence of TAM was independently associated with a favorable outcome in patients with PRCC and was shown to reduce the risk of death from cancer by 66%. Presence of TAM should therefore be part of routine pathology reporting in PRCC. No significant financial relationships to disclose.
Neoadjuvant temsirolimus in high-risk renal cell carcinoma: Results from a single-center prospective study.
Authors: Sheikh A. A. , Gharajeh A. , Hotte S. J. , Pinthus J. H. , Kapoor A. 
Published: February 2017

387 Background: The current first-line treatment for advanced renal cell carcinoma (RCC) includes targeted therapy with or without cytoreductive radical nephrectomy. There is a paucity of data as to the effectiveness of adjuvant and neoadjuvant treatment before radical nephrectomy for localized high-risk or advanced disease. We initiated a trial of neoadjuvant Temsirolimus before radical nephrectomy for locally advanced and metastatic RCC examining tumor response and survival. Methods: Patients who presented with advanced RCC were offered enrolment into a prospective, single-centre, ethics approved trial with 12 weeks of temsirolimus before radical nephrectomy. Biopsy tissue was obtained at enrollment and at time of cytoreductive nephrectomy for diagnosis. Patients were administered 25 mg in temsirolimus on a weekly basis for 12 weeks, and then underwent radical nephrectomy. Computed tomography scans and biomarkers were obtained on enrolment, 6 weeks and 12 weeks (before nephrectomy). Ongoing outcome and survival data were analyzed. Results: Eight patients were enrolled into the trial. Patient #1 (10-cm renal mass with bulky adenopathy T2N2M0) had no evidence of disease (NED) at 6 months post-nephrectomy. Patient #2 (9-cm renal mass, bulky adenopathy, pulmonary metastases T2N2M1) also had NED at 6 months postnephrectomy. Patients #3 and #4 experienced regression of the primary mass and have recently undergone uneventful surgery with follow-up pending. Patients #5 and #6 expired prior to the full course of therapy, but had diagnoses other than RCC. Patient #7 experienced disease progression, however, this patient's nephrectomy was delayed by 3 months due to an unrelated myocardial infarct. Patient #8 experienced adverse events. Conclusions: Our findings suggest that neoadjuvant temsirolimus before radical nephrectomy for advanced RCC may improve disease regression post-surgery, and may lead to disease resolution in patients with low-volume disease. Randomized studies with longer term follow-up is necessary to assess overall progression-free survival and overall survival. [Table: see text]
Fuhrman grade and concomitant bisphosphonates as additional prognostic factors in metastatic renal cell carcinoma with bone metastases treated with sunitinib.
Authors: Beuselinck B. L. , Medioni J. , Wolter P. , Blesius A. , Karadimou A. , Schöffski P. , Escudier B. J. , Zucman-Rossi J. , Paridaens R. , Oudard S. 
Published: February 2017

388 Background: With a median progression-free survival(PFS) of 8.2 months (mo) (vs. 19.1 mo; p<0.0001) and overall survival (OS) of 19.5 mo (vs. 38.5 mo; p<0.0001), metastatic renal cell carcinoma (m-RCC) patients (pts) with bone metastases (BM) have a poorer outcome under sunitinib (SUN) than pts without BM (Beuselinck et al, Annals of Oncology 2010). The aim of this retrospective study was to determine additional prognostic factors in this poor risk subgroup of pts. Methods: We collected data on classical prognostic factors for m-RCC, Fuhrman grade, number of BM, and bone-oriented therapy in the charts of 80 m-RCC pts with BM who started first-line SUN between 01/2005 and 12/2009 in 4 academic centers in Belgium and France. Univariate analysis was conducted using Maentel Hetzel test. Validation of these findings on a second series of m-RCC patients is ongoing. Multivariate analysis will be performed on the total series. Results: In the total population, median PFS and OS were 9.8 and 20.6 mo. Pts with Fuhrman grade 4 tumors (MSKCC prognosis: intermediate 50%; poor 50%) had a PFS of 4.5 mo vs. 12.3 mo for Fuhrman grade 1-2-3 tumors (MSKCC prognosis: good 20%; intermediate 60%; poor 20%) (p=0.005). OS was 13.5 mo vs. 26.5 mo respectively (p=0.003). There was no difference in PFS and OS between pts with Fuhrman grade 1-2 and Fuhrman grade 3 tumors. The number of BM had no significant influence on PFS and OS. Whether or not radiation therapy and/or surgery had been applied to all BM before starting SUN was a factor without influence on PFS or OS. Concomitant bisphosphonates (BF) and SUN administration was analyzed on all the evaluable pts (24) treated at the University Hospitals Leuven. 14 pts (MSKCC prognosis: poor: 8; intermediate: 6) received concomitant BF. 10 pts (MSKCC prognosis: poor: 5; intermediate: 5) did not. Median PFS was 16.3 and 3.4 mo (p=0.03) and OS 18.1 and 13.9 mo respectively (not significant). Results of the validation series and multivariate analysis will be presented. Conclusions: m-RCC pts combining BM and Fuhrman grade 4 tumors have a very poor outcome on SUN. Concomitant use of BF may be a strategy to improve PFS in pts with bone metastatic RCC. No significant financial relationships to disclose.
The effect of bevacizumab on tumor response and primary resistance to systematic therapy.
Authors: Ranpura V. , Su X. , Wu S. 
Published: February 2017

399 Background: The angiogenesis inhibitor bevacizumab in combination with chemotherapeutic agents or cytokines are used extensively in the treatment of metastatic tumors including renal cell carcinoma (RCC). Risk factors for the treatment response are not clear. We performed a systemic review and meta-analysis of published randomized controlled trials (RCT) to determine the effect of bevacizumab on tumor response to systematic therapy. Methods: We searched databases from Pubmed, Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences up to May 2010 to identify relevant studies. Tumor response was defined according to RECIST criteria. Eligible studies include RCTs in which bevacizumab in combination with systematic therapy was compared with systematic therapy alone. Relative risk (RR), and 95% confidence intervals (CIs) were calculated using a random-effects or fixed-effects model based on heterogeneity of included studies. Results: A total of 8,972 patients from 16 studies were included for analysis. Overall, bevacizumab significantly increased the response rate with an RR of 1.67 (95% CI: 1.41–1.84). The effect varied significantly with tumor types (p=0.007), with the highest seen in RCC (RR 2.17, 95% CI: 1.71–2.74), and the lowest seen in mesothelioma (RR 1.14, 95% CI: 0.89–1.44). No significant difference was found between bevacizumab at 2.5 and 5 mg/kg/week. Also, bevacizumab significantly reduced the risk of primary resistance to systematic therapy (RR 0.83, 95% CI: 0.70–0.99; p=0.04). The risk reduction varied significantly with tumor types (p=0.02), with the highest reduction seen in RCC (RR 0.76, 95% CI: 0.51–1.14) and colorectal cancer (RR 0.74, 95% CI: 0.51–1.09). Notably, bevacizumab significantly increased the risk of primary resistance to chemotherapy in mesothelioma (RR 1.34, 95% CI: 1.03–1.74). No significant correlation was found between the effect on response rates and progression-free survival (p=0.62) or overall survival (p=0.63). Conclusions: Bevacizumab has a significant effect on tumor response and primary resistance to systematic therapy, particularly in RCC. [Table: see text]
Validation of MSKCC-criteria in metastatic renal cancer patients treated with sorafenib or sunitinib.
Authors: Hoffmeister I. , Riesenbeck L. , Bierer S. , Koepke T. , Hertle L. , Thielen B. , Herrmann E. 
Published: February 2017

401 Background: To validate the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) treated with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Methods: Clinical and laboratory parameters from 83 patients with mRCC were investigated. All patients were treated at our institution between 2006 and 2009. Specifically, the MSKCC criteria (Karnofsky performance status <80%, time between diagnosis and treatment < 1 year, baseline anemia, elevated LDH > 1.5 times upper limit of normal, and elevated serum calcium) were evaluated as surrogate parameters for progression-free survival (PFS). Results: 34 (41.0%) patients were treated as first-line, and 49 (59.0%) patients were treated as second-line treatments, respectively. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Albeit statistically not significant, prior nephrectomy (p=0.056), histologic subtype (p=0.052) as well as baseline anemia (p=0.079) tended to be associated with PFS. In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.001) and best treatment response (p<0.001) were independent prognostic markers, but not MSKCC criteria. Conclusions: In this patient cohort, MSKCC criteria did not show prognostic relevance in terms of PFS. The role of risk group stratification according to MSKCC in patients with mRCC and treatment with TKIs must be questioned. No significant financial relationships to disclose.
Alkaline phosphatase (ALP) normalization and overall survival in patients with bone metastases from castration-resistant prostate cancer (CRPC) treated with radium-223.
Authors: Parker C. , O'Bryan-Tear C. G. , Bolstad B. , Lokna A. , Nilsson S. 
Published: February 2017

49 Background: Radium-223 (Alpharadin) is a first-in-class alpha-pharmaceutical. It targets bone metastases with high-energy alpha-radiation of extremely short range that spares bone marrow. Radium-223 has a profound effect on serum markers of bone metabolism, including ALP, in patients with bone metastases from CRPC. In an exploratory analysis, we studied whether this effect is associated with a meaningful clinical benefit. Methods: Patients with CRPC and bone metastases were treated in 2 randomized phase II studies. BC1-02 was a placebo-controlled study of radium-223 (50 kBq/kg) every 4 weeks for 12 weeks. BC1-04 evaluated radium-223 (25, 50, or 80 kBq/kg) every 6 weeks for 12 weeks. Baseline total ALP values > 128 U/L were considered elevated; those decreasing to below 128 U/L during treatment with radium-223 were defined as normalized, and those remaining above that value as non-normalized. Results: In BC1-02, ALP normalization was seen in 12/26 (46%) patients treated with radium-223. Median survivals of those with and without ALP normalization were 102 weeks and 42 weeks, respectively (log-rank P < 0.001). In BC1-04, ALP normalization was seen in 25/75 (33%) cases: 5/29 (17%) in the 25 kBq/kg group, 10/25 (40%) with 50 kBq/kg, and 10/21 (48%) with 80 kBq/kg, indicating a dose-response relationship. Median survivals for the 25 patients with, and the 50 patients without, ALP normalization were 102 weeks and 58 weeks, respectively (log-rank P = 0.0086). Conclusions: Inpatients with metastatic CRPC and bone metastases treated with radium-223, ALP normalization was associated with significantly better overall survival. These data support the rationale for the ongoing ALSYMPCA phase III trial of radium-223. [Table: see text]
Capture and analysis of prostate cancer circulating tumor cells (CTCS) using geometrically enhanced differential immunocapture (GEDI).
Authors: Jodari M. , Loftus M. , Gleghorn J. , Gakhar G. , Pratt E. , Tagawa S. T. , Bander N. H. , Giannakakou P. , Kirby B. , Nanus D. M. 
Published: February 2017

53 Background: EpCAM-based immunocapture of prostate cancer (PC) CTCs yields relatively low purity and specificity. We developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that incorporates flow dynamics and utilizes a mAb to prostate-specific membrane antigen (PSMA) to optimize isolation and analysis of CTCs from PC patients. Methods: GEDI microfluidic silicon chips, fabricated using standard photolithography techniques, were functionalized by chemical cross-linking ending with a neutravidin terminated surface to which anti-PSMA biotinylated-mAb J591 was bound. C4-2 (PSMA+) and PC-3 (PSMA-) cells were used for chip optimization. 1 mL of peripheral blood from PC patients was flowed (1mL/hour) over functionalized chips. Captured cells were washed with PBS × 30 min, fixed with 3.7% formaldehyde, immunofluorescently stained for DAPI, androgen receptor (AR), tubulin and EpCAM and analyzed by high resolution point-scanning confocal microscopy. PSMA+, DAPI+, and CD45- cells were manually scored. RNA was extracted from unfixed captured CTCs using lysis buffer flowed thru the chip. Results: ∼80% capture efficiency was achieved from 26 PSMA positive C4-2 cells spiked into 1 mL blood flowed through the GEDI chip. RNA extracted from 50 C4-2 cells in 1 mL blood flowed thru the chip detected a known AR point mutation by RT-PCR and Sanger sequencing. Immunofluorescence staining of PSMA+ cells captured on the chip detected changes in AR subcellular localization and microtubule structure following treatment with DHT or paclitaxel, respectively. 10 patients with metastatic PC were analyzed by CellSearch (range 0-201 cells/7.5 mL) and GEDI chip (range 35->1200 cells/mL) yielding a 7->350 fold enrichment using GEDI. Captured PC cells isolated from PC patient incubated in 50 nm paclitaxel (ex vivo) overnight demonstrated microtubule bundling, indicative of drug-target engagement. Conclusions: PSMA based GEDI microfluidic CTC capture is highly specific and sensitive in capturing PSMA positive PC CTCs; and allows detailed CTC analysis including protein expression and subcellular localization, mutational analysis and drug sensitivity assessment. [Table: see text]
Detection of prostate cancer with HistoScanning.
Authors: Epplen R. , van Erps T. , Thueer D. , Knuechel-Clarke R. , Heidenreich A. 
Published: February 2017

55 Background: HistoScan is a tool for differentiation, visualization and quantification of changes in solid organ tissue. It is used in combination with transrectal ultrasound that transmits data to a computer program. Data is processed and suspicious areas shown. Our objective was to compare HistoScan with histopathology of radical prostate specimens and to determine sensitivity in detection regarding cancer volume and localization. Methods: 52 patients who underwent radical prostatectomy HistoScan was performed one day preoperatively. Scan with the largest suspicious volume was used for evaluation. All prostatectomy specimens were processed according to the Stanford protocol. The prostate specimens were divided into a grid of 9 different areas. HistoScan findings were correlated with final pathology regarding localization and volume. A match was defined as well a positive lesion in HistoScan as in a correspondent histopathologically proven area. Results were analyzed regarding to T-stadium, Gleason Score (GS), PSA, tumor volume and volume of HistoScan lesions. Results: Mean patient age was 63.6 years, mean PSA was 8.97 ng/ml, mean prostate volume was 45.4 ml and mean tumor volume was 4.1 ml. 27 patients (pts) had a pT2 tumour, 25 pT3 carcinoma. 4 pts had salvage prostatectomy. 6 pts had a final GS, 34 and 8 pts had GS 7 and GS ≥8 respectively. Sensitivitiy was 75% for detecting prostate cancer. 64% of the cases showed a good correlation for tumor volume. Results were identical for normal and salvage prostatectomy. Sensitivity was higher for T3 tumors than for pT2 tumors. HistoScan detected 50% of the GS 6 tumors, 74% of GS 7 and 100% of GS ≥8. HistoScan detected small tumors (<1 ml) in 60%, intermediate tumours (1-5 ml) and large tumours (>5 ml) in 87 and 82% respectively. Similar findings are seen regarding the volume of suspicious lesions in HistoScan. For small (≤ 0.5 ml), intermediate (0.5-2 ml) and large (>2ml) lesions, HistoScan correctly predicted localisation in 53%, 86% and 85% respectively. Conclusions: HistoScan has a great potential in detection of significant prostate cancer. In particular extracapsular poor differentiated and large tumors show a high detection rate. However, larger prospective studies are needed to verify these preliminary results. No significant financial relationships to disclose.
Novel image analysis tools for evaluating the androgen receptor in the prostate needle biopsy: Impact on future systems-based outcome models.
Authors: Fernandez G. , Ajemba P. , Khan F. , Bayer-Zubek V. , Liu Q. , Donovan M. J. 
Published: February 2017

56 Background: A systems-based model was previously developed and validated to predict disease progression (DP) using pretreatment clinical data and standardized, robust prostate needle biopsy (PNB) tissue metrics. We sought to apply novel, advanced immunofluorescent (IF) image analysis methods to re-assess PNB androgen receptor (AR) and Ki67 expression profiles and identify cut-points useful for understanding and guiding therapeutic decision making. Methods: Pretreatment clinical features and PNB H&E / IF images on 306 patients (91% cT1-T2b, 66% PSA</=10ng/mL; 49% Gleason biopsy score </=6) from the original study cohort were obtained. IF images were re-processed using a novel CK18 and DAPI algorithm to optimize segmentation of the tumor (epithelial) nuclear (TEN) and stromal compartments. The original threshold for determining TEN Ki67was retained. An enhanced image analysis approach was applied to calculate the normalized ratio of maximum AR levels in TEN to stromal nuclei. Feature performance was evaluated with the concordance index (CI); AR and Ki67 cut-point (CP) analysis and new multivariate models were completed. Results: Increasing amounts of Ki67 and two new AR features reflecting different percentages of the maximum AR level in TEN were associated with a shorter time to DP (Ki67 CI0.37, AR-ratio 21, CI0.30 and AR-ratio 22, CI0.33). Several cut-points were identified including: Ki67 CP 0.04, hazard ratio (HR) of 3.1, p-value 0.0005 (sensitivity 64%, specificity 68%); ARratio-21 CP 0.90, HR 3.8, p-value 0.0001 (sensitivity 78%, specificity 73%) and ARratio-22 CP 0.87, HR 2.2, p-value 0.013 (sensitivity 68%, specificity 68%). A multivariate model for predicting DP consisted of 4 weighted features including the biopsy Gleason score, the ARratio-22, and two morphometric (H&E&IF) variables. Conclusions: Novel image analysis methods to analyze biomarker attributes in PNB specimens confirm and enhance our understanding of AR and Ki67 in disease progression. Such approaches will become useful tools for finalizing biomarker cut-points, performing pharmacodynamic assessment and establishing parameters for guiding therapy. [Table: see text]