Cancer-specific Survival In Multivariate Analysis Research Articles

Clinicopathological and molecular characteristics of Ku 70/80 expression in Nigerian breast cancer and its potential therapeutic implications

Ku 70/80 is a regulator of the Non-Homologous End Joining (NHEJ) roles in clinicopathological features, and has prognostic significance in breast cancer (BC) in Caucasian populations. However, its significance in the Nigerian BC population, which is characterized by a higher rate of the triple-negative and basal phenotype, p53 mutation rate and BRCA1 deficiency, still needs to be investigated. We hypothesize that Ku70/80 expression shows adverse expression in Nigerian BC and, furthermore, that it is likely to have a therapeutic implication for Black BC management.This study investigated the biological, clinicopathological and prognostic significance of Ku 70/80 expression in a BC cohort from a Nigerian population. Ku 70/80 expression was determined in 188 well-characterized formalin-fixed, paraffin-embedded (FFPE) BC samples using tissue microarray and immunohistochemistry. Ku 70/80 expression was correlated with clinicopathological, molecular and prognostic characteristics of patients.Ku 70/80 was expressed in 113 (60.1%) tumors, and was positively associated with metastatic disease, triple-negative and basal phenotype, BRCA1 down regulators (MTA-1 and ID4), p-cadherin, PI3KCA and p53 expression. It inversely correlated with BRCA1, BRCA2, BARD1 and p27. Ku 70/80 was predictive of breast cancer-specific survival in multivariate analysis, but not of disease-free interval.This study demonstrated that Ku 70/80 expression is associated with triple negativity and down-regulation of the homologous recombination pathway of DNA repair. Therefore, the development of novel drugs to target KU70/80 may improve the patients’ outcome in the treatment of Black BC.

Poor prognostic value of lymphovascular invasion for pT1 urothelial carcinoma with squamous differentiation in bladder cancer.

Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (−) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation.

Upper Tract Urothelial Carcinomas Accompanied by Previous or Synchronous Nonmuscle-Invasive Bladder Cancer and Preoperative Hydronephrosis Might Have Worse Oncologic Outcomes After Radical Nephroureterectomy

BackgroundThe purpose of the study was to identify predictors of clinicopathologic features and oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy (RNU). Patients and MethodsThe medical records of 172 patients treated with RNU from January 2001 to September 2014 were retrospectively reviewed. Logistic regression and survival analysis methodology were respectively used to evaluate predictors of clinicopathologic features and oncologic outcomes. ResultsOf the enrolled 172 patients, 80 (46.5%) had renal pelvic tumors, 67 (39%) had ureteral tumors, and the remaining 25 (14.5%) patients had multifocal tumors. Compared with patients with renal pelvic tumors, those with ureteral and multifocal tumors were more likely to have previous or synchronous nonmuscle-invasive bladder cancer (NMIBC) and severe hydronephrosis (P = .001 and P < .001, respectively). Logistic regression analysis showed that previous or synchronous NMIBC was significantly associated with worse renal function and high grade (P = .034 and P = .014, respectively), and severe hydronephrosis independently predicted worse renal function and positive lymph node or lymphovascular invasion status (P = .001 and P = .007, respectively). Moreover, severe hydronephrosis was an independent risk factor for overall survival and cancer-specific survival in multivariate analysis (P = .025 and P = .045, respectively). Multifocality and previous or synchronous NMIBC were significantly associated with bladder-recurrence-free survival (P = .023 and P = .001, respectively). ConclusionUpper tract urothelial carcinoma accompanied by previous or synchronous NMIBC and preoperative severe hydronephrosis could have worse oncologic outcomes after RNU. These common accompanied diagnoses could be valuable for guiding preoperative planning and postoperative adjuvant therapy.

Muscle-invasive bladder cancer is characterized by overexpression of thymidine kinase 1

ObjectiveThymidine kinases have an important role in the synthesis of DNA and exhibit high activity in rapidly proliferating cells. Thymidine kinase 1 (TK1) activity has been shown to be increased in various cancer types and proposed as a prognostic parameter. Aim of the present study was to investigate TK1 in muscle-invasive urothelial carcinoma (UC). MethodsCorresponding UC and benign samples from paraffin embedded tissue of 111 patients treated with cystectomy for invasive UC from 1996 to 2006 were immunohistochemically (IHC) assessed for TK1. IHC expression patterns were evaluated in a semiquantitative fashion by 2 independent reviewers. Localization of staining was categorized into pure nuclear and additional cytoplasmic localization. Uni- and multivariate analyses were performed to assess differential expression in normal and UC tissue and to evaluate the diagnostic and predictive capability of TK1 by correlation to clinical data. To correlate TK1 expression with molecular subtypes of UC, analysis of TK1 RNA expression levels of the Cancer Genome Atlas UC cohort was performed. ResultsTK1 was significantly overexpressed in invasive UC, compared to benign urothelium (P<0.0001), and cytoplasmic expression was more often found in cancer tissue than in benign tissue (P = 0.0001). No correlations of TK1 protein expression patterns to standard histopathological determinants were detected. In univariate analysis, TK1 nuclear and cytoplasmic expression was associated with improved cancer-specific survival (P = 0.0119). However, only metastasis status and histologic grade were identified as independent predictors of cancer-specific survival in multivariate analysis. TK1 expression was merely found in the basal layers of benign urothelium. RNA overexpression of TK1 could be correlated to the biologically more aggressive basal UC subtype. ConclusionsTK1 expression is significantly different in invasive UC and benign urothelium, which underlines its potential as a diagnostic marker. Although TK1 is considered to be a marker of proliferation, and TK1 RNA overexpression is associated with an aggressive UC subtype, its capability as a predictive IHC biomarker for invasive UC remains limited.

Abstract 3357: Glucose transporter 1 positivity on primary lesions of esophageal squamous cell carcinoma is associated with hematogenous recurrence

Abstract Purpose: Glucose transporter type 1 (Glut1) plays a crucial role in cancer specific metabolism to adapt to the rapid growth and tumor microenvironment in diverse malignant tumors. We recently reported the relationship between Glut1 status and 18F-FDG uptake. PET-positive lesions had higher Glut1 expression than PET-negative lesions in both primary tumors and metastatic lymph nodes. In this study, it was showed that the clinical, pathological and prognostic features of Glut1 expression on primary lesions of esophageal squamous cell carcinoma. Methods: Immunohistochemical staining of Glut1 and CD34 was performed using paraffin sections of tissues obtained from 145 resectable esophageal squamous cell carcinoma patients without preoperative treatment. Microvessel density was calculated from CD34 staining. Results: Glut1 positivity was observed in 41 patients (28.2%) and associated with depth of invasion (odds ratio (OR)=2.984; 95% confidence interval (CI): 1.208-7.371; P=0.018) and vascular invasion (OR=2.771; 95% CI: 1.118-6.871; P=0.028) in multivariate analysis. Glut1 positivity was a significant disadvantage to both relapse-free survival (hazard ratio (HR)=2.021; 95% CI: 1.100-3.712; P=0.023) and esophageal cancer-specific survival (HR=2.223; 95% CI: 1.121-4.411; P=0.022) in univariate Cox hazard analysis, but was not independently associated with relapse-free survival or cancer-specific survival in multivariate analysis. The relationship between Glut1 expression and first relapse site was investigated. Glut1 positivity was not associated with lymph node recurrence (HR 1.009; 95% CI: 0.402-2.530; P=0.985) but was significantly associated with hematogenous recurrence (HR=3.701; 95% CI: 1.655-8.273; P=0.001) in univariate Cox hazard analysis. Microvessel density was calculated to evaluate angiogenesis and high microvessel density was associated with invasion depth (P=0.044) and vascular invasion (P=0.016). The median microvessel densities for Glut1-negative tumors and Glut1-positive tumors were 38.0 and 54.0, respectively. The microvessel density for Glut1-positive tumors was significantly higher than that of Glut1-negative tumors (Mann-Whitney U-test: P&amp;lt;0.001) Conclusions: Glut1 expression was associated with hematogenous recurrence. The relationship between Glut1 expression and hematogenous recurrence may stem from an acquired survival ability resulting from upregulated Glut1 and angiogenesis to adapt to the tumor microenvironment. The findings provide evidence of the significance of Glut1 expression as a biomarker in esophageal squamous cell carcinoma. Citation Format: Hiroshi Sawayama, Takatsugu Ishimoto, Masayuki Watanabe, Naoya Yoshida, Yoshifumi Baba, Hidetaka Sugihara, Daisuke Izumi, Hideo Baba. Glucose transporter 1 positivity on primary lesions of esophageal squamous cell carcinoma is associated with hematogenous recurrence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3357. doi:10.1158/1538-7445.AM2014-3357

The impact of tumor location and multifocality on prognosis for patients with upper tract urothelial carcinoma: a meta-analysis.

There is lack of consensus regarding the prognostic significance of primary tumor location of upper tract urothelial carcinoma(UTUC). We performed a meta-analysis to evaluate the impact of primary tumor location on prognosis in patients with UTUC who had undergone radical nephroureterectomy(RNU). We included eligible studies that reported hazard ratios(HRs) estimates with 95% confidence intervals(CIs) for the association between tumor location and recurrence-free survival(RFS) and cancer-specific survival(CSS) of UTUC. The local advanced tumors(pT3/4) and nodal positive(pN+) tumors in patients stratified by tumor location were also estimated. The review contained 17 studies including a total of 12094 patients were identified. Although it was not significant in univariable analysis, meta-analysis demonstrated that ureteral tumors had a worse prognosis than renal pelvic tumors on RFS and CSS in multivariable analysis after adjusted for all covariates. Multifocal tumors also showed a significantly association with both disease progression and cancer-specific mortality in univariable and multivariable analyses. However, no statistically significant differences were found between renal pelvic and ureteral tumors in presentation of pT3/4 and pN+ tumors. Our meta-analysis indicated that ureteral and multifocal tumors are independent prognosticators of disease progression and cancer-specific survival in patients with UTUC treated with RNU.

Postoperative nomogram to predict cancer‐specific survival after radical nephroureterectomy in patients with localised and/or locally advanced upper tract urothelial carcinoma without metastasis

To propose and validate a nomogram to predict cancer-specific survival (CSS) after radical nephroureterectomy (RNU) in patients with pT1-3/N0-x upper tract urothelial carcinoma (UTUC). The international and the French national collaborative groups on UTUC pooled data from 3387 patients treated with RNU. Only 2233 chemotherapy naïve pT1-3/N0-x patients were included in the present study. The population was randomly split into the development cohort (1563) and the external validation cohort (670). To build the nomogram, logistic regressions were used for univariable and multivariable analyses. Different models were generated. The most accurate model was assessed using Harrell's concordance index and decision curve analysis (DCA). Internal validation was then performed by bootstrapping. Finally, the nomogram was calibrated and externally validated in the external dataset. Of the 1563 patients in the nomogram development cohort, 309 (19.7%) died during follow-up from UTUC. The actuarial CSS probability at 5 years was 75.7% (95% confidence interval [CI] 73.2-78.6%). DCA revealed that the use of the best model was associated with benefit gains relative to prediction of CSS. The optimised nomogram included only six variables associated with CSS in multivariable analysis: age (P < 0.001), pT stage (P < 0.001), grade (P < 0.02), location (P < 0.001), architecture (P < 0.001) and lymphovascular invasion (P < 0.001). The accuracy of the nomogram was 0.81 (95% CI, 0.78-0.85). Limitations included the retrospective study design and the lack of a central pathological review. An accurate postoperative nomogram was developed to predict CSS after RNU only in locally and/or locally advanced UTUC without metastasis, where the decision for adjuvant treatment is controversial but crucial for the oncological outcome.

Preoperative serum cholesterol is an independent prognostic factor for patients with renal cell carcinoma (RCC)

To assess the prognostic role of preoperative serum cholesterol in patients with renal cell carcinoma (RCC), as increasing evidence suggests that alterations in the lipid profile are associated with the development, progression and prognosis of various cancers. We analysed 867 patients, who underwent radical or partial nephrectomy for RCC between 2002 and 2012. Preoperative total cholesterol levels were determined in serum using colorimetric analysis (CHOD-PAP method). The association with cancer-specific survival (CSS) was assessed with Cox models. Discrimination was quantified with the C-index. The median follow-up was 52 months. The median (interquartile range) serum cholesterol was 195 (166-232) mg/dL. Decreasing serum cholesterol was associated with more advanced T, N and M stages (P < 0.001), higher grades (P = 0.001) and presence of tumour necrosis (P = 0.002). Continuously coded cholesterol was associated with CSS in both univariable (hazard ratio [HR] 0.87, P < 0.001) and multivariable analyses (HR 0.93, P = 0.001). The discrimination of a multivariable base model increased significantly from 88.3% to 89.2% following inclusion of cholesterol (P = 0.006). In patients with clinically localised disease (T1-3N0/+M0), cholesterol remained associated with CSS in multivariable analysis (HR 0.90, P = 0.002) and increased the discrimination from 74.6% to 76.9% (P = 0.002). Preoperative serum cholesterol is an independent prognostic factor for patients with RCC, with lower levels being associated with worse survival. Its use increases the discrimination of established prognostic factors. As cholesterol is a broadly available routine marker, its use may provide a meaningful adjunct in clinical practice. The biological rationale underlying this association remains to be clarified.

PD35-06 POST-OPERATIVE NOMOGRAM TO PREDICT CANCER-SPECIFIC SURVIVAL AFTER RADICAL NEPHROURETERECTOMY IN PATIENTS WITH PT1-T3 N0/NX UPPER TRACT UROTHELIAL CARCINOMA WITHOUT METASTASIS

You have accessJournal of UrologyBladder Cancer: Upper Tract Tumors I1 Apr 2014PD35-06 POST-OPERATIVE NOMOGRAM TO PREDICT CANCER-SPECIFIC SURVIVAL AFTER RADICAL NEPHROURETERECTOMY IN PATIENTS WITH PT1-T3 N0/NX UPPER TRACT UROTHELIAL CARCINOMA WITHOUT METASTASIS Thomas Seisen, Pierre Colin, VIncent Hupertan, David Yates, Evanguelos Xylinas, Laurent Nison, Olivier Cussenot, Alxandre De La Taille, Yann Neuzillet, Karim Bensalah, Giacomo Novara, Francesco Montorsi, Richard Ziguener, Mesut Remzi, Jay Raman, Shahrokh Shariat, and Morgan Rouprêt Thomas SeisenThomas Seisen More articles by this author , Pierre ColinPierre Colin More articles by this author , VIncent HupertanVIncent Hupertan More articles by this author , David YatesDavid Yates More articles by this author , Evanguelos XylinasEvanguelos Xylinas More articles by this author , Laurent NisonLaurent Nison More articles by this author , Olivier CussenotOlivier Cussenot More articles by this author , Alxandre De La TailleAlxandre De La Taille More articles by this author , Yann NeuzilletYann Neuzillet More articles by this author , Karim BensalahKarim Bensalah More articles by this author , Giacomo NovaraGiacomo Novara More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Richard ZiguenerRichard Ziguener More articles by this author , Mesut RemziMesut Remzi More articles by this author , Jay RamanJay Raman More articles by this author , Shahrokh ShariatShahrokh Shariat More articles by this author , and Morgan RouprêtMorgan Rouprêt More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2419AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To propose and validate a nomogram to predict cancer specific survival (CSS) after radical nephroureterectomy (RNU) in patients with pT1-3/N0-x upper tract urothelial carcinoma (UTUC). METHODS The international and the French national collaborative groups on UTUC pooled data on 3387 patients treated with RNU. Only 2233 pT1-3/N0-x patients naïve from chemotherapy were included in the current study. Population was randomly split into the development cohort (1563) and external validation cohort (670). To build the nomogram, logistic regressions were used for univariable and multivariable analyses. Different models were generated. The most accurate model was assessed using Harrell’s concordance index (c-index) and decision curve analysis (DCA). Internal validation was then performed by bootstrapping. Finally, the nomogram was calibrated and externally validated in the external dataset. RESULTS Out of 1563 patients in the nomogram development cohort, 309 (19.7%) died during follow-up as a consequence of UTUC. The actuarial CSS probability at 5 years was 75.7% (95% CI, 73.2-78.6). DCA revealed that the use of the best model was associated with benefit gains relative to prediction of CSS. The optimized nomogram included only six variables associated with CSS in multivariable analysis (Fig A): age (p<0.001), pT stage (p<0.001), grade (p=0.02), location (p<0.001), architecture (p=0.001) and LVI (p=0.001). The nomogram’s accuracy was 0.81 (95% CI, 0.78-0.85). Limitations included the retrospective study design and lack of a central pathological review. CONCLUSIONS An accurate post-operative nomogram was developed for predicting CSS post RNU only in locally and/or locally advanced UTUC without metastatis where the decision of an adjuvant treatment is controversial but crucial for the oncologic outcome. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e892-e893 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Thomas Seisen More articles by this author Pierre Colin More articles by this author VIncent Hupertan More articles by this author David Yates More articles by this author Evanguelos Xylinas More articles by this author Laurent Nison More articles by this author Olivier Cussenot More articles by this author Alxandre De La Taille More articles by this author Yann Neuzillet More articles by this author Karim Bensalah More articles by this author Giacomo Novara More articles by this author Francesco Montorsi More articles by this author Richard Ziguener More articles by this author Mesut Remzi More articles by this author Jay Raman More articles by this author Shahrokh Shariat More articles by this author Morgan Rouprêt More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

High Expression of Glucose Transporter 1 on Primary Lesions of Esophageal Squamous Cell Carcinoma is Associated with Hematogenous Recurrence

Glucose transporter type 1 (Glut1) plays a crucial role in cancer-specific metabolism to adapt to the rapid growth and tumor microenvironment in diverse malignant tumors. This study examined the clinical, pathological, and prognostic features of Glut1 expression on primary lesions of esophageal squamous cell carcinoma. Immunohistochemical staining of Glut1 and CD34 was performed using paraffin-embedded sections of tissues obtained from 145 resectable esophageal squamous cell carcinoma patients without preoperative treatment. Microvessel density was calculated from CD34 staining. Glut1 positivity was observed in 41 patients (28.2 %) and associated with depth of invasion [odds ratio (OR) 2.984; 95 % confidence interval (CI) 1.208-7.371; P = 0.018] and vascular invasion (OR 2.771; 95 % CI 1.118-6.871; P = 0.028) in multivariate analysis. Glut1 positivity was a significant disadvantage to both relapse-free survival [hazard ratio (HR) 2.021; 95 % CI 1.100-3.712; P = 0.023] and esophageal cancer-specific survival (HR 2.223; 95 % CI 1.121-4.411; P = 0.022) in univariate Cox hazard analysis, but was not independently associated with relapse-free survival or cancer-specific survival in multivariate analysis. The relationship between Glut1 expression and first relapse site was investigated. Glut1 positivity was not associated with lymph node recurrence (HR 1.009; 95 % CI 0.402-2.530; P = 0.985) but was significantly associated with hematogenous recurrence (HR 3.701; 95 % CI 1.655-8.273; P = 0.001) in univariate Cox hazard analysis. Microvessel density was calculated to evaluate angiogenesis, and it was observed that Glut1 positivity was significantly associated with high microvessel density (P < 0.001). Glut1 expression was associated with hematogenous recurrence. The findings provide evidence of the significance of Glut1 expression as a biomarker.

The impact of tumor size on outcomes in patients with upper urinary tract urothelial carcinoma

To investigate the association between tumor size and clinicopathologic factors and outcomes of upper urinary tract urothelial carcinoma (UTUC) in patients treated surgically for UTUC. A single-center series of 235 consecutive patients who were treated surgically for UTUC between January 1999 and December 2011 was evaluated. Patients with a history of muscle-invasive urothelial carcinoma of the urinary bladder, those who received neoadjuvant therapies, and those with previous contralateral UTUC were excluded. Bladder-only recurrence, any recurrence, and cancer-specific mortality after surgery were analyzed. Recurrence-free probabilities and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method and Cox regression analyses. Tumor size was significantly associated with age of the patient (P = 0.001), tumor location (P < 0.0001), tumor multifocality (P = 0.005), higher tumor stage (P < 0.0001), higher tumor grade (P = 0.038), lymphovascular invasion (P = 0.002), and mode of operation (P = 0.001). Tumor size was not associated with bladder-only recurrence (HR 0.91; 95% CI 0.46-1.80; P = 0.79). The Kaplan-Meier method showed that tumor size >3 cm was significantly associated with worse CSS (P = 0.006, log rank). The 5-year CSS for patients with tumor size ≤ 3 cm was 70.1% and for patients with tumor size >3 cm was 56.1%. Tumor size was not associated with cancer-specific survival in multivariable analysis (HR 1.53; 95% CI 0.89-2.61; P = 0.12). Tumor size >3 cm was associated with a lower 5-year CSS at Kaplan-Meier analysis, but was not an independent predictor of CSS, bladder-only recurrence, and any recurrence-free survival at multivariable analysis.

Investigating the association of cytoplasmic and nuclear HIF-2 expression with cancer specific survival (CSS) in clear cell renal cell carcinoma.

387 Background: Studies support the prognostic importance of HIF-2α for ccRCC. Interestingly, a recent study has implicated HIF-2α as part of a protein translational initiation complex, a cytoplasmic function that goes far beyond its role as a nuclear transcription factor. We hypothesized that both the absolute expression as well as the subcellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. Methods: A tissue microarray (TMA) study was conducted on 308 ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values. Results: The median follow-up was 2.29 years (IQR 11.82). The mean percentage of positive cells was 22.45±18.00 and 0.12 ± 0.29 for HIF-2α nuclear (N) and cytoplasmic (C), respectively. High HIF-2α N (cutoff&gt;32%) expression was associated with smaller tumor sizes (p = 0.002) and less advanced Fuhrman grades (p = 0.044). To the contrary, tumors with high HIF-2α C (&gt;0%) more often had lymph node (p = 0.004), distant metastases (p = 0.021), and higher Fuhrman grades (p&lt;0.0001). Univariate analyses showed an association of high HIF-2α N (p = 0.035) with better CSS. This was not found when HIF-2α N was used as a continuous variable (p = 0.067). In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p &lt; 0.0001) and as a dichotomized variable (p &lt; 0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p &lt; 0.0001) and dichotomized (p &lt; 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p = 0.001; HR 4.83 [95% CI: 1.99 – 11.76]). Conclusions: Our investigation suggests an important role for HIF-2α as a cytoplasmic protein translational initiation complex in ccRCC. This novel observation warrants further molecular and genetic studies examining biological pathways that are involved in the tumor promotive properties of HIF-2α in the cytoplasm.

Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence, Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer

BackgroundThe prognostic value of CK20, Ki-67, and p53 has been investigated for non–muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers. ObjectiveTo evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers. Design, setting, and participantsData from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected. InterventionAdjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4–8 wk. A total of 76 patients underwent cystectomy. Outcome measurements and statistical analysisWe conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS). Results and limitationsAt a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44–24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45–5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59–9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16–61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (p<0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study. ConclusionsOur present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.

Application of simplified Fuhrman grading system in clear‐cell renal cell carcinoma

To investigate the efficacy of simplified (two- or three-tiered) Fuhrman grading systems as prognostic indicators in clear-cell renal cell carcinoma (RCC). By reviewing records, various clinicopathological factors were assessed in 431 patients who received surgical management for clear-cell RCC. A conventional four-tiered Fuhrman grading system was compared with a modified two-tiered grading system (Fuhrman grades I and II were combined as one class, and grades III and IV as another) and also with a three-tiered grading system (only grades I and II were combined). Efficacies of grading systems were assessed via univariate analyses and multivariate models for prediction of cancer-specific survival. In univariate analysis, the four-tiered and three-tiered grading systems showed similar accuracies (76.5 vs 76.2%, P =0.614) for predicting cancer-specific survival, which were greater than that of the two-tiered system (72.5%; both P < 0.05). Of the three grading systems, only the three-tiered system was an independent predictor of cancer-specific survival in multivariate analysis (P = 0.046). When receiver operating characteristic-derived areas under the curve (AUCs) of multivariate models for predicting cancer-specific survivals were assessed, AUCs for models including the three-tiered Fuhrman grading system and the conventional four-tiered Fuhrman grading system were the same (95.3%), followed by that of a model incorporating the two-tiered grading system (95.1%). A modified, three-tiered Fuhrman grading system can be considered an appropriate option in the application of a nuclear grading system to the prognostication of clear-cell RCC in both univariate analysis and multivariate model setting.

Diabetes mellitus negatively impacts survival of patients with colon cancer, particularly in stage II disease

This retrospective study aimed to determine the effects of diabetes on overall survival (OS) and cancer-specific survival (CSS) in patients with newly diagnosed colon cancers, with particular focus on the impact of diabetes on survival at each stage of colon cancer. From January 1999 to January 2008, 2762 consecutive patients diagnosed with colon cancer in Taipei Veterans General Hospital were enrolled. The general characteristics as well as presence of diabetes prior to colon cancer diagnosis were identified. Cox proportional hazard analyses were used for prognostic factors determination; and survival was analyzed using the Kaplan-Meier method with log-rank test. A total of 469 patients (17%) had diabetes at diagnosis of colon cancer. Patients with diabetes had baseline characteristics comparable to those without diabetes with the exception that the patients with diabetes were older (>65years). Diabetes significantly and negatively impacted OS and CSS in multivariate analyses. After adjusting for possible confounding factors, the prognostic impact of diabetes on OS and CSS was particularly significant in patients with stage II colon cancer. Diabetes is a poor prognostic factor in patients with newly diagnosed colon cancer, and it may directly impact the tumor behavior of stage II disease. Further study is required to elucidate the underlying pathophysiologic mechanisms.

Cancer‐specific survival after radical cystectomy and standardized extended lymphadenectomy for node‐positive bladder cancer: prediction by lymph node positivity and density

To investigate the associations between different overall or topographically restricted lymph node (LN) variables and cancer-specific survival (CSS) after radical cystectomy (RC) and extended LN dissection (LND) with curative intent in patients with LN-positive bladder cancer. Between 2001 and 2006, 152 patients had RC with standardized extended LND for bladder cancer with curative intent. Patients with positive LNs were stratified according to the median of the LN variables (LNs removed, number of positive LNs, LN density). CSS was related to overall and topographically restricted LN variables, e.g. different levels of LND, and relationships were tested by univariate and multivariate analyses. Level 1 LND comprised the regions of the external and internal iliac LNs and of the obturator LNs, level 2 the templates of common iliac and presacral LNs, and level 3 the para-aortic and paracaval LNs up to the inferior mesenteric artery. The mean (range) follow-up was 22 (1-84) months. LN metastases were diagnosed in 46 of the 152 patients (30%) with extended LND. In these 46 patients, the median number of removed LNs was 33 (level 1, 15.5; level 2, 9.0; level 3, 7.0), the median number of positive LNs was 3 (1.5, 0.5 and 0.0, respectively) and the median LN density was 0.11 (0.10, 0.02 and 0.0, respectively). The CSS was 76% at 1 year and 23% at 3 years. There were significant correlations between the 3-year CSS and the overall LN density (< or =0.11 vs >0.11; 34% vs 8%, P = 0.008), and the total number of positive LNs (< or =3 vs >3; 33% vs 8%; P = 0.05). Overall LN density (hazard ratio 0.33, 95% confidence interval 0.15-0.72; P = 0.006) was an independent predictor for CSS in multivariate analysis. CONCLUSIONS Overall LN density is an independent predictor of survival after RC and extended LND with curative intent. Evaluation of topographically restricted LN positivity and density for different regions and levels of LND does not improve the prediction of CSS compared with overall LN positivity and density. A low incidence of level 3 LN positivity questions the clinical relevance of removing para-aortic and paracaval LNs. However, our data need to be confirmed by a prospective randomized trial.

Comparison of type I and II papillary renal cell carcinoma (RCC) and clear cell RCC

To compare the pathological features of clear cell renal cell carcinoma (ccRCC) with papillary RCC (pRCC) and further differentiate type I and II pRCC as independent prognosticators for survival. From September 1994 to February 2007 557 RCCs were treated and reviewed. All patients underwent radical nephrectomy or nephron-sparing surgery. We reviewed patient data and correlated RCC subtypes to tumour size, pathological stage, nuclear grade, and 5-year cancer-specific survival (CSS). pRCC was re-evaluated in to type I and II. The 2002 Tumour-Node-Metastasis and Fuhrman classifications were used. In all, 391 (70%) patients had ccRCC, 96 (17%) had pRCC, 34 (6%) had chromophobe RCC, seven (1%) had ductus Bellini RCC and 29 (5%) had unclassified RCC. Upon re-evaluation 34 patients had type I pRCC and 62 had type II. The pRCCs were significantly smaller than the ccRCCs, at a mean (sd) of 4.5 (2.5) cm vs 5 (2.9) cm (P = 0.013), and multifocal (25% vs 12%, P = 0.001). Whereas patients with ccRCC had significantly more primary metastases (12% vs 3%, P = 0.014). The mean (sd) follow-up was 42.3 (41.4) months. The 5-year CSS for M0 patients was 84% for ccRCC and 90% for pRCC (P = 0.573). At multivariate analyses predictors for 5-year CSS were only tumour size (hazard ratio, HR 2.6, P < 0.001), pathological stage (HR 3.9, P < 0.001) and nuclear grade (HR 2.7, P < 0.001). The type I and II pRCCs had significantly different lymphovascular invasion (LVI) and 5-year CSS rates (94% vs 74%, P = 0.03). The ccRCCs were significantly larger at diagnosis than the pRCCs. The histological subtype (pRCC vs ccRCC) had no impact on the 5-year CSS in multivariate analyses. The type I and II pRCCs had similar histopathological features except for a significant difference in LVI. However, the 5-year CSS was significantly different in type I and II pRCC.

Increased Expression of SIM2-s Protein Is a Novel Marker of Aggressive Prostate Cancer

The human SIM2 gene is located within the Down's syndrome critical region of chromosome 21 and encodes transcription factors involved in brain development and neuronal differentiation. SIM2 has been assigned a possible role in the pathogenesis of solid tumors, and the SIM2-short isoform (SIM2-s) was recently proposed as a molecular target for cancer therapy. We previously reported SIM2 among the highly up-regulated genes in 29 prostate cancers, and the purpose of our present study was to examine the expression status of SIM2 at the transcriptional and protein level as related to outcome in prostate cancer. By quantitative PCR, mRNA in situ hybridization, and immunohistochemistry, we evaluated the expression and significance of SIM2 isoforms in 39 patients with clinically localized prostate cancer and validated the expression of SIM2-s protein in an independent cohort of 103 radical prostatectomies from patients with long and complete follow-up. The SIM2 isoforms (SIM2-s and SIM2-l) were significantly coexpressed and increased in prostate cancer. Tumor cell expression of SIM2-s protein was associated with adverse clinicopathologic factors like increased preoperative serum prostate-specific antigen, high histologic grade, invasive tumor growth with extra-prostatic extension, and increased tumor cell proliferation by Ki-67 expression. SIM2-s protein expression was significantly associated with reduced cancer-specific survival in multivariate analyses. These novel findings indicate for the first time that SIM2 expression might be important for clinical progress of human cancer and support the recent proposal of SIM2-s as a candidate for targeted therapy in prostate cancer.

Microscopic venous invasion in renal cell carcinoma as a predictor of recurrence after radical surgery.

The objective of the present study was to investigate the significance of microscopic venous invasion (MVI) as a prognostic factor for patients with renal cell carcinoma (RCC) who underwent radical surgery. The study included a total of 157 consecutive patients with non-metastatic RCC who underwent radical surgery between January 1986 and December 2002. The median follow-up period was 45 months (range 6-162 months). Microscopic venous invasion was defined by the presence of a cancer cell in blood vessels based on the examination of hematoxylin-eosin stained specimens. Other prognostic variables were assessed by multivariate analysis to determine whether there was a significant impact on cancer-specific and recurrence-free survivals. Microscopic venous invasion was found in 70 patients, and of this number, 17 (24.7%) developed a tumor recurrence and 12 (17.1%) died of cancer progression, while only six (6.9%) of the remaining 87 patients without MVI presented with disease-recurrence and three (3.5%) died of cancer. Among the factors examined, the presence of MVI was significantly associated with age, mode of detection, tumor size, pathological stage and tumor grade; however, only pathological stage was an independent predictor for disease-recurrence, and none of these factors were available to predict cancer-specific survival in multivariate analyses. In 120 patients with pT1 or pT2 disease, MVI was noted in 36 patients. In this subgroup, recurrence-free survival rates in patients with MVI were significantly lower than those in patients without MVI, and MVI was the only independent prognostic predictor for disease-recurrence in a multivariate analysis. Microscopic venous invasion is not an independent prognostic factor in patients with non-metastatic RCC who underwent radical surgery; however, it could be the only independent predictor of disease-recurrence after radical surgery for patients with pT1 or pT2 disease.

Clinical significance of cell proliferation, microvessel density, and CD44 adhesion molecule expression in renal cell carcinoma

Renal cell carcinoma (RCC) is known to have a wide variation in clinical outcome despite the use of conventional prognostic factors, such as staging or grading. A better knowledge of the biologic aggressiveness of RCC could facilitate the selection of patients at high risk of tumor progression. The aim of this study was to determine if use of measurements of vascular density, cell proliferation, and cell adhesion could better predict the biologic behavior of RCC. We immunohistochemically analyzed CD34, Ki-67, and CD44H expression on formalin-fixed, paraffin-embedded tissues from 73 RCCs for quantifying microvessel density (MVD), Ki-67 labeling index (LI), and CD44H LI, respectively. Univariate cancer-specific survival analysis showed that tumor stage (P <.01), tumor size (P <.001), nuclear grade (P <.01), metastasis (P <.001), MVD (P <.03), Ki-67 LI (P <.001), and CD44H LI (P <.0001) were predictors of tumor-related death. There was a statistical correlation between CD44H LI and both Ki-67 LI (r' =.3) and MVD (r' = −44). Ki-67 LI (P <.04) and CD44H LI (P <.02), as well as metastasis (P <.008), emerged as independent predictors of cancer-specific survival in multivariate analysis in patients with metastases (P <.04 and P <.02, respectively) and in patients without metastases (P <.006 and P <.00001, respectively). Our study suggests that vascular density, cell proliferation, and cell adhesion represent a complex tumor–host interaction that may favor progression of RCC. Cell proliferation and CD44H expression appear to be powerful markers to identify patients with an adverse prognosis. HUM PATHOL 32:1209-1215. Copyright © 2001 by W.B. Saunders Company