Independent Predictor Of Disease-specific Survival Research Articles

Influence of Young Age on Outcome After Esophagectomy for Cancer

The incidence of esophageal cancer has risen among all age groups. Controversy exists about the clinical presentation and prognosis of young patients. The aim of this study was to compare the clinicopathologic characteristics and outcomes after surgery between patients with esophageal cancer who were <50 years of age and those ≥50 years of age. Patients diagnosed with esophageal carcinoma who underwent esophagectomy between January 1990 and December 2010 in a single institution were selected from a prospective database. Patients aged <50 years at diagnosis (n = 163) were compared with those ≥50 years (n = 1151) with respect to clinicopathologic stage and oncologic outcome. Younger patients had less co-morbidity (p < 0.001). There were no significantly differences in tumor localization, histology, differentiation, or TNM stage in the two groups. In both groups, 37 % of the patients underwent neoadjuvant chemo(radio)therapy. One or more nonsurgical complications developed in 53 % of the older group versus 42 % in the younger group (p = 0.012). In-hospital mortality was 6.3 % for patients ≥50 years compared to 1.8 % for younger patients (p = 0.021). The 5 year overall survival was significantly better for the younger patients than for those ≥50 years (41 vs. 31 %, p < 0.001), but median disease-specific and disease-free survival did not differ between the groups (37 vs. 30 months, p = 0.140 and 49 vs. 28 months, p = 0.079, respectively). Multivariate analysis identified moderate, poorly, and undifferentiated tumors; tumor-positive resection margins (pR1-2); and TNM stage IIB-IV as independent predictors of disease-specific survival. A considerable proportion (12 %) of patients diagnosed with resectable esophageal carcinoma were <50 years. Phenotypic tumor characteristics and disease-specific survival were comparable for the two age groups.

Poorly differentiated resectable pancreatic cancer: Is upfront resection worthwhile?

Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading. A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading. Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P < .0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P < .0001). Adjuvant therapy improved disease-specific survival in G2 (P < .04) and G3 (P < .0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116). G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.

Abstract LB-444: SATB2 is a novel prognostic factor in colorectal cancer

Abstract SATB2 is a nuclear matrix-associated transcription factor that orchestrates gene expression in a tissue-specific manner by regulating higher order chromatin structure. Using antibody-based screening of 48 normal human tissues and 20 cancer types, we identified SATB2 as a protein almost exclusively expressed in gastrointestinal tissue. Differential expression of SATB2 was observed in colorectal cancer, with loss of expression occurring along the adenoma-carcinoma sequence. We further confirmed this observation at the mRNA level in 10,533 colorectal cancer samples. Additionally, SATB2 expression was markedly decreased in a metastatic variant of SW480 colon cancer cells and siRNA knockdown of SATB2 expression in parental SW480 cells increased their growth and migratory capacity. Ectopic expression of SATB2 in the metastatic variant reversed the observed phenotype. Using tissue microarray and automated image analysis of SATB2 expression in colorectal cancers (n=309), SATB2 was demonstrated by multivariate Cox regression analysis to be an independent predictor of disease-specific survival (HR=0.52, 95% CI 0.32-0.83, p=0.006) and loss of SATB2 expression significantly correlated with poor differentiation (p=0.001). SATB2 mRNA levels were examined in a second cohort (n=290) and again, SATB2 was demonstrated to be an independent predictor of disease-specific survival (HR=0.40, 95% CI 0.18-0.92, p=0.031). Interestingly, in colorectal cancer patients, SATB2 levels significantly correlate with CD3+ T-cell infiltrates in the tumours (p=0.006) and inversely correlate with COX2 expression (p=0.019). Gene set enrichment analysis in two independent colorectal cancer cohorts (n&amp;gt;500) revealed that SATB2 low tumours demonstrate altered immune signalling with significant increases in IFN-gamma(p=0.001), IL6 (p=0.021) TFGβ (p&amp;lt;0.001). Furthermore, in patients with inflammatory bowel disease (n&amp;gt;1000), we observed a significant correlation between loss of SATB2 expression and occurrence of future cancers (p=0.013). We therefore postulate that SATB2 acts as a master regulator of the inflammatory response in the gut and loss of expression is significantly associated with the progression of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-444. doi:1538-7445.AM2012-LB-444

Previous pregnancy is a favourable prognostic factor in women with localised cutaneous melanoma

Background. The influence of pregnancy on survival in melanoma has been a controversial issue. Objective. In this retrospective study we investigated whether pregnancy (overall or temporally melanoma-related) has any effect on melanoma progression or patient outcome. Methods. Patient data were collected from Turku University Hospital records concerning all women in fertile age (15–45 years) and diagnosed with melanoma between January 1, 1990 and December 31, 2009. We collected data on melanoma characteristics, treatment, pregnancies and patient outcomes. Results. Of the 334 patients, 248 (74%) had been pregnant in some point during their life while 55 (17%) were nulliparous. The history of pregnancies could not be verified in 31 women (9%). Progression of melanoma to advanced stage was found in 58 (17%) of these women. Altogether, 35 women (14%) with at least one pregnancy had disease progression in contrast to 14 women (26%) with no pregnancies (p =0.049). Women with at least one pregnancy had a 94% probability to survive from melanoma compared to nulliparous women of whom only 83% survived (p =0.041). In Multivariate (COX) analysis pregnancy was a favourable factor for disease-specific survival (DSS) (HR 3.75; 95% CI 1.24–11.34; p =0.019) when adjusted for age (HR 1.064; 95% CI 1.00–1.13; p =0.50), localisation and stage (p =0.040), and Breslow (HR 1.32; 95% CI 1.10–1.58; p =0.002). However, when ulceration of the primary tumour was included in the multivariate model, Breslow remained as the only independent predictor of DSS (HR 1.58; 95% CI 1.34–1.86; p =0.0001) and pregnancy was dropped from the stepwise backward model in the step preceding the last one (p =0.081). Conclusion. Pregnancy is not a risk factor for disease recurrence or progression in melanoma patients, but instead can exert some favourable influence on prognosis.

Prognostic Value of Proliferation Markers: Immunohistochemical Ki-67 Expression and Cytometric S-Phase Fraction of Women with Breast Cancer in Libya

Background: We evaluated the association of the immunohistochemical Ki-67 expression, and S-phase fraction with clinicopathological variables and patient outcome.Patients and methods: Histological samples from 100 primary Libyan breast carcinoma patients were retrospectively studied with monoclonal antibody to Ki-67. S-phase fraction was determined by DNA image cytometry.Results: The median Ki-67 percentage for all tumors was 27.5%, ranging from 1 to 80% and the median S-phase fraction (SPF) was 11%, ranging from 0 to 62 %. Tumors with high Ki-67 expression were found in 76% of patients and with high SPF values in 56%. Ki-67 expression was more frequent in tumors with high SPF than low SPF. High Ki-67 and high SPF were associated with advanced stages, poor differentiation of tumors, positive lymph nodes, and distant metastasis. The Ki-67 was associated with hormone receptor negative tumors. The SPF was higher in young patients (<50 years) than in older patients. In the overall population (median follow-up 49 months), patients with high Ki-67 and high SPF had shorter survival time and predicted recurrence than patients with low Ki-67 and low SPF. In a Cox multivariate analysis, high SPF (p= 0.007), hormonal status (p= 0.001) and clinical stage (p=0.005) were independent predictors of disease-specific survival. The Ki-67 (p=0.065) in borderline significance proved to be independent predictor of disease-free survival. The SPF showed more statistically significance with a high grade of malignancy and survival time than Ki-67.Conclusions: The SPF value is useful cell proliferation marker to assess tumor prognosis. These markers may reflect the aggressive behavior of Libyan breast cancer and predict of the recurrence. It is therefore important to take these markers into consideration to select a high risk subgroup of the patients for intensive treatment.

Tumor Location Is an Independent Prognostic Factor in Head and Neck Merkel Cell Carcinoma

Explore the relationship between tumor location and prognosis among patients with Merkel cell carcinoma (MCC) of the head and neck. Retrospective analysis of large population database. Surveillance Epidemiology and End Results (SEER) database/multiple settings. Using the SEER database, the authors identified patients with MCC of the head and neck. They compared clinicopathologic characteristics and disease-specific survival (DSS) between patients with head and neck MCC at different anatomic subsites. DSS was estimated by the Kaplan-Meier method, and a multivariable regression model was constructed so that independent predictors of DSS could be determined. Of the 2104 patients identified, 61.0% were men. The mean age at diagnosis was 77.5 years. Tumors were most commonly located on the face (61.1%). Scalp tumors were significantly larger (10.4% >5 cm, P = .0001) and more likely to present with distant metastasis (8.7%, P = .07) than other head and neck tumors. Lip tumors had the highest rate of invasion into bone, cartilage, and muscle (13.7%, P = .012), and ear tumors had the highest rate of nodal metastasis (63.2%, P = .011). Patients with scalp/neck and lip primary sites had significantly worse survival on univariable analysis (P = .0054 and P = .0007, respectively); however, the lip was the only site associated with worse survival on multivariable analysis (hazard ratio = 1.8, P = .005). This study is the first to report lip location as an independent prognostic factor in head and neck MCC. More aggressive treatment of patients with MCC of the lip may be warranted to improve outcomes.

Expression of Cell Cycle Regulators P21 and P27 as Predictors of Disease Outcome in Colorectal Carcinoma

Recent studies suggest that aberrations in cell cycle checkpoint controllers are a common feature in human malignancies and predict prognosis independent of stage. This study correlated two cell cycle regulators (p27 and p21) with clinical and pathological variables in colorectal cancer (CRC) patients to assess their role as prognostic factors. A series of 65 CRC patients were analyzed for p27 and p21 expression in their tumors using immunohistochemistry. Forty-six percent of tumors showed positive nuclear p27 expression, whereas 72% of cases were completely p21 negative. There were no significant correlations between p27 and p21 expression and gender, age, lymph node involvement, stage, and grade. However, p27 (but not p21) expression revealed highly significant correlation with tumor location (p < 0.01), depth of invasion (p < 0.03), and lympho-vascular invasion (p < 0.02). Tumors with high p27 expression showed a higher recurrence rate than tumors with no expression (p < 0.03). In Kaplan-Meier survival analysis, there was a significant (p = 0.046) difference in disease-free survival (DFS) between p27-positive and p27-negative tumors in favor of the latter. p21 did not show any predictive value of DFS (p < 0.7). Neither p27 nor p21 did predict disease-specific survival (DSS) in Kaplan-Meier analysis, but DSS time was much shorter for p27-positive tumors. In multivariate (Cox) model, p27 lost its value as independent predictor of DFS, and none of the covariates were independent predictors of DSS. p27 expression seems to be more powerful than p21 expression in providing useful prognostic information in CRC, particularly in predicting the patients at high risk for recurrent disease. Larger cohort and longer follow-up are needed to fully elucidate the value of p27 (and p21) as independent predictors of disease outcome.

Surgery for Locally Recurrent Rectal Cancer in the Era of Total Mesorectal Excision

To evaluate the perioperative outcome and long-term survival of patients who underwent surgical resection for recurrent rectal cancer within a multimodal approach in the era of total mesorectal excision (TME). Introduction of TME has reduced local recurrence and improved oncological outcome of patients with rectal cancer. Local recurrence after TME still occurs in 2% to 8% of patients and presents a challenge to surgical and medical oncologists. However, there has been very limited data on the perioperative and long-term outcome of patients who are operated for local recurrence in the era of TME. A total of 107 patients who were identified from a prospective rectal cancer database underwent surgical exploration for recurrent rectal cancer after previous TME between October 2001 and April 2009. Risk factors of perioperative morbidity were analyzed using a multivariate logistic regression model. Independent predictors of disease-specific survival were identified by a Cox proportional hazards regression model, as were those of local recurrence and disease recurrence at any site. Surgical resection was performed in 92 patients and negative resection margins were achieved in 54 (58.7%) of these. Recurrent disease was located intraluminally and extraluminally in 35 (38.0%) patients and 57 (62.0%) patients, respectively. A total of 19 (20.6%) patients had metastatic extrapelvic disease at the time of surgery. Perioperative surgical morbidity and in-hospital mortality accounted for 42.4% and 3.3%, respectively. On multivariate analysis, partial sacrectomy was associated with surgical morbidity (P = 0.004). Three- and 5-year disease-specific survival rates were 61% and 47%. Three-year survival rate of patients with extrapelvic disease who underwent R0 resection was 42%. On multivariate analysis, surgical morbidity (P = 0.001), presence of extrapelvic disease (P = 0.006), and noncurative (R1; R2) resection (P < 0.0001) were identified as independent adverse predictors of disease-specific survival, whereas a transabdominal resection (as opposed to an abdominoperineal resection/pelvic exenteration) was associated with a more favorable prognosis (P = 0.04). Surgical resection of local recurrence from rectal cancer in the era TME can be carried out with acceptable morbidity and curative resection rates. Curative resection remains the major prognostic factor and may enable long-term survival even in patients with extrapelvic disease.

Prognostic Value of Lymph Node Density in Node-Positive Patients with Oral Squamous Cell Carcinoma

Lymph node density (LND) is superior to TNM nodal status in predicting survival after surgery for bladder and other cancers. Little is known, however, about whether LND can predict survival in patients with oral squamous cell carcinoma (OSCC). We therefore evaluated the utility of LND for predicting survival for patients with OSCC and positive nodes (pN+). We reviewed the clinical, pathologic, and follow-up data of 211 OSCC patients who underwent surgery. All lymph nodes harvested from neck dissection were carefully examined, with LND calculated as the ratio of positive lymph nodes to total lymph nodes removed. Univariate and multivariate analyses of variables predicting overall survival (OS) and disease-specific survival (DSS) were performed for all patients and in pN+ patients. Kaplan-Meier analyses showed that the 5-year OS and DSS rates in all patients were 72% and 79%, respectively. Multivariate analysis showed that variables independently prognostic for DSS were T classification (hazard ratio [HR] = 2.97, 95% confidence interval [95% CI] = 1.59-5.57; P = .001), and N classification (HR = 4.91, 95% CI = 2.47-9.75; P < .001). In pN+ patients, univariate analysis showed that T classification, >2 positive nodes, and LND >0.06 (median) were significant predictors of DSS (P < .015 each), and multivariate analysis showed that LND was an independent predictor of DSS (HR = 3.24, 95% CI = 1.61-6.53; P = .001). LND may be useful in stratifying the likelihood of survival in patients with OSCC.

Smarcc1 expression: A significant predictor of disease-specific survival in patients with clinically localized prostate cancer treated with no intention to cure

The clinical outcome of prostate cancer (PC) is extremely variable and therefore difficult to predict at the early stage of the disease. Since curative-intended therapies are bound up with the risk of severe adverse events, identification of new prognostic markers in PC is essential in individualized clinical treatment. The Smarcc1 protein, a part of the intranuclear SWI/SNF complex, is up-regulated in PC, and has been suggested to be implicated in tumour dedifferentiation, progression and biochemical recurrence. This makes Smarcc1 a possible candidate marker for PC survival. Immunohistochemistry was used to measure protein expression levels of Smarcc1in on a tissue microarray containing specimens from 100 patients suffering from clinically localized PC treated with no intention to cure and followed to death. The median age at diagnosis was 75.5 years (55-95 years) and the median survival time was 5 years (0.01-15 years). In total, 41 patients (41%) died of PC. Statistically, there was no significant association between Smarcc1 immunostaining (negative/positive) and Gleason score (p = 0.7/0.8) or the clinical T stage (p = 0.9). Positive staining for Smarcc1 in patients with clinically localized PC correlated with a prolonged disease-free survival as opposed to negative staining (p = 0.025). In patients with clinically localized PC treated without intention of cure, Smarcc1 expression was a statistically significant and independent predictor of disease-specific survival.

Relative 8q gain is a poor prognostic factor in the diagnosis of prostate biopsies irrespective of the TMPRSS2-ERG fusion status

ETS transcription factor family genes are involved in recurrent genetic rearrangements in prostate carcinoma (PCa). In 50% of PCa patients there is a fusion between the androgen-regulated elements of TMPRSS2 with the ETS transcription factor ERG, causing over-expression of the latter. Other ETS family genes, namely ETV1, ETV4, and ETV5, have more rarely been found to be fused with TMPRSS2 or other 50 partners. We have previously demonstrated that TMPRSS2-ERG is present in pre-malignant prostate lesions in addition to PCa and that relative 8q gain detected in diagnosis needle biopsies is an independent predictor of disease-specific survival. In order to evaluate the prognostic value of these two alterations, we have analyzed a consecutive series of 200 PCa patients by fluorescence in situ hybridization (FISH) assays in paraffin-embedded diagnostic needle biopsies collected from 1997 to 2001. Most of the biopsies displayed Gleason scores (GS) equal to 7 (40.9%) or higher (47%), with the remaining tumors graded with Gleason scores lower than 7 (12.1%). The fusion gene TMPRSS2eERG was detected in 43.2% of PCa cases, being less frequent in higher GS PCa biopsies (54.2%, 50.6%, and 33.3% for GS ! 7, GS 5 7, and GS O 7, respectively; P 5 0.035). On the other hand, relative 8q gain was less frequent in lower GS PCa biopsies (8.3%, 50.6%, 57% for GS ! 7, GS 5 7, and GS O 7, respectively; P ! 0.01). ERG rearrangements alone were not associated with clinical outcome, whereas 8q gain predicted a worse prognosis in PCa patients irrespective of the TMPRSS2eERG fusion status. The prognostic value of relative 8q gain was independent of clinical variables in a multivariate analysis. To the best of our knowledge, this is the first study combining the aforementioned genetic aberrations to assess its prognostic value. The use of genetic prognostic markers in diagnostic prostate biopsies might impact decision making and has, therefore, the potential to become a common procedure in clinical practice. ANALYSIS OF ALTERNATIVE MECHANISMS FOR RET GENE ACTIVATION IN HEREDITARY AND SPORADIC MEDULLARY THYROID CARCINOMA

Gene expression profiles to predict outcome following liver resection in patients with metastasis of colorectal cancer.

3576 Background: A validated clinical risk scoring (CRS) system developed at our institution has proven to be a powerful predictor of long-term outcome after hepatic resection for metastatic colorectal cancer (MCRC). The CRS, however, does not preclude long-term survival and is imperfect. The aim of this study was to build a model predictive of survival based on gene signatures. Methods: Using the Illumina Human HT-12 expression gene chip containing 25,000 annotated genes, RNA samples from the liver metastases from 96 patients were analyzed. The patients were randomly assigned to a training set or a test set. All patients underwent R0 liver resection and no extrahepatic disease. At a median follow-up of 30 months, 39 patients (41%) died of recurrent cancer. The genes associated with cancer-related death were identified by Cox-regression and selected to construct a molecular risk score (MRS) using the supervised principle component method in a training set of patients (n = 60). The MRS was then evaluated in an independent test set of patients (n = 36) using the Log-rank test and Cox-regression. The prognostic strength of MRS and CRS was assessed with a concordance index. Results: Nineteen genes were selected to construct the MRS. The MRS was validated to predict disease-specific survival (DSS); 5-year predicted DSS rates were 77% and 36% for patients with low MRS and those with high MRS, respectively (p = 0.0046). In multivariate analysis, MRS emerged as an independent predictor for DSS, while CRS did not (p = 0.034 and p = 0.11, respectively). The concordance index of MRS and CRS predicting DSS were 0.71 and 0.65, respectively. Conclusions: An MRS based on gene expression profiling is highly predictive of outcome and is independent of CRS. This finding provides a potential strategy for better risk-stratification of patients with resected liver MCRC. No significant financial relationships to disclose.

429 PREDICTORS OF LONG-TERM ONCOLOGICAL OUTCOMES OF LAPAROSCOPIC NEPHROURETERECTOMY FOR UPPER TRACT TCC

You have accessJournal of UrologyUrothelial Cancer: Upper Tract Tumors1 Apr 2010429 PREDICTORS OF LONG-TERM ONCOLOGICAL OUTCOMES OF LAPAROSCOPIC NEPHROURETERECTOMY FOR UPPER TRACT TCC Michael Lee, Georges-Pascal Haber, Kazumi Kamoi, Sebastian Crouzet, and Inderbir Gill Michael LeeMichael Lee More articles by this author , Georges-Pascal HaberGeorges-Pascal Haber More articles by this author , Kazumi KamoiKazumi Kamoi More articles by this author , Sebastian CrouzetSebastian Crouzet More articles by this author , and Inderbir GillInderbir Gill More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.499AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Laparoscopic nephroureterectomy (LNU) is now an accepted treatment alternative for patient with upper tract transitional cell carcinoma (UT-TCC). We analyzed factors which predict disease-specific and recurrence-free survival of patients following LNU. METHODS 217 consecutive patients underwent with LNU for UT-TCC between 9/1997 and 2/2008. Data were collected prospectively and retrospectively when missing. Survival was determined from clinical follow up and the Social Security Death Index. Factors affecting disease-specific and recurrence-free survival were analyzed using Cox proportional hazard model. RESULTS At 2, 5 and 8 years overall survival was 72%, 54% and 43%, disease-specific survival was 81%, 76% and 73%, and recurrence-free survival was 64%, 60% and 58%, respectively. In multivariate analysis T stage (muscle invasive) and positive surgical margin were independent predictors for disease-specific survival (P<0.01 for both, Table 1). Five-year disease-specific survival rate was 92% in the non-invasive diseases (127 patients) and 52% in the muscle invasive diseases (90 patients). Positive surgical margin occurred in 20 patients whose median survival was 17 months. In multivariate analysis grade 3 tumor in the pathological specimen was an independent predictor for recurrence-free survival (p<0.05, Table 2). Five-year recurrence-free survival rates were 79% in the patients without grade 3 tumor (71 patients) and 49% in the patients with grade 3 tumor (146 patients). CONCLUSIONS Long-term oncological outcomes for LNU appear comparable to those of open surgery. For patients undergoing LNU, T stage 2 or higher was an independent predictor for disease-specific survival and tumor grade 3 was an independent predictor for recurrence-free survival. Patients with positive surgical margin had overall poor prognosis. Cleveland, OH© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e169-e170 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Lee More articles by this author Georges-Pascal Haber More articles by this author Kazumi Kamoi More articles by this author Sebastian Crouzet More articles by this author Inderbir Gill More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Nuclear factor‐κB activation predicts an unfavourable outcome in human upper urinary tract urothelial carcinoma

to examine the hypothesis that nuclear factor-κB (NF-κB), a transcription factor involved in anti-apoptosis, invasion, and angiogenesis, plays a role in the carcinogenesis of upper urinary tract urothelial carcinoma (UUT-UC) and has prognostic value for survival. in all, 90 patients with UUT-UC [mean (range) age, 64.5 (24-84) years] who underwent surgery at our institution from January 1991 to December 2005 were included. Clinicopathological data were collected retrospectively. We performed immunohistochemical staining for NF-κB (p65) on paraffin-embedded sections of the tumour and corresponding normal tissues. The association between survival and potential prognostic factors was examined. the median follow-up was 40 months. In all, 55 patients (61.1%) with UUT-UC overexpressed cytoplasmic NF-κB, and nuclear immunoreactivity for NF-κB was detected in 24 patients (26.7%). On univariate analysis, significant prognostic factors for survival were tumour location, stage, grade, lymph node involvement, and nuclear NF-κB expression. On multivariate analysis, nuclear NF-κB positivity was an independent predictor for disease-specific survival [Cox regression hazard ratio (HR) 2.87; P= 0.025] and overall survival (HR 2.24; P= 0.037). these results imply a role for nuclear NF-κB expression in the tumorigenesis of UUT-UC. Nuclear NF-κB may serve as a useful independent molecular marker to predict outcome and may represent a promising therapeutic target for patients with UUT-UC.

Preoperative radiotherapy downregulates the nuclear expression of hypoxia-inducible factor-1α in rectal cancer

Objective. To assess the value of hypoxia-inducible factor-1α (HIF-1α) expression as a predictor of disease outcome in rectal cancer treated by preoperative radio- or chemoradiotherapy. Material and methods. Operative samples from 168 rectal cancer patients and 79 respective preoperative biopsies were analyzed for nuclear HIF-1α protein expression using immunohistochemistry by three approaches: (a) positive/negative, (b) the percentage of HIF-positive cancer cells and (c) staining intensity. The patients had received either short- (n = 75) or long-course radiotherapy with or without chemotherapy (n = 39) or no treatment preoperatively (n = 54). Results. HIF-1α staining was positive in 70% of the diagnostic biopsies but negative in most of the post-radiotherapy specimens (60%). HIF-1α expression in the biopsies was downregulated in 56% of samples taken after preoperative treatment, while negative HIF-1α expression was upregulated in 25% of samples. Patients who had HIF-negative tumours after long-course radiotherapy had significantly (P = 0.001) better disease-specific survival (DSS) in univariate analysis. In the multivariate (Cox) regression model, HIF-1α lost its significance and only being in the preoperative treatment group was an independent predictor of disease-free survival. In a similar Cox model, disease recurrence and the number of metastatic lymph nodes were independent predictors of DSS. Conclusions. HIF-1α expression was positive in most of the preoperative biopsies but downregulated in most of the operative samples, implicating that preoperative radiotherapy downregulates HIF-1α expression in rectal cancer. Negative HIF expression after preoperative long-course radiotherapy was associated with significantly better DSS.

Predicting Outcome by Growth Rate of Locally Recurrent Retroperitoneal Liposarcoma

To identify the prognostic variables that predict disease-specific survival and second local recurrence-free survival in patients with recurrent retroperitoneal liposarcoma so as to guide clinical management. Local recurrence after complete resection of primary retroperitoneal liposarcoma is a common clinical problem that frequently leads to morbidity and mortality. Factors that determine survival in patients with a local recurrence after complete resection of the primary and rerecurrence after resection of the first local recurrence have not been clearly defined. From a prospective sarcoma database we selected 105 patients who had at least one local recurrence following complete resection of a primary retroperitoneal liposarcoma between July 1982 and December 2005. Of these patients, 61 underwent complete resection of their first local recurrence. Study endpoints included second local recurrence-free survival for these 61 patients and disease-specific survival for all 105 patients. Univariate analysis was performed with the Kaplan-Meier method and log-rank test, and multivariate analysis with the Cox proportional hazards model and score test. Local recurrence growth rate was defined as the radiographic size of the local recurrence divided by the time to local recurrence from the primary resection. Median follow-up was 65 months. Local recurrence size, primary histologic variant and grade, and local recurrence growth rate were independent predictors of disease-specific survival. For those undergoing reresection, local recurrence size and local recurrence growth rate independently influenced development of a second local recurrence. Only patients with local recurrence growth rates of less than 0.9 cm/mo were associated with improved survival after aggressive resection of the local recurrence. Local recurrence growth rate is strongly associated with disease-specific survival and local control for patients with completely resected locally recurrent retroperitoneal liposarcoma. Despite aggressive operative management patients with a local recurrence growth rate greater than 0.9 cm/mo were associated with poor outcomes and should be considered for enrollment in clinical trials employing novel agents.

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

Nurr1 belongs to a novel class of orphan nuclear receptors (the NR4A family). The authors have previously shown that Nurr1 is important in carcinogenesis. In the current study, they examined the clinicopathologic relevance of expression patterns of Nurr1 in bladder tumors. Nurr1 expression was determined using immunohistochemical staining in a bladder cancer tissue array (145 tumors). Tumors were classified according to Nurr1 protein levels in both cytoplasm and nucleus. Disease-specific survival and recurrence-free survival were investigated by Kaplan-Meier analysis and Cox proportional hazards analysis in multivariate models and correlated with variables such as tumor stage, growth pattern, and clinical outcome (recurrence and survival). In vitro, Nurr1 was examined for its role in bladder cancer cell proliferation and migration using small interfering RNA silencing. Nurr1 expression in tumor cells correlated with increasing tumor stage and invasive growth pattern. Disease-specific survival was significantly shorter in patients whose tumors demonstrated a high level of cytoplasmic Nurr1 compared with those with lower levels of cytoplasmic Nurr1 expression. Furthermore, cytoplasmic Nurr1 expression level was found to be an independent predictor of disease-specific survival (odds ratio, 4.894; P < .001). In vitro, silencing of endogenous Nurr1 attenuated the migration of bladder cancer cells. The expression of Nurr1 in the cytoplasm correlates with adverse outcome and is an independent prognostic marker for tumor progression and survival in patients with bladder cancer. This might represent a novel target in bladder cancer therapy.

Significance of nuclear grade and tumor size in Korean patients with chromophobe renal cell carcinoma: A comparison with conventional renal cell carcinoma

Objectives To analyze the clinical behavior of chromophobe renal cell carcinoma (RCC) in Korean patients. Materials and methods A total of 657 patients with conventional RCC and 71 with chromophobe RCC were included in the analysis. The median follow-up for all patients was 44 months (95% confidence interval, 10 to 126). Results Patients with chromophobe RCC differed significantly from those with conventional RCC on the following parameters: a greater female ratio ( P = 0.019), less advanced TNM stage ( P = 0.004), and higher Fuhrman nuclear grade ( P < 0.001). There was no statistical difference with regard to age and tumor diameter. The 5- and 10-year disease-specific survival rates in patients with chromophobe RCC (92.9% and 92.9%) were higher than in patients with conventional RCC (84.9% and 79.8%). When patients were divided according to T stage, Fuhrman's grade, and tumor size for the subgroup analysis, disease-specific survival probabilities of chromophobe RCC were higher in only tumors with a high Fuhrman's grade (G3/G4) ( P = 0.002) and larger than 4 cm ( P = 0.025). The multivariate analysis showed that the histologic type was not an independent predictor of disease-specific survival. Conclusions Although Korean patients with chromophobe RCC had a better survival probability than patients with conventional RCC, the histologic type was not an independent predictor of survival probability. In addition, our findings suggest that chromophobe RCC has a better survival probability than conventional RCC in patients with Fuhrman's grade 3 to 4 or with a tumor diameter > 4.0 cm.

Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer

Aryl hydrocarbon receptor (AhR) and the activation of the AhR pathway are involved in xenobiotic-induced toxicity and carcinogenesis. Although xenobiotics, such as cigarette smoke, contribute to the development of urothelial carcinoma (UC), the relationship between AhR and UC is unclear. In the present study, we investigated AhR expression in 209 patients with upper urinary tract UC. The nuclear expression of AhR was significantly associated with histological grade, pathological T stage, lymphovascular invasion and lymph node involvement. A multivariate Cox analysis revealed that nuclear AhR expression was a significant and independent predictor for disease-specific survival (hazard ratio = 2.469, P = 0.013). To determine whether the AhR pathway can be activated in the T24 UC cell line, we examined the expression of cytochrome P450 (CYP) 1A1 and CYP1B1, which are target genes of the AhR pathway, following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR. TCDD treatment upregulated the expression levels of AhR, CYP1A1 and CYP1B1. TCDD enhanced T24 cell invasion associated with the upregulation of matrix metalloproteinase (MMP)-1 and MMP-9. Furthermore, targeting AhR messenger RNA (mRNA) expression in T24 cells with small interfering RNA (siRNA) downregulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9; furthermore, the cells transfected with siRNA for AhR showed decreased invasion activity in comparison with the cells transfected with a non-targeting siRNA. Our results therefore suggest that AhR plays a role in the invasiveness of UC cells and can serve as a marker for the prognosis of upper urinary tract UC.

Multivariate analysis of prognosis of patients with upper urinary tract transitional cell carcinoma

Objective:To retrospectively analyze the clinical data of 71 patients with upper urinary tract transitional cell carcinoma (UUT-TCC), so as to assess the prognosis of patients and search for factors influencing the prognosis of patients. Methods: Totally 71 UUT-TCC patients treated surgically from Feb. 2004 to Jan. 2007 were included in this study. All patients underwent radical nephroureterectomy via retroperitoneoscopic approach or open approach. The patients were followed up once a month after operation. Traditional prognostic factors including age, sex, tumor stage, grade, location, type of surgical treatment and some pathological biomarkers, such as p53, Ki-67, nm23, and C-erB-2, were collected and analyzed with respect to disease-specific survival by Kaplan-Meier method. Predictive factors influencing the disease-specific survival were also analyzed by Cox proportional hazards model. Results: The 1-, 2-or 3-year disease-specific survival rates were 95.8 %, 89.3% and 83.5%, respectively. Only tumor stage was found to be a factor for prognosis by multivariate analysis (P0.001). Conclusion: Tumor stage is an independent predictor of disease-specific survival. Retroperitoneoscopic radical nephroureterectomy achieves similar outcomes to the traditional open surgery on oncology control, with the long-term outcome remains to be further studied.