Strong Independent Prognostic Factor Research Articles

Extranodal metastasis predicts poor survival in advanced colorectal cancer.

The prognostic significance of extranodal metastasis (ENM) in colorectal cancer (CRC) is disregarded by the TNM classification system. The influence of ENM on survival among locally advanced CRC patients was examined. We reviewed retrospectively the clinical course of 263 patients who underwent surgical resection of locally advanced CRC at our Department between 2005 and 2009. We analyzed the prognostic factors with special reference to the clinicopathological factors of primary tumors. Thirty-eight cases of ENM were detected among patients with CRC. Compared with ENM negative cancers, ENM-positive cancers were associated with poorer tumor differentiation grade (p=0.026) and higher prevalence of TNM-stage (p<0.0001), T-status (p=0.024), N-status (p<0.0001) and postoperative recurrence (p<0.0001). In univariate analysis, TNM-stage (p<0.0035), T-status (p=0.002), N-status (p<0.0024) and positive ENM (p<0.0001) were significant predictors of poor survival. Multivariate analyses showed a positive ENM to be a highly significant independent predictor of mortality (HR=1.98, 95% CI=1.23- 3.23, p=0.0053). Survival analyses using Kaplan-Meier curves demonstrated that patients with ENM-positive cancers had significantly poorer survival than patients with ENM-negative cancers. Patients with ENM-negative cancers did not show significantly different survival from patients with node-negative cancers (p=0.272, data not shown). ENM appears to be a strong independent negative prognostic factor of poor survival in locally advanced CRC.

Vasculogenic mimicry and its clinical significance in medulloblastoma

Vasculogenic mimicry (VM), a process involving the formation of a tubular structure by highly invasive and genetically dysregulated tumor cells, can supplement the function of blood vessels to transport nutrients and oxygen to maintain the growth of tumor cells in many malignant tumors. We aimed to explore the existence of VM and its clinical significance in medulloblastoma in this study. VM was identified in 9 out of 41 (22%) medulloblastoma tissues. Immunohistochemical studies revealed that the presence of VM was associated with the expression of MMP-2, MMP-14, EphA2 and laminin 5γ2. Tumor tissues with VM were associated with lower microvessel density (MVD), which was indirect evidence of the blood supply function of VM. Survival analysis and log-rank tests showed that patients with VM had shorter overall survival time than those without VM. Multivariate analysis and the Cox proportional hazards model identified VM as independent prognostic factor for overall survival. Our results confirmed the existence of VM for the first time and revealed that VM is a strong independent prognostic factor for survival in patients with medulloblastoma.

New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge.

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.

Abnormal expression of E‐cadherin in tumor cells is associated with poor prognosis of gastric carcinoma

The purpose of this study was to clarify the relationship of hepatocyte growth factor (HGF), c-Met, and E-cadherin with clinicopathological parameters and prognosis in gastric carcinoma (GC). 114 specimens were collected from GC patients and expression of HGF, c-Met, and E-cadherin in tissue microarray was evaluated by immunohistochemical staining. Correlation between immunostainings and clinicopathological parameters, follow-up data of patients, was analyzed statistically. Abnormal E-cadherin expression was found in 60.5% (69/114) and associated with tumor depth (P = 0.003), lymph node metastasis (P = 0.001) and advanced clinical stage (P = 0.001). High-expression of HGF and c-Met were found in 64.0% (73/114) and 82.4% (94/114), respectively. High c-Met expression was significantly associated with advanced clinical stage (P = 0.001) and lymph node metastasis (P = 0.011) of GC. In univariate survival analysis, high-expression of HGF and c-Met, and abnormal E-cadherin were significantly associated with poor prognosis of GC patients. However, only abnormal E-cadherin expression (P = 0.001) and tumor depth (P = 0.010) emerged as strong independent prognostic factors for overall survival of GC patients. We found significant correlation among HGF/c-Met, E-cadherin expression and worse prognosis of patients with GC. Abnormal E-cadherin expression may serve as an independent predictive factor for prognosis of GC patients.

P5-01-02: Wnt5a Is a Prognostic Biomarker in Estrogen Receptor-Positive Premenopausal Breast Cancer.

Abstract Background Wnt proteins belong to a family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories; the canonical, β-catenin-dependent pathway and the non-canonical β-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Studies in two smaller cohorts of breast cancer revealed that loss of Wnt5a was associated with early relapse, metastatic disease and poor survival. Moreover, reconstitution of Wnt5a signalling decreased the migratory capacity and invasiveness of cultured breast cancer cells and administration of a Wnt5a-mimicking peptide was proven to inhibit metastases in a mouse model. Material and methods: Premenopausal women (n=564) were included in a controlled randomised trial and allocated to tamoxifen for two years versus no adjuvant treatment. A tumour tissue microarrays was constructed and 390/500 samples were evaluable for Wnt5a protein expression by immunohistochemistry. Only cases with at least 2 evaluable cores were included. Wnt5a levels were determined semiquantitatively (scores 0–3). Clinical and pathological data such as patient age, histological subtype, pT stage, tumor size, pN stage, ER, PR, Ki67 and HER2 status were available. The end-point was 10 year recurrence-free survival. Results: Wnt5a protein expression was lost in 158/390 of the analyzed tumors and more common in younger (&amp;lt;45 yrs) women (p=0.032). Furthermore, loss of Wnt5a was significantly associated with ER and PR negativity (p=0.019 and p= 0.033, respectively). Loss of Wnt5a was significantly correlated to poor survival in the whole cohort, p=0.02. When analyzing the data according to breast cancer subtype, we found that Wnt5a was a strong independent prognostic factor in ER+ breast cancer p=0.009, but not in ER- breast cancer p=0.8. This was true both in the adjuvantely treated and untreated cohorts, verifying that Wnt5a indeed is a true prognostic factor and not a predictor of response to therapy. Discussion: While associated with a better short-time prognosis than ER negative tumors, a subset of ER positive breast cancer patients are known to experience tumor recurrencies &amp;gt;5 years after primary treatment and hence have a dismal prognosis. Those patients need to be identified and their tumors targeted with more aggressive treatment regimens. We have identified and validated Wnt5a as a prognostic biomarker in ER positive breast cancer in premenopausal women. Wnt5a signalling could potentially be reconstituted by administration of a Wnt5a-mimicking peptide, shown to inhibit metastases in mice, thereby offering ER positive premenopausal patients a targeted adjuvant therapy that potentially could lower their risk of metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-02.

Circulating Tumor Cells in Early-Stage Breast Cancer.

Disseminated tumor cells (DTC) are routinely detected in bone marrow (BM) in 30-40 % of primary breast cancer patients. Positive BM status at the time of diagnosis as well as DTC persistence after therapy are strong independent prognostic factors. Since repeated BM aspirations are not well tolerated, detection of single tumor cells in peripheral blood (circulating tumor cells; CTC) have become of interest in recent years. CTC are found in 10-80 % breast cancer patients. Variability can be explained by stage of the disease and detection method. Emerging data have shown CTC to be of prognostic relevance for both, patients with primary and metastatic disease. The assessment of CTC in blood may become an important biomarker for prognostication and therapy monitoring. Determination of their molecular characteristics will enable specific targeting of minimal residual as well as metastatic disease. This review summarizes recent research and future perspectives.

Serum Soluble Tumor Necrosis Factor Recepter 2 Levels Is Associated with the Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Regimen

Abstract 1575 Background:We have previously reported that serum concentration of serum-soluble tumor necrosis factor receptor 2 (sTNF-R2) predicts the clinical outcome of patients with aggressive non-Hodgkin’s lymphoma (NHL) treated with CHOP without rituximab (Goto et al. 2005). We extracted the diffuse large B-cell lymphoma (DLBCL) patients from aggressive NHL, used in our previous study, and extended our observation period. We found that serum sTNF-R2 level was a strong independent prognostic factor even for long-term observation in the CHOP era (8-year overall survival (OS); high serum sTNF-R2 group: 17.6%, low sTNF-R2 group: 69.8%, P<0.0001). Based on the result, we analyzed serum sTNF-R2 for patients with DLBCL who had received the CHOP plus rituximab (R-CHOP) regimen. Purpose:We aim to re-assess the prognostic significance of serum sTNF-R2 for DLBCL patients treated with R-CHOP regimen, and to assess sTNF-R2 with subtype of DLBCL, such as germinal center B cell type (GCB type) and non-GCB type which were classified by Hans et al. method (Hans et al. 2004). Methods:Consecutive 154 untreated patients with DLBCL prospectively participated in this study between 2002 and 2008. The patients were treated with R-CHOP. Results:In all patients with DLBCL, the median of serum sTNF-R2 level was 13.72 ng/ml (range 2.66–112.5 ng/ml). Various poor prognostic indicators, such as elderly age, poor performance status, increased LDH, multiple extranodal involvement sites, advanced disease, and existence of B-symptoms, were strongly associated with high serum sTNF-R2 levels. Serum sTNF-R2 levels significantly correlated with the increasing grade of international prognostic index (IPI), revised-IPI (R-IPI) (Sehn et al. 2007), and subtype, respectively (P<0.0001, P<0.0001, P=0.0058). We established the cut-off value for sTNFR2 at 20 ng/ml which was determined by ROC analysis. Patients with high sTNF-R2 (20 ng/ml and over) at onset had significantly lower OS rate (5-year: 29%), than that with low sTNF-R2 (5-year: 83%), respectively (P <0.0001). Multivariate analysis involving R-IPI, subtypes of DLBCL and serum sTNF-R2 revealed that sTNFR-2 significantly correlated with OS and progression free survival (PFS) (OS: P = 0.0001, PFS: P= 0.0085). Additionally, as the OS rate was about 50% even in the poor prognosis group of R-IPI, we tried to divide risk categories of R-IPI into low and high sTNF-R2 groups, resulting actually in five groups: very good risk group, good risk group with high sTNF-R2, good risk group with low sTNF-R2, poor risk group with high TNF-R2, and poor risk group with low sTNF-R2. A strong significant difference was observed. (5-year OS; very good risk group: 100%, good risk group with high sTNF-R2: 20%, good risk group with low sTNF-R2: 85%, poor risk group with high TNF-R2: 28.6%, and poor risk group with low sTNF-R2: 77.8%.) Conclusion:These results suggest that a high serum sTNF-R2 level predicts a poor prognosis in DLBCL and may be a useful biomarker for selecting appropriate treatment. Upfront high dose chemotherapy or alternative therapy of first line chemotherapy instead of R-CHOP might be well indicated for DLBCL patients with high serum sTNF-R2. Disclosures:No relevant conflicts of interest to declare.

Role of FDG-PET As Prognostic Indicator in Patients with Follicular Lymphoma(FL) After Immunochemotherapy Induction. A Retrospective Study From the Fondazione Italiana Linfomi

Abstract 2636 Background and objectives:Quality of response assessed with [18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a strong independent prognostic factor in patients with Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Recently the prognostic role of response assessment with PET was also shown in patients with Follicular Lymphoma (FL) (Trotman et al JCO 2011). We conducted a retrospective analysis to investigate the role of FDG-PET after immunochemotherapy in FL. Patients and methods:The study was designed as a retrospective unplanned analysis of newly diagnosed FL patients randomized among R-CVP, R-CHOP, R-FM in the FOLL05 clinical trial (NCT00774826). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. As mandatory patients should have undergone staging and restaging at the end of treatment with FDG-PET. Local PET interpretation was used to identify clearly positive and clearly negative cases. For this phase of the study uncertain cases were not analyzed for study endpoints: centralized review is ongoing. Contrast enhanced computed tomography (CECT) scans were also collected to confirm quality of response: in particular a cut off of 1.5 cm for the maximum transverse diameter of residual lymph nodes was considered to separate Complete vs. Partial remissions according to International Workshop Criteria (IWC) (Cheson et al JCO 1999). The primary study endpoint was Progression Free Survival. Results:Among 534 patients enrolled in the FOLL05 trial, 114 cases fulfilled eligibility criteria for this study. Baseline patients characteristics did not differ from the overall FOLL05 patient population. In particular FLIPI was 0–1 in 23%, 2 in 42% and 3–5 in 35%. First-line immunochemotherapy, included R-CHOP (36 pts.), R-CVP (33), and R-FM (45). No maintenance therapy with Rituximab was given. Overall response rate at the end of therapy, defined according to IWC, was 97% including a 78% complete remissions (CR) rate. Baseline PET scan was positive in all patients. In 16 cases an interim PET was also available and resulted clearly positive in 6 patients (38%). At the end of treatment 10 cases had inconclusive final PET results and were excluded from subsequent analyses; a clearly positive PET scan was recorded in 26 out of the remaining 104 (25%). In univariate logistic analysis number of nodal sites (>4) was predictive of final positive PET. Although a trend towards a higher rate of PET positive scans was observed with increasing FLIPI and FLIPI2 this difference was not statistically significant. The rate of patients with negative final PET was 81%, 57%, and 60% for those in CR, PR, and less than PR (Fisher exact test: P=0.021). Assessing response with International Harmonization Project (IHP) criteria (Cheson et al JCO 2007), that also consider PET, 14/74 (19%) of patients previously defined in CR according to IWC were changed to PR and 13/23 (57%) of those in PR were switched to CR. The CR rate changed from 78% to 75% with an agreement rate of 70% between IWC and IHP. With a median follow up of 28 months (range 9–56), 3 year PFS was 68% (95% IC 54%–79%). In univariate analysis a shorter 3yr PFS was observed in post-treatment PET+ vs. PET- patients: 48% vs 84% (log rank p=0.036, HR 2.34, 95% CI 1.03–5.3). A positive final PET was confirmed as a poor prognostic factor when adjusted by FLIPI and FLIPI2 (HR 2.33 P=0.048, and HR 2.41 P=0.039, respectively). Prognostic role of final PET was not affected by treatment arm or by any of analyzed prognostic factors. Finally a trend toward a prolonged duration of remission was observed for patients who achieved a PET negative CR, compared with PET+ CRs and and both PET+/− PRs. Conclusions:This FOLL05 ancillary study confirms that post-treatment PET-CT can modify response allocation and is a predictor of PFS after first line immunochemotherapy in patients with FL. If the prognostic role of PET assessment of response will be confirmed in a larger series and in prospective studies a response adapted treatment strategy could be tested also in FL. Disclosures:Di Raimondo:Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Prognostic Impact of Number of Resected and Involved Lymph Nodes at Complete Resection on Survival in Non-small Cell Lung Cancer

Lymph node (LN) status is a major determinant of stage and survival in patients with lung cancer. In the 7th edition of the TNM Classification of Malignant Tumors, the number of involved LNs is included in the definition of pN factors in breast, stomach, esophageal, and colorectal cancer, and the pN status significantly correlates with prognosis. We retrospectively investigated the prognostic impact of the number of resected LNs (RLNs) and involved LNs in the context of other established clinical prognostic factors, in a series of 928 consecutive patients with non-small cell lung cancer (NSCLC) who underwent complete resection at our institution between 2000 and 2007. The mean number of RLNs was 15. There was a significant difference in the total number of RLNs categorized between less than 10 and ≥10 (p = 0.0129). Although the incidence of LN involvement was statistically associated with poor prognosis, the largest statistically significant increase in overall survival was observed between 0 to 3 and ≥4 involved LNs (hazard ratio = 7.680; 95% confidence interval = 5.051-11.655, p < 0.0001). On multivariate analysis, we used the ratio between the number of involved LNs and RLNs. The number of RLNs was found to be a strong independent prognostic factor for NSCLC (hazard ratio = 6.803; 95% confidence interval = 4.137-11.186, p < 0.0001). Complete resection including 10 or more LNs influenced survival at complete NSCLC resection. Four involved LNs seemed to be a benchmark for NSCLC prognosis. The number of involved LNs is a strong independent prognostic factor in NSCLC, and the results of this study may provide new information for determining the N category in the next tumor, node, metastasis classification.

Anaemia is a predictor of early death or cardiac transplantation in children with idiopathic dilated cardiomyopathy

The aim of our study was to establish the prevalence and the prognostic value of haematological abnormalities in children with cardiac failure. A series of 218 consecutive children with a first diagnosis of idiopathic dilated cardiomyopathy were retrospectively examined. Haematological evaluation was performed at first diagnosis. Death or cardiac transplantation was the main outcome measure. The median age was 0.6 years, ranging from 1 day to 15.8 years and median follow-up was 2.65 years, ranging from 0 to 17.2 years. After a median interval of 0.2 years, ranging from 0 to 8.7 years, 56 patients died and 25 were transplanted. Event-free survival at 1 and 5 years was 68% (95% confidence interval, 63-75%) and 62% (95% confidence interval, 56-69%). Blood levels of haemoglobin less than 10 grams per decilitre, urea over 8 millimoles per litre, and C-reactive protein over 10 milligrams per litre were found in 24%, 20%, and 24% of patients, respectively. The log-rank test showed that haemoglobin (p = 0.000) and C-reactive protein (p = 0.021) were predictors of death or transplantation. In the multivariate Cox model, haemoglobin (hazard ratio = 0.735; confidence interval = 0.636-0.849; p = 0.000) and urea (hazard ratio = 1.083; confidence interval = 1:002-1:171; p = 0.045) were predictive of poor outcome. Cubic spline functions showed that the positive role of haemoglobin on survival was linear for values less than 12 grams per decilitre and null for values more than 12 grams per decilitre. Adaptive index models for risk stratification and Classification and Regression Tree analysis allowed to identify the cut-off values for haemoglobin (less than 10.2 grams per decilitre) and urea (more than 8.8 millimoles per litre), as well as to derive a predictor model. In children with idiopathic dilated cardiomyopathy, anaemia is the strongest independent prognostic factor of early death or transplantation.

Human equilibrative nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3—T4 pancreatic cancer patients treated with preoperative gemcitabine‐based chemoradiotherapy

We aimed to determine the relationship between the intratumoral expression of human equilibrative nucleoside transporter (hENT1), the main gemcitabine transporter into cells, and the outcome of gemcitabine-based chemoradiotherapy (Gem-CRT) in patients with International Union Against Cancer (UICC) T3-T4 pancreatic adenocarcinoma. The expressions of hENT1, thymidylate synthase (TS), and dihydropyrimidine dehydrogenase were immunohistochemically analyzed using the resected specimens from 55 patients (T3, 38 and T4, 17) who had received curative-intent resection after Gem-CRT. The status of hENT1 expression (positive in 39 and negative in 16) was significantly associated with "clinical efficacy" (defined as more than 50% reduction of the serum carbohydrate antigen [CA] 19-9 level with stable disease [SD] or partial response [PR] according to the Response Evaluation Criteria in Solid Tumors [RECIST]) for Gem-CRT. The 1- and 3-year overall survival (OS) rates were significantly higher in the positive hENT1 expression group (82.9, 39.5%) than in the negative expression group (42.9, 14.3%) (p=0.0037). According to combination analysis of hENT1 and TS expressions, the 1- and 3-year OS rates were significantly higher in the positive-low combination (89.1, 51.0%) group than in the negative-high group (66.7, 0%) (p=0.023). Multivariate analysis revealed that positive hENT1 expression and R0 resection were significant prognostic factors for OS. The hENT1 expression in pancreatic adenocarcinoma strongly influences the outcome of preoperative Gem-CRT treatment. This biomarker could become a useful predictor of therapeutic effect for gemcitabine-based therapy in pancreatic cancer patients.

Impact of established prognostic factors and molecular subtype in very young breast cancer patients: pooled analysis of four EORTC randomized controlled trials

IntroductionYoung age at the time of diagnosis of breast cancer is an independent factor of poor prognosis. In many treatment guidelines, the recommendation is to treat young patients with adjuvant chemotherapy regardless of tumor characteristics. However, limited data on prognostic factors are available for young breast cancer patients. The purpose of this study was to determine the prognostic value of established clinical and pathological prognostic factors in young breast cancer patients.MethodsData from four European Organisation for Research and Treatment of Cancer (EORTC) clinical trials were pooled, resulting in a dataset consisting of 9,938 early breast cancer patients with a median follow-up of 11 years. For 549 patients aged less than 40 years at the time of diagnosis, including 341 node negative patients who did not receive chemotherapy, paraffin tumor blocks were processed for immunohistochemistry using a tissue microarray. Cox proportional hazard analysis was applied to assess the association of clinical and pathological factors with overall and distant metastasis free survival.ResultsFor young patients, tumor size (P = 0.01), nodal status (P = 0.006) and molecular subtype (P = 0.02) were independent prognostic factors for overall survival. In the node negative subgroup, only molecular subtype was a prognostic factor for overall survival (P = 0.02). Young node negative patients bearing luminal A tumors had an overall survival rate of 94% at 10 years' follow-up compared to 72% for patients with basal-type tumors.ConclusionsMolecular subtype is a strong independent prognostic factor in breast cancer patients younger than 40 years of age. These data support the use of established prognostic factors as a diagnostic tool to assess disease outcome and to plan systemic treatment strategies in young breast cancer patients.

Abstract 474: Tumor CD57+ immune cell infiltration is a strong independent prognostic factor in stage II-III colorectal cancer

Abstract Background: CD3+ CD45RO+ tumor infiltrating lymphocytes (TIL) density within colorectal cancer (CRC) has been shown to be a better predictor of outcome than UICC TNM. Conversely, Laghi and coll. showed that CD3+ TIL density was not a prognostic factor in stage III CRC. The aim of our study was to evaluate the prognostic role of immune infiltrating tumor cells in stage II and III CRC patients using a tissue microarray (TMA) analysis. Methods: A tissu-array was constructed using 202 stage II and III resected CRC (154 CC, 48 rectal cancers) and their matched non tumor tissue (NT). Tumors exhibiting deficient mismatch repair phenotype have been excluded. On the basis of previous data on the prognostic role of immune response in CRC, the following stainings were quantified in tumor (TT) and NT: CD3, CD68, CD57, CD8 and CD4 in order to quantify macrophage, lymphocyte cell infiltration as effectors of IFN-γ production, CXCL9/MIG, PPAR γ, CXCL10/IP-10, INDO, CXCL13/BCA-1. For prognostic analysis, immunohistochemistry (IHC) data was dichotomized at the median value. Results: All proteins (except CXCL10/IP-10, INDO for which no reliable IHC data could be obtained) were significantly underexpressed in TT as compared to NT (p&amp;lt;0.0001, paired t-test). CD57 expression was significantly correlated with both CD3 and CD8 expression in TT (Spearman rank correlation coefficients equal to 0.41 (p&amp;lt;0.001) and 0.22 (p=0.002) respectively). After the exclusion of patients who received preoperative irradiation for rectal cancer (n=38), and after adjustment for tumor stage, adjuvant chemotherapy and tumor site in Cox models, CD3 and CD57 tumor staining were associated to recurrence-free survival (RFS) (HR=0.48 and 0.33 and p-value=0.02 and 0.003 respectively) whereas none of the NT staining was found to be prognostic. When CD3 and CD57 tumor staining were included together in the Cox model, only CD57 remained significantly associated with RFS (HR=0.37, p=0.015), especially in stage III CRC but without statistically significant interaction between stage and CD57. Conclusion: Tumor CD57+ immune cell infiltration is associated with prolonged recurrence-free survival in stage II and III colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 474. doi:10.1158/1538-7445.AM2011-474

The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer

Genetic variations in cancer patients may serve as important prognostic indicators of clinical outcome. The GNAS1 T393C single nucleotide polymorphism (SNP) diversely correlates with the clinical outcome in cancer. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected only surgically treated esophageal cancer (EC). Genomic DNA was extracted from peripheral blood leucocytes of 190 patients who underwent only complete surgical resection for EC. T393C-SNP was correlated with clinic-pathological parameters, tumor cell dissemination in bone marrow (DTC) and clinical outcome. T-allele carriers had more advanced disease due to presence of lymph node metastasis (P < 0.0001) and DTC (P = 0.01) and higher recurrence rate (P = 0.01) compared to CC genotype. The disease-free (P < 0.001) and overall survival (P < 0.001) was better in CC compared to TT and TC patients. In the multivariate Cox regression disease-stage adjusted analysis the T393C-SNP was identified as a strong independent prognostic factor for recurrence (hazard ratio 1.8, P = 0.01) and survival (hazard ratio 2.5, P < 0.001) in EC patients. Determination of T393C-SNP preoperatively will allow allocation of EC patients into different risk profiles which may help to stratify patients eligible for neoadjuvant and or adjuvant therapy.

Neurological outcome in patients with traumatic brain injury and its relationship with computed tomography patterns of traumatic subarachnoid hemorrhage

Traumatic subarachnoid hemorrhage (SAH) is a poor prognostic factor for traumatic brain injury. The authors aimed to further investigate neurological outcome among head injury patients by examining the prognostic values of CT patterns of traumatic SAH, in particular, the thickness and distribution. The study was conducted using a database in a regional trauma center in Hong Kong. Data had been prospectively collected in consecutive trauma patients between January 2006 and December 2008. Patients included in the study had significant head injury (as defined by a head Abbreviated Injury Scale [AIS] score of 2 or more) with traumatic SAH according to admission CT. Over the 36-month period, 661 patients with significant head injury were admitted to the Prince of Wales Hospital in Hong Kong. Two hundred fourteen patients (32%) had traumatic SAH on admission CT. The mortality rate was significantly greater and a 6-month unfavorable outcome was significantly more frequent in patients with traumatic SAH. Multivariate analysis showed that the maximum thickness (mm) of traumatic SAH was independently associated with neurological outcome (OR 0.8, 95% CI 0.7-0.9) and death (OR 1.3, 95% CI 1.2-1.5) but not with the extent or location of hemorrhage. Maximum thickness of traumatic SAH was a strong independent prognostic factor for death and clinical outcome. Anatomical distribution per se did not affect clinical outcome.

Abstract P1-11-02: Pathologic Response and Survival after Neoadjuvant Therapy for Breast Cancer: A 30-Year Single-Center Study

Abstract Background: Triple-negative (TN) and HER2-positive (HER2+) breast cancers have usually a worse prognosis than the luminal subtypes despite an initial chemosensitivity. The aim of this single-center study was to compare pathologic complete response (pCR) rates, disease-free (DFS) and overall (OS) survivals rates after neoadjuvant therapy according to both HER2 and hormonal status. Patients and Methods: Between 1978 and 2008, 461 patients were treated with neoadjuvant therapy at Georges-François Leclerc Cancer Center. Patients were classified in 3 groups: TN (defined by both estrogen/progesterone receptor negative and HER2 negative), HER2+ (3+ in immunohistochemistry or 2+ with amplification in fluorescence in situ hybridization) and HR+ (estrogen and/or progesterone receptor positive without HER2 overexpression or amplification). Median follow-up lasted 7.1 years [range: 0.49-29.8]. Number of events was 213 for DFS calculation and number of deaths was 150 for OS calculation. Response rates were compared using Chi2-tests. Survivals were calculated according to Kaplan-Meier and compared using log-rank tests. Univariate and multivariate Cox proportional hazards models were performed. The multivariate models were internally validated using bootstrapping (400 replications). Results: 86 of 461 were TN (19%), 125 were HER2+ (27%) and 250 were HR+ (54%). Patients with TN and HER2+ breast cancer were younger (p=0.032), had more inflammatory cancer (p=0.033) and aggressive tumors (SBR 3, P&amp;lt;0.001). Pathologic complete response rate (grades 1 and 2 of Chevallier's classification) was significantly higher for TN (22.4%) and HER2+ (29.6%) than in for HR+ (3.6%) (P&amp;lt;0.001). In univariate analysis, the following characteristics were related to a higher pCR rate: smaller clinical size (p=0.029), higher grade tumor (p=0.001) and HER2+ or TN status (P&amp;lt;0.001). In multivariate analysis, only tumor grade (p=0.022) and hormonal/HER2 status (p=0.003) were independently associated with pCR. Median DFS was 4.4years for TN, 7.8y for HER2+ and 9y for HR+ (p=0.003, logrank test). In HER2+ patients, neoadjuvant trastuzumab was associated with a higher DFS (8.65 vs. 3.24y, p=0.002). Patients who achieved a pCR had a higher DFS (p=0.015) than those with only partial pathologic response (median=6.9y vs. 12.7y). In multivariate analysis, pCR remained significant (HR (bootstrapping) = 0.5 [IC95%, 0.28-0.91], p=0.023). Median OS was 6.4y for TN, 15.1y for HER2+ and 13.1y for HR+ (P&amp;lt;0.001, logrank test). Patients who achieved a pCR had a higher OS (p=0.004) than those with non-pCR (median=not reached vs. 10.9y). In multivariate analysis, OS was lower for patients&amp;gt;50years (HR (bootstrapping)=1.79 [IC95%, 1.23-2.60], p=0.002), in TN subgroup (HR=2.46 [IC95%, 1.5-4.03], p=0.001) and when pCR was not achieved (HR=0.28, [IC95%, 0.12-0.66], p=0.003). Conclusion: After neoadjuvant therapy, TN breast cancers have a worse prognosis despite their initial chemosensitivity with a high pCR rate. HER2+ have a lower DFS than HR+/HER2- breast cancers but a better OS, mainly due to anti-HER2 targeted therapies. Pathologic complete response is a strong independent prognostic factor after neoadjuvant therapy for breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-02.

The Effect of Adding Rituximab to CHOP-Based Therapy on Clinical Outcomes for Patients In Different Subgroups of DLBCL

AbstractAbstract 4893The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been shown to improve the outcome in all age groups with newly diagnosed diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in china. A propensity score method was used to compensate for the non-randomized study design. From January 2004 to December 2009, 68 patients were newly diagnosed with DLBCL Using Hans' algorithm based on CD10, BCL-6, and MUM1, the non-germinal center (N-GCB) subgroup 45(66.2%) and germinal center B-cell-like (GCB) 23(33.8%). 32 in the rituximab plus CHOP-based chemotherapy (R+) group, and 36 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (81.1 vs. 68.1%, P < 0.005,); The complete response rate of N-GCB and GCB in the R+ group was78.2% and 82.1%, p>0.05 respectively. The complete response rate of N-GCB and GCB in the R- group was58.2% and 71.3 %, p P < 0.001. The rituximab can overcome poor outcomes for N-GCB subgroup of DLBCL. The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 69.5% for the R- group, P < 0.001. The 2-year overall survival (OS) was 72% in N-GCB Subgroup and 78% in GCB Subgroup for the R+ group, and 48% in N-GCB Subgroup and 68% in GCB Subgroup for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43–0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited N-GCB subgroup patients). IPI also showed significant impact for PFS (hazard ratio 1.72, 95% CI 1.34–2.14 for one score increase, P < 0.001 as well as OS P < 0.001. In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for DLBCL patients, particularly patients N-GCB subgroup of DLBCL. Disclosures:No relevant conflicts of interest to declare.

Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis

To assess the prognostic role of clinical parameters and histology in early childhood medulloblastoma. Clinical and histologic data from 270 children younger than age 5 years diagnosed with medulloblastoma between March 1987 and July 2004 and treated within prospective trials of five national study groups were centrally analyzed. Two hundred sixty children with medulloblastoma and specified histologic subtype were eligible for analysis (median age, 1.89 years; median follow-up, 8.0 years). Rates for 8-year event-free survival (EFS) and overall survival (OS) were 55% and 76%, respectively, in 108 children with desmoplastic/nodular medulloblastoma (DNMB) or medulloblastoma with extensive nodularity (MBEN); 27% and 42%, respectively, in 145 children with classic medulloblastoma (CMB); and 14% and 14%, respectively, in seven children with large-cell/anaplastic (LC/A) medulloblastoma (P < .001). Histology (DNMB/MBEN: hazard ratio [HR], 0.44; 95% CI, 0.31 to 0.64; LC/A medulloblastoma: HR, 2.27; 95% CI, 0.95 to 5.54; P < .001 compared with CMB), incomplete resection and metastases (M0R1: HR, 1.86; 95% CI, 1.29 to 2.80; M+: HR, 2.28; 95% CI, 1.50 to 3.46; P < .001 compared with M0R0), and national group were independent prognostic factors for EFS, and OS. The HRs for OS ranged from 0.14 for localized M0 and DNMB/MBEN to 13.67 for metastatic LC/A medulloblastoma in different national groups. Our results confirm the high frequency of desmoplastic variants of medulloblastomas in early childhood and histopathology as a strong independent prognostic factor. A controlled de-escalation of treatment may be appropriate for young children with DNMB and MBEN in future clinical trials.

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

Aim The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results HIF-1α was positively correlated with HIF-2α ( p < 0.0001), PHD1 ( p = 0.024), PHD2 ( p < 0.0001), PHD3 ( p = 0.004), FIH ( p < 0.0001) and VHL ( p = 0.031). HIF-2α levels were significantly associated with FIH ( p < 0.0001) and PHD2 ( p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis ( p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis ( p = 0.009). Conclusion These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

Proteomic profiling of proteins associated with lymph node metastasis in colorectal cancer

Lymph node metastasis (LNM) is associated with poor prognosis in colorectal cancer (CRC). The presence or absence of lymph node metastases is a strong independent prognostic factor for CRC survival. Investigation of proteins associated with the process of lymph node metastasis (LNM) is crucial for understanding of the molecular mechanisms underlying the LNM process and for predicting the CRC prognosis. In the present study, proteins from CRC tissues and adjacent normal mucosa (NMC) were examined using two-dimensional gel electrophoresis coupled with MALDI-TOF-MS. The expression levels of Ferritin Heavy Chain (FHC) were decreased in LNM CRC as compared to those in non-LNM CRC, while the expression of Cathepsin D and Ubiquitin C-terminal hydrolase-L1 (UCH-L1) were increased in LNM CRC. The results were confirmed by Western blotting and immunohistochemical staining. Furthermore, in vitro cell invasion assay showed that the overexpression of UCH-L1 through gene transfection increased the invasive ability of HCT8 cells, suggesting that UCH-L1 is not only a biomarker for LNM in CRC, but also a functional protein that may play a significant role in cell migration. The proteins identified in the present study should further our understanding of the LNM process of CRC and may become useful markers for diagnosis and targets for therapeutic interventions.