Independent Predictor Of Disease-free Survival Research Articles

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Extracellular signal-regulated kinase (ERK) promotes proliferation, metastasis, and poor survival in cancers of the breast, lung, and liver. Advanced localized renal cell carcinoma (RCC) is extraordinarily treatment resistant and has high recurrence rates despite surgery. Limited data exist regarding the prognostic significance of activated (phosphorylated) ERK in RCC. The authors hypothesized that activated ERK (pERK) promotes disease progression and metastasis in localized RCC and may be of value as a biomarker to predict disease recurrence. The expression profile of pERK was examined by immunocytochemistry using a tissue microarray constructed from 174 drug treatment-naive patients who had undergone radical nephrectomy for localized RCC. Levels of tumor-cell specific pERK were scored and correlated with clinicopathologic parameters of RCC and disease-free survival. Immunostaining for pERK was present in 36% of all RCCs, with a predominance found in the clear cell histologic subtype. High expression was associated with increased tumor size, increased TNM stage, and vascular invasion. Patients with pERK-positive tumors had a mean disease-free survival of 4.19 years, compared with 6.38 years for patients with pERK-negative tumors (P<.001). Cox regression models revealed pERK to be a significant independent predictor of disease-free survival, with a hazards score of 2.9 (P<.001), a value similar to tumor grade (hazards ratio, 3.01; P<.001). Expression of pERK is an independent prognostic factor in RCC that is associated with advanced and aggressive pathologic features of renal tumors and predicts the onset of metastasis in patients with localized disease.

Immunohistochemical analysis of tumor regression grade for rectal cancer after neoadjuvant chemoradiotherapy

e22089 Background: Tumor regression grade (TRG) as defined by Rodel et al. has been suggested as an independent prognostic factor for rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). However TRG 2 and 3 determination, semiquantitatively defined as more/less than 50% tumor regression, respectively, do not clearly correlate with prognosis. TRG 2 vs 3 discrimination is largely subjective hurdling prognostic analysis. The purpose of our study was to find an immunohistochemical pattern to better stratify these patients according to prognosis in term of disease free survival (DFS) and overall survival (OS). Methods: Immunohistochemistry of EGFR, VEGF, CD133, p53 and Ki67 was evaluated by tissue microarrays on surgical specimens from 88 patients. Preoperative chemotherapy was UFT-LV (30%) or oxaliplatin-based (70%) plus pelvic radiotherapy (50 Gy) followed by mesorectal excision. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 1 when regression was less than 25%. TRG 2 and 3 were defined as described above. Univariate analyses were performed according to the Kaplan-Meier method. Comparisons between curves were evaluated by the log-rank test. Cox regression was used for the multivariate analysis. Results: At a median follow-up of 39 months, the TRG was an independent predictor of DFS (p=0.05) and OS (p=0.001) but no differences were found between TRG 2 and 3 in terms of DFS (p=0.74) or OS (p=0.41). Our results show an immunohistochemical bad prognostic profile for tumors TRG 2 and 3 configured by double negativity of EGFR and CD133 expression (less than 5% of tumor cells membrane immunoreactivity for both antibodies). 3-year DFS and OS for these patients (vs. TRG 2 and 3 not-double negative) were 33 vs 65% (p=0.05) [HR=2.4 (95%CI, 0.9–6.1) p=0.06] and 77 vs 95% (p=0.06) [HR=4.1 (95%CI, 0.7–21.5) p=0.09]. Conclusions: The EGFR/CD133 double negative rectal tumors with TRG 2 or 3 after chemoradiotherapy show a higher risk of relapse or death. These results can help clinicians to determine better individual prognosis and are worth to confirm prospectively. No significant financial relationships to disclose.

Expression of Erk5 in Early Stage Breast Cancer and Association with Disease Free Survival Identifies this Kinase as a Potential Therapeutic Target

BackgroundBreast cancer is the most common neoplasia in women. Even though advances in its treatment have improved disease outcome, some patients relapse. Therefore, attempts to better define the molecular determinants that drive breast cancer cell proliferation may help in defining potential therapeutic targets. Mitogen-activated protein kinases (MAPK) play important roles in tumorigenesis. One of them, Erk5, has been linked to the proliferation of breast cancer cells in vitro. Here we have investigated the expression and prognostic value of Erk5 in human breast cancer.Methodology/Principal FindingsAnimal and cellular models were used to study Erk5 expression and function in breast cancer. In 84 human breast tumours the expression of Erk5 was analyzed by immunohistochemistry. Active Erk5 (pErk5) was studied by Western blotting. Correlation of Erk5 with clinicopathological parameters and with disease-free survival in early stage breast cancer patients was analyzed. Expression of Erk5 was detected in most patients, and overexpression was found in 20%. Active Erk5 was present in a substantial number of samples, as well as in tumours from an animal breast cancer model. Overexpression of Erk5 was associated with a decrease in disease-free survival time, which was independent of other clinicopathological parameters of prognosis. Transient transfection of a short hairpin RNA (shRNA) targeting Erk5, and a stable cell line expressing a dominant negative form of Erk5 (Erk5AEF), were used to investigate the influence of Erk5 on drugs used in the clinic to treat breast tumours. We found that inhibition of Erk5 decreased cancer cell proliferation and also sensitized these cells to the action of anti-HER2 therapies.Conclusions/SignificanceOverexpression of Erk5 is an independent predictor of disease-free survival in breast cancer, and may represent a future therapeutic target.

The expression of E-cadherin at the invasive tumor front of oral squamous cell carcinoma: immunohistochemical and RT-PCR analysis with clinicopathological correlation

Pathologists having drawn attention to the morphological and functional characteristics of invasive tumor front (ITF), we attempted to investigate the difference of E-cadherin expression between the ITF and center/superficial part as well as the prognostic value of E-cadherin expression at the ITF. We performed a retrospective analysis of the correlation between E-cadherin protein expression at the ITF and center/superficial part and prognostic factors. We also detected the difference of E-cadherin expression at the ITF and center/superficial part using immunohistochemical method, which was further supported in 20 fresh OSCC samples by confocal laser microscopy and RT-PCR methods. The expression of E-cadherin in the same tumor was heterogeneous. Both protein (t test, P <or= .05) and mRNA (t test, P <or= .05) expression level at the ITF were statistically lower than that of center/superficial part. There was a statistically significant correlation between E-cadherin expression (E-cadherin-negative and E-cadherin-positive group) at the ITF and invasive front grading (IFG) score (P = .026), tumor size (P = .038), and tumor thickness (P = .029). There was a significant difference in 5-year survival between positive (18.18%) and negative (49.59%) expression of E-cadherin at the ITF (P ' .05). Using the Cox regression equation in a stepwise fashion, we found that E-cadherin at the ITF had predictive values in univariate analysis, while it was not an independent predictor of disease-free survival in the multivariate analysis. E-cadherin expression at the ITF is lower than that in center/superficial part for most of OSCCs. E-cadherin at the ITF is statistically associated with IFG score, PT and tumor thickness and poor survival of OSCC patients.

Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer

The aim of the study is to assess the value of carbonic anhydrase isozyme IX (CA IX) expression as a predictor of disease-free survival (DFS) and disease-specific survival (DSS) in rectal cancer treated by preoperative radio- or chemoradiotherapy or surgery only. Archival tumour samples from 166 patients were analysed for CA IX expression by three different evaluations: positive/negative, proportion of positivity and staining intensity. The results of immunohistochemical analysis were confirmed by demonstrating CA IX protein in western blotting analysis. Forty-four percent of the operative samples were CA IX positive, of these 34% had weak and 66% moderate/strong staining intensity. In univariate survival analysis, intensity of CA IX expression was a predictor of DFS (P=0.003) and DSS (P=0.034), both being markedly longer in tumours with negative or weakly positive staining. In multivariate Cox model, number of metastatic lymph nodes and CA IX intensity were the only independent predictors of DFS. Carbonic anhydrase isozyme IX intensity was the only independent predictor of DSS, with HR=9.2 for dying of disease with moderate-intense CA IX expression as compared with CA IX-negative/weak cases. Negative/weak CA IX staining intensity is an independent predictor of longer DFS and DSS in rectal cancer.

Tumor-Associated Lymphangiogenesis Correlates with Prognosis after Resection of Human Hepatocellular Carcinoma

Experimental results from animal models as well as studies of human cancers indicate a critical role for tumor-associated lymphangiogenesis in tumor progression. However, its significance in hepatocellular carcinoma (HCC) is not well established. We analyzed tissue specimens from healthy liver (n = 36), cirrhotic liver (n = 24), and HCC (n = 60) by immunohistochemistry, using antibody D2-40 specific for lymphendothelia. We subsequently quantified lymphatic microvessel density (LVD). The LVD was correlated with clinicopathological characteristics of the tumors as well as survival and disease-free survival of the patients. In contrast to healthy as well as cirrhotic liver, lymphangiogenesis was induced in HCC. Lymphatic vessels were detected in the intratumoral septa as well as within the bulk of tumor cells. Tumors with high LVD (24 of 60) had developed significantly more frequently in cirrhotic livers (P = 0.001) and were more frequently restricted to one liver lobe (P = 0.04). Univariate analysis revealed high LVD as a marker for reduced survival and disease-free survival disadvantage (median >60 vs. 21 months, P = 0.018, and 19 vs. 8 months, P = 0.047, respectively). In multivariate analysis, LVD showed a trend toward association with reduced survival (P = 0.059) and represented an independent prognostic factor for disease-free survival (P = 0.017). Tumor-associated lymphangiogenesis is involved in neovascularization of hepatocellular carcinoma. Quantitative analysis of LVD demonstrated a significant influence of lymphangiogenesis on survival and established LVD as an independent predictor of disease-free survival. Quantification of LVD may be helpful in identifying patients with a high risk of tumor recurrence.

L1 cell adhesion molecule as a predictor for recurrence in pulmonary carcinoids and large‐cell neuroendocrine tumors

Pulmonary neuroendocrine tumors are a distinct subset of neoplasms with indolent to aggressive behavior. This study was conducted to evaluate the prognostic role of L1 cell adhesion molecule (L1CAM) in pulmonary neuroendocrine tumors. We retrospectively analyzed L1 expression in 55 cases of completely resected carcinoids and large-cell neuroendocrine carcinomas, by the immunohistochemistry with monoclonal antibody A10-A3 against human L1. L1 immunoreactivity was detected in 34 (61.8%) of 55 specimens. There was a significant correlation between L1 expression and the World Health Organization classification of this tumor (Spearman rank correlation, rho=0.60, p<0.001). With median follow-up of 52.0 months, the 5-year survival rate for patients with low expression of L1 (<20% of tumor cells stained) was significantly better compared with those with high expression of L1 (82.6% vs. 43.7%, p=0.005). L1 was also a significant independent predictor of disease-free survival, and patients with high L1 expression have a higher risk for recurrence compared with those with low L1 expression (hazard ratio, 3.0; 95% confidence interval, 1.2-8.3; p=0.034). L1 expression is significantly associated with aggressiveness and further studies with larger samples are needed to validate potential prognostic value for pulmonary neuroendocrine tumors.

Eight years experience of local prostate cancer treatment with permanent I 125 seed brachytherapy – Morbidity and outcome results

Background and purpose There are only a limited number of reports of treatment of prostate cancer with permanent prostate seed I 125 brachytherapy (PPB) in Europe. We describe results from one Finnish institution having treated 444 patients with a follow-up of eight years. Material and methods Morbidity was evaluated by International Prostate Symptom Score and International Index of Erectile Function questionnaires. Urine flow, residual urine volume and the PSA values were measured pre-treatment and during follow-up. Any additional treatments were recorded. Results PPB was well tolerated. Median IPSS increased from 8 at baseline to 18 at three months post-therapy and returned to baseline score within 12 months. Median urine flow decreased from 15.2 ml/s at baseline to 10.2 ml/s at three months and returned to baseline value within two years. Acute urinary retention, potency preservation and severe proctitis were observed in 11%, 86% and 2% of patients, respectively. The PSA bounce was observed in 13% and PSA nadir ⩽0.5 μg/l was reached by 81% of patients. Disease-free survival (DFS) was 90.2%. In the Cox regression analysis, the independent predictors of DFS were risk group and PSA nadir ⩽0.5 μg/l ( p < 0.0001 for both). PC-specific survival was 98.5% and overall survival was 94.6%. Conclusions Our results are in concordance and comparable with other reports on PPB.

Clinical impact of pathological axillary downstaging in locally advanced breast cancer after primary systemic chemotherapy.

Abstract Abstract #5103 Background Primary Systemic Chemotherapy (PSC) can result in pathologic axillary downstaging even in Locally Advanced Breast Cancer (LABC), which is generally associated with unfavorable prognosis and high incidence of nodal metastases. Aims were to evaluate: the clinical and biological factors associated with the likelihood of obtaining negative pathological nodes (pN0); the relationship between outcome and axillary nodal status at diagnosis (cN) and at surgery after PSC (pN).&amp;#x2028; Methods Women with LABC consecutively treated at the Istituto Nazionale Tumori in Milan from 1991 to 2007 were evaluated. Patients received PSC containing Doxorubicin ± Paclitaxel (+ adjuvant or neoadjuvant CMF) and endocrine therapy ± trastuzumab. Fixed right-censoring at 5 years was performed. Associations with Disease-Free Survival (DFS) and Overall Survival (OS) were evaluated using Kaplan-Meier (log-rank test) and Cox regression analysis. All confidence intervals are at 95%.&amp;#x2028; Results 451 women submitted to surgery and complementary RT were included in the analysis. 68% of surviving patients were followed for at least 5 yrs. 5y-DFS and OS were 51% (46-57%) and 70% (65-75%) respectively. ER negative, PGR negative, high grade and age &amp;lt;50 yrs were correlated with likelihood of pN0 at univariate logistic analysis, while ER negative only (OR 3.49, CI 1.65-7.66; p=0.001) retained significant role in the multivariate analysis.&amp;#x2028; Relationship between axillary status and outcome are shown in table 1.&amp;#x2028; &amp;#x2028; Multivariate Cox regression analysis showed that positive nodes at diagnosis (HR 2.13, CI 1.07-4.22; p=0.03) and at surgery (2.84, CI 1.77-4.56; p&amp;lt;0.001), negative PGR (HR 1.79, CI 1.12-2.86; p=0.01), inflammatory status (HR 1.51, 1.02-2.23; p=0.04) and age &amp;lt; 50 yrs (HR 2.23, CI 1.58-3.16; p&amp;lt;0.001) were independent predictors of DFS. Multivariate analysis for OS demonstrated positive nodes at surgery (HR 3.46, 1.80-6.67; p&amp;lt;0.001), negative PGR (HR 2.21, CI 1.16-4.20; p=0.01) and age &amp;lt; 50 yrs (HR 2.00, CI 1.26-3.17; p=0.003) as significant variables. Pathologic complete response in breast was not significant in both multivariate analysis.&amp;#x2028; Conclusions Axillary downstaging was obtained in a significant proportion of patients with LABC. pN0 status after PSC identifies a clinical subgroup with better prognosis irrespectively of locally advanced disease and, in this subgroup of patients, it is a prognostic factor stronger than pathologic complete response in the breast. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5103.

Up-regulation of HOXA13 in esophageal squamous cell carcinoma of stage IIa and its effect on the prognosis

To investigate the expression of HOXA13 gene in stage-II(a esophageal squamous cell carcinoma(ESCC), and to evaluate its relationship with clinicopathological characteristics and prognosis. The expression of HOXA13 was examined by immunohistochemistry(IHC) in specimens from 39 patients with ESCC of stage-II(a, who underwent resection from 1995 to 2002. SPSS software was used to analyze the relationship between HOXA13 expression and clinicopathological characteristics and prognosis of patients. The expression of HOXA13 protein was detected in ESCC tissue, and the positive rate was 61.5%. The median survival time of patients without HOXA13 expression(>72 months) was significantly longer than those with HOXA13 expression (24 months)( P=0.023). Multivariate analysis showed that HOXA13 expression was independent predictor of disease-free survival time of patients with ESCC. The expression of HOXA13 can be detected in ESCC and is a negative independent predictor of disease-free survival, which implies that HOXA13 might play a role in ESSC, and may be used as a clinical tumor marker of ESCC.

Impact of Molecular Staging Methods in Primary Melanoma: Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) of Ultrasound-Guided Aspirate of the Sentinel Node Does Not Improve Diagnostic Accuracy, But RT-PCR of Peripheral Blood Does Predict Survival

This study analyzes (1) the value of tyrosinase reverse-transcriptase polymerase chain reaction (RT-PCR) of aspirates obtained by ultrasound-guided fine-needle aspiration cytology (US-FNAC) of sentinel nodes (SNs) in patients with melanoma before sentinel lymph node biopsy (SLNB) and (2) the value of RT-PCR of blood samples of all SLNB patients. Between 2001 and 2003, 127 patients with melanoma (median Breslow depth, 2.1 mm) underwent SLNB. FNAC was performed in all SNs of all patients pre- and post-SLNB. The aspirates were partly shock-frozen for RT-PCR and were partly used for standard cytology. Peripheral blood was collected at the time of SLNB and at every outpatient visit thereafter. Thirty-four (23%) of 120 SNs were positive for melanoma. SN involvement was predicted by US-FNAC with a sensitivity of 82% and a specificity of 72%. Additional tyrosinase RT-PCR revealed the same sensitivity of 82% and a specificity of 72%. At a median follow-up time of 40 months from first blood sample, peripheral-blood RT-PCR was a significant independent predictor of disease-free survival (DFS) and overall survival (OS; P < .001). US-FNAC is highly accurate and eliminates the need for SLNB in 16% of all SLNB patients. RT-PCR of the aspirate or excised SN does not improve sensitivity or specificity. RT-PCR of blood samples predicts DFS and OS.

Abstract A9: Expression of insulin-like growth factor II and of the type 1 receptor gene in esophageal adenocarcinoma

Abstract A9 Aim To explore potential biological mechanisms underlying the association between obesity and esophageal malignancy, we studied the expression of insulin-like growth factor-II (IGF-II) and of the type 1 receptor (IGF-IR) gene in a well characterized series of patients with primary esophageal adenocarcinoma (EADC) and matched histologically normal esophageal epithelia (NE). Patients and Methods Banked esophageal tissues (EADC and matched NE, obtained with informed consent) were available from a consecutive series of 52 patients who underwent esophageal resection without preoperative chemoradiation therapy. Following extraction of RNA, expression of IGF-II and IGF-IR mRNA was determined using reverse transcription and real time polymerase chain reaction (RT-PCR). The 2-ΔΔCT (Livak) method was used to quantitate tissue expression of IGF-II and IGF-IR mRNA, which was correlated with measured body mass index (BMI), clinicopathological findings, and outcome. Results As expected, significant correlations between tumor stage, differentiation and survival were found for the 49 male and 3 female patients in this series, who ranged in age from 36 to 85 years (median: 60.5 years). A significant association was seen between BMI and IGF-II mRNA expression in NE tissues (rs=0.26, p=0.075). Significantly higher IGF-II mRNA expression was seen in EADC tumors (median 6.45, 95%CI 7.00-13.46) compared to matched NE tissues (median 1.32, 95%CI 1.37-4.31, p&amp;lt;0.01), particularly in poorly differentiated tumors. On multivariate analysis, IGF-II expression was an independent predictor of disease-free survival (p=0.02) and overall survival (p=0.03). Expression levels of IGF-II mRNA correlated significantly with IGF-IR in both EADC (rs=0.47, p&amp;lt;0.01) and NE (rs=0.46, p&amp;lt;0.01). Furthermore, IGF-IR mRNA expression was found to be significantly higher in EADC (median 1.57; 95%CI 1.47-3.86) compared with matched NE (median 0.57; 95%CI 0.50-0.85) (p&amp;lt;0.01), but only in patients with the A variant of the common IGF-IR G3174A polymorphism, which has recently been shown to modulate the obesity risk for EADC. Conclusions These studies further implicate perturbations of the IGF axis in the molecular pathogenesis of human EADC, and suggest a plausible mechanistic basis to explain the association between obesity and risk for malignancy. The significant association between IGF-II expression and survival suggests that IGF-II may be a clinically relevant biomarker for prognosis, or molecular target for novel anti-cancer therapies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A9.

Expression of theHCRP1mRNA in HCC as an independent predictor of disease-free survival after surgical resection

Hepatocellular carcinoma (HCC)-related protein-1 (HCRP1) gene was located at chromosome 8p22, a frequently deleted region in HCC. The gene product was a subunit of mammalian Endosomal Sorting Complex Required for Transport (ESCRT)-I, essential for degradation of epidermal growth factor receptors. In this study, we examined the prognostic role of HCRP1 mRNA expression in HCC. The expression of HCRP1 mRNA in HCC was assessed in 125 patients receiving surgical resection of HCC. Using the adjacent non-cancerous tissues as a reference, 55 and 70 patients expressing high and low levels of HCRP1 mRNA, respectively, were identified. The predictive value of HCRP1 mRNA expression in postoperative survival was evaluated. Expression of HCRP1 mRNA was not associated with any of the baseline clinicopathological parameters. However, univariate analysis showed that it was associated with a better disease-free survival (P < 0.001) and overall survival (P = 0.032). Stepwise Cox multivariate proportional hazards regression analysis showed that the expression of HCRP1 mRNA (hazard ratio [HR], 0.396; 95% confidence interval (CI), 0.233-0.674; P = 0.001), tumor number (HR, 1.596; 95% CI, 1.221-2.087; P = 0.001), serum aspartate aminotransferase (HR, 1.002; 95% CI, 1.000-1.003; P = 0.031) and the presence of microvascular invasion (HR, 1.852; 95% CI, 1.131-3.032; P = 0.014) were included as independent predictors for disease-free survival. Expression of HCRP1 mRNA served as an independent predictor for postoperative disease-free survival in HCC patients.

Risk of Recurrence in Surgically Resected Stage I Adenocarcinoma of the Lung: Histopathologic and Immunohistochemical Analysis

Stage I adenocarcinoma of the lung is the most common type of lung cancer. A better understanding of the histopathology and molecular biology of lung cancer might improve the capability to predict the outcome for any individual patient. The purpose of this study was to evaluate several histopathologic and molecular markers in order to assess their prognostic value in stage I adenocarcinoma. Fifty-five patients at the Seoul National University Bundang Hospital were enrolled in the study. Histopathologic factors and molecular markers were selected. Multivariate analysis demonstrated that necrosis, lymphatic vessel invasion, E-cadherin, p53, and Ki-67 emerged as independent prognostic factors of recurrence. When patients were grouped according to low or high risk according to the number of factors involved, the difference in disease-free survival between these groups was statistically significant. In resected stage I adenocarcinoma, necrosis, lymphatic vessel invasion, E-cadherin, and p53 have been identified as independent predictors of disease-free survival.

S‐phase fraction determined on fine needle aspirates is an independent prognostic factor in breast cancer – a multivariate study of 770 patients

The prognostic significance of DNA ploidy and the S-phase fraction (SPF) have been extensively studied in breast cancer, but their clinical utility remains controversial. The type of tumour material can substantially influence flow cytometric DNA measurements. Material obtained by fine needle aspiration (FNA) biopsy is very suitable for flow cytometric DNA analysis because it contains a low proportion of non-tumour cells and less debris than tissue samples. The prognostic significance of DNA ploidy and SPF, determined on FNA samples, was analysed in 770 breast cancer patients, diagnosed between 1992 and 1997. DNA ploidy and SPF were determined at the time of diagnosis as part of the diagnostic work-up. The median follow-up was 90 months. Survival analysis included overall cancer specific survival (OS), disease free survival (DFS) and survival after recurrence (SAR). Other variables included in survival analyses were age, histological grade, histological type, lymph node status and tumour size. Disease free interval and the site of recurrence were also included in SAR analysis. DNA ploidy and SPF correlated with tumour type, size, lymph node involvement and, especially, tumour grade. In a univariate analysis, both aneuploidy and high SPF were associated with shorter OS, DFS and SAR, but only SPF retained its independent prognostic significance in multivariate analyses. Independent prognostic variables for OS were node status, histological grade, SPF and tumour size. Node status, histological grade and SPF were independent predictors of DFS, while the site of recurrence, SPF, histological grade, disease free interval and age were independent predictors of SAR. DNA ploidy and SPF can be efficiently and routinely determined on FNA samples. High SPF is independently associated with a worse clinical outcome of patients with breast cancer. Although SPF and histological grade share prognostic information to some degree, SPF provides additional, less subjective prognostic information. The prognostic value of SPF determined on FNA samples could be even more relevant in neoadjuvant settings and for patients not amenable for surgical treatment, when histological grade cannot be assessed.

Hürthle cell carcinoma of the thyroid: Retrospective review of 62 patients treated at the Royal Marsden Hospital between 1946 and 2003

Introduction Previous studies have included Hürthle cell carcinoma (HCC) as a variant of follicular thyroid carcinoma in analysis of clinical outcome and others have failed to adequately distinguish between benign and malignant Hürthle cell neoplasms. The aim of this study was to report our experience of histologically confirmed malignant HCC, identifying patient, tumour and treatment factors that predict outcome. Methods A retrospective review was undertaken of all patients treated with HCC between 1946 and 2003. Study end-points were disease-free survival (DFS) and cause-specific survival (CSS). Demographic, pathological and treatment-related factors were all correlated with the study end-points. Results Sixty-two patients were followed up for a median (range) of 58 months (2–629). On multivariate analysis, only extent of surgery ( p < 0.001) was an independent factor affecting CSS. Lymph node status ( p = 0.008), presence of metastases at diagnosis ( p = 0.005) and tumour stage ( p = 0.009) were independent predictors of DFS. Conclusions HCC appears to be a separate entity from follicular thyroid carcinoma (FTC), with a more aggressive disease profile. Lymph node status, tumour stage, and the presence of metastases are independent predictors of DFS. Radical surgery may improve outcome in HCC.

Prognostic Value of Lymph Node Dissection in Patients with Muscle-Invasive Transitional Cell Carcinoma of the Upper Urinary Tract

ObjectivesTo analyze the prognostic role of lymphadenectomy (LND) in patients with muscle-invasive transitional cell carcinoma (TCC) of the upper urinary tract (UUT) managed with radical surgery. MethodsFrom 1986 to 2003, 132 consecutive patients with muscle-invasive TCC of the UUT underwent radical surgery. LND was performed in 95 cases. Patients were stratified according to the presence of LND and lymph node (LN) status. Univariable and multivariable Cox regression models determined the effect of age, pT, grade, nodal status (pN), number of LNs removed, year of surgery, and postoperative chemotherapy on disease-free survival (DFS) and cancer-specific survival (CSS) in the overall population and in patients who underwent LND. ResultsThe actuarial 5-yr CSS in pNx patients was significantly worse than in pN0 patients (48% vs. 73%, p=0.001) and comparable to pN+ outcome (48% vs. 39%, p=0.476). In the entire population, multivariable Cox regression analyses indicated that pT and pN status were independent predictors of DFS (p=0.04, hazard ratio [HR]=1.82 and p<0.01, HR=1.34, respectively) and CSS (p<0.01, HR=2.42 and p=0.04, HR=1.32, respectively). In patients who underwent LND, the number of LNs removed was an independent predictor of DFS (p=0.03, HR=0.928) and of CSS (p=0.007, HR=0.903). The extent of LND again resulted in an independent predictor either of DFS or CSS (p=0.04, HR=0.904 and p=0.01, HR=0.867, respectively) in the subgroup of pN0 patients. ConclusionsLND emerged as a strong independent predictor of DFS and CSS in patients surgically managed for a muscle-invasive TCC of the UUT.

The number of residual metastatic lymph nodes following neoadjuvant chemotherapy predicts survival in patients with stage III NSCLC

The prognosis of patients with stage III non-small-cell lung cancer (NSCLC) who achieve a pathological complete response or downstaging following neoadjuvant therapies are better than the prognosis of patients with residual metastatic lymph nodes (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty-four (81.0%) of the 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum-based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). After neoadjuvant chemotherapy, a pathological complete response was achieved in one patient and downstaging was achieved in 24 patients. Pathological LN metastasis was absent in 9 patients (21.4%) and present in 33 patients (78.6%). With a median follow-up of 23 months, the 2-year disease-free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% vs. 18% respectively, P=0.03). Among 33 patients with residual LN metastasis, age (P=0.01), pathological downstaging (P=0.098) and the number of residual metastatic LNs (median 14 months in 1-4 LN vs. median 5 months in LN > or =5; P=0.011) were significant predictors of DFS in univariate analysis. In multivariate analysis, the number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. The number of residual metastatic lymph nodes following neoadjuvant chemotherapy is an independent predictor of DFS in patients with stage III NSCLC.

Prognostic significance of HIF‐1α polymorphisms in transitional cell carcinoma of the bladder

Recently, two single nucleotide polymorphisms in the hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene, P582S and A588T, were shown to cause significantly higher transcriptional activity than the wild type. We investigated the association between the HIF-1 alpha polymorphisms and the incidence and progression of transitional cell carcinoma of the bladder, and the relationship between the polymorphisms and the tissue vascular endothelial growth factor (VEGF) level or microvessel density (MVD). A total of 219 patients with bladder cancer and 464 healthy native Japanese control subjects were enrolled. Tissue VEGF and HIF-1 alpha expression levels and the mean MVD were evaluated in 73 radical cystectomy specimens by immunohistochemistry. The HIF-1 alpha genotype did not significantly influence the incidence or disease status of bladder cancer. Among patients who underwent radical cystectomy, those with a variant allele had significantly worse disease-free survival (p = 0.001) and disease-specific survival (p = 0.006) than those without a variant allele. Multivariate analysis using a Cox proportional hazard model revealed that the presence of a variant allele was an independent predictor of disease-free survival (HR = 3.10, 95%CI = 1.38-6.99, p = 0.006). Although not statistically significant, the moderate/high expression levels of VEGF in tumor tissues were more frequently observed in patients with a HIF-1 alpha variant allele (11/13, 84.6%) than in those without (33/60, 55%, p = 0.063). The HIF-1 alpha polymorphisms may have a significant influence on the poor prognosis of the patients undergoing radical cystectomy for bladder cancer, while they seem to have no relation to the bladder cancer occurrence.

The number of residual metastatic lymph nodes following neoadjuvant chemotherapy predicts disease-free survival in patients with stage III NSCLC

18024 Background: The prognosis of patients with stage III non-small cell lung cancer (NSCLC) who achieved pathological complete response or downstaging following neoadjuvant chemotherapy is better than those with residual metastatic lymph node (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. Methods: From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty four of 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). Results: After neoadjuvant chemotherapy, pathological complete response and downstaging was achieved in one patient and 24 patients, respectively. No pathological LN metastasis was present in 9 patients (21.4%), and LN metastasis was present in 33 patients (78.6%). With a median follow up of 23 months, the 2-year disease free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% and 18% in patients with residual LN, p=0.03). Among 33 patients with residual LN metastasis, age (p=0.01), pathological downstaging (p=0.09) and number of residual metastatic LNs (median 14 months in LN =4 vs median 5 months in LN =5; p=0.01) were significant predictors of DFS in univariate analysis. In multivariate analysis, number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. Conclusions: The number of residual metastatic lymph nodes following neoadjuvant chemotharpy is an independent predictor of DFS in patients with stage III NSCLC. No significant financial relationships to disclose.