Poor Prognosis For Overall Survival Research Articles

A New Prognostic Index for Overall Survival in Malignant Pleural Mesothelioma

ABSTRACT Aim: Existing prognostic indices for malignant pleural mesothelioma (MPM) do not incorporate recent advances in oncology care and were not based on real-world clinical data. This study aimed to provide a prognostic index for overall survival (OS) in MPM patients receiving chemotherapy with pemetrexed (CTx) or best supportive care (BSC) in a present, real-world setting. Methods: A retrospective cohort study was performed using MPM patients treated in two tertiary hospitals in Japan between 2007 and 2013. The prognostic index was developed using CTx patients, then diagnostic performance of the index was evaluated in both CTx and BSC patients. The primary outcome was OS. The Cox proportional hazards model was used for multivariable analyses to detect prognostic factors. A final model was chosen based on both clinical and statistical significance. Harrell's c index was calculated to examine the discrimination of the model. The bootstrapping technique was used for internal validation. Results: Participants comprised 283 patients (CTx, n=228; BSC, n=55). On multivariate Cox proportional regression analysis, risk factors for poor prognosis of OS for CTx patients included performance status >0, non-epithelial histological type, and stage IV disease. Since hazard ratios of individual risk factors ranged from 1.81 to 2.07, a prognostic index for OS was constructed using a simple count of the number of risk factors (PHS index). Median OS in CTx patients was shortened by each 1-point increase in PHS index: 948 days (95% confidence interval (CI), 884–1012 days) for score 0; 544 days (95%CI, 526–561 days) for 1; 362 days (95%CI, 347–375 days) for 2; and 214 days (95%CI, 186–242 days) for 3. Internal validation showed the model was robust (c index, 0.670; 95%CI, 0.619–0.721). Median OS for each PHS index with BSC was: 573 days (95%CI, not evaluable (NE) - NE) for 0; 402 days (95%CI, 370–434 days) for 1; 94 days (95%CI, 82–105 days) for 2; and 34 days (95%CI, 15–52 days) for 3. Discrimination was consistent in BSC patients (c-index, 0.799; 95%CI, 0.725–0.874). Conclusions: This index will provide clinicians and patients with a better framework for discussing prognosis at the time of diagnosis. Disclosure: All authors have declared no conflicts of interest.

Prognostic significance of preoperative serum carcinoembryonic antigen in non-small cell lung cancer: a meta-analysis.

Observational studies on the prognostic role of preoperative serum carcinoembryonic antigen (CEA) in non-small cell lung cancer (NSCLC) are controversial. Electronic databases updated until June 1, 2014 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between preoperative serum CEA level and survival of patients with NSCLC. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 16 studies (n = 4,296 patients) that evaluated the correlation between preoperative serum CEA level and survival in patients with NSCLC. Combined hazard ratios suggested that preoperative serum CEA overexpression was associated with poor prognosis of overall survival (OS) (hazard ratio (HR) = 2.28, 95 % confidence interval (CI) 2.24-2.31) in patients with NSCLC. Meanwhile, for p-stage I NSCLC, the HR (95 % CI) was 1.98 (1.73-2.15). In the stratified analysis by patient source, significant risks were found among Asians and non-Asians. However, significant heterogeneity was observed among all studies. In the present meta-analysis, preoperative serum CEA overexpression indicates a poor prognosis for patients with NSCLC.

VEGF-C expression is associated with the poor survival in gastric cancer tissue

Vascular endothelial growth factor-C (VEGF-C) is considered as a prime mediator of lymphangiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF-C overexpression and the clinical outcome in patients with gastric cancer, but yielded conflicting results. Electronic databases updated to July 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF-C overexpression and survival of patients with gastric cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 13 studies that evaluated the correlation between VEGF-C overexpression and survival in patients with gastric cancer. Combined hazard ratios suggested that VEGF-C overexpression had an unfavorable impact on overall survival (OS) (hazard ratio (HR) = 1.38, 95% confidence interval (CI) = 1.08-1.68), but not disease-free survival (DFS) (HR = 1.25, 95% CI = 0.89-1.62) in patients with gastric cancer. No significant heterogeneity (P = 0.132) was observed among 11 studies for OS and among 5 studies for DFS (P = 0.105). VEGF-C overexpression indicates a poor prognosis for overall survival, but not disease-free survival in patients with gastric cancer.

Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study

Background:Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease.Methods:A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000–2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS).Results:Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43–7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable.Conclusion:Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.

Gain of Function of Mutant TP53 in Glioblastoma: Prognosis and Response to Temozolomide

Our aim was to investigate the relationship between mutant p53 and the prognosis of malignant glioma treated with temozolomide, and the regulation of mutant TP53 induced drug resistance, by molecular experimentation and a clinical trial. Adult patients with newly surgical diagnosed glioblastoma were randomly assigned to receive either temozolomide or semustine after radiation treatment. The statuses of TP53 and expression of TP53 and O(6)-methylguanine DNA-methyltransferase (MGMT) were determined retrospectively in tumor tissue from enrolled patients. The primary end point was overall survival. Synthetic small interfering RNA was used to knock down mutant TP53 in T98G and U138 cells, which are human glioblastoma cells with a P53 mutation, by screening of exons 4-8. Viable cell survival was measured when these cells were exposed to temozolomide or semustine. Expression of MGMT at the messenger RNA level was also determined. The overall survival was 34.3 % at 2 years, 22.9 % at 3 years, 11.4 % at 4 years, and 8.6 % at 5 years with temozolomide, versus 18.2, 12.1, 3.0, and 0 %, respectively, with semustine. TP53 mutation and expression of mutant TP53 and MGMT showed significant inverse correlations with overall survival. Knockdown of mutant TP53 led to a fivefold increase in chemosensitivity to temozolomide but not semustine. Mutant TP53 knockdown induced down-regulation of MGMT expression. Mutant TP53 is strongly associated with a poor prognosis for overall survival in patients with glioblastoma. Also, TP53 mutation may decrease the chemosensitivity of glioblastoma to temozolomide by increasing MGMT expression.

Immunity In Cytogenetically Normal Acute Myeloid Leukemia (iCN-AML)

BackgroundCytogenetic normal acute myeloid leukemia (CN-AML) represents 40-50% of new AML patients, where molecular characterisation of this subgroup is paramount in the therapeutic algorithm. Flt3, NPM1, cKIT and CEBPA molecular mutations are clinically established, whilst mutations in epigenetic modifiers such as, Tet2, IDH1, IDH2 and DNMT3A are rapidly evolving into clinical relevance. However, not all centres have access to these state-of-the-art molecular assays, a good proportion of CN-AML patients will either not express or have contrasting predictive molecular phenotypes and the positive predictive value for especially, “favourable” (eg. NPM1 mutation) molecular markers are modest. In situ analysis of T cell immunity in colorectal cancer has been reported to be a better predictor of survival than the histopathology TNM score (J.Galon et al. Science 2006). Also, in NPM1 mutated CN-AML, T cell responses have been documented both at diagnosis (J. Greiner et al., Blood 2012) and post donor lymphocyte infusion therapy at relapse (S. Hofmann et al., JCO 2012). Given the molecular heterogeneity and disparity in clinical outcome of CN-AML, and evidence of T cell activity in both solid and blood cancers, we hypothesised that the adaptive immune state may be a novel prognostic marker in the CN-AML subgroup. MethodsA retrospective analysis was performed on available diagnostic trephine biopsies from CN-AML patients over 2 non-consecutive years in 2006-2007 and 2010-2011. Primary endpoint was overall survival. Trephine sections were stained for CD3, CD4, CD8 and Granzyme B. Accurate quantification of these cells was determined using automated imaging thresholding techniques developed by Monash Micro Imaging platform that utilised ImageJ (v1.46s) macro programmes. Survival was estimated using the Kaplan-Meier method and patient categories based on percentage positivity for each immunostain were compared using the log-rank test. Results26 evaluable patients (15 female; 11 male; Age range 23-90 years) were identified. Median follow up was 26 months. 7 patients were in 1st complete remission (CR1); 4 patients were in 2nd CR; 2 patients had stable disease; 9 patients were deceased; 4 patients were lost to follow up. 3/18 patients tested were positive for FLT3 ITD (2 in CR; 1 deceased). 5/14 patients tested were positive for NPM1, of which 1/5 was also FLT3-ITD positive (2 in CR; 3 deceased). Prominent non-specific background staining prevented CD4 analyses. The mean staining scores for CD3 and CD8 were 16% and 11%, respectively. Six patients (23%) in each of the CD3 and CD8 groups scored =<5% staining, where 5 of these respective 6 patients scored =<5% for both CD3 and CD8. Analyses for both CD3 and CD8 stains at >5% vs =<5% showed a trend for increased survival with estimated 3-year survivals of 71% vs. 33%, p=0.054 and 72% vs. 25%, p=0.027, respectively (Figures 1 and 2). The median for Granzyme B stain was 1% and when analysed at >1% vs =<1%, also showed improved survival, although this was not statistically significant (69% vs. 53%, p=0.317). ConclusionOur initial evaluation of immunity in CN-AML patients suggests reduced T cell status at diagnosis may predict a poor prognosis for overall survival. Of note, there was not a vast difference in the age of patients with CD3 and/or CD8 stains =<5% vs >5% (mean age of 62 vs 54.5 years, respectively). Based on these preliminary results, we will further assess the prognostic value of CD3, CD8 and Granzyme B staining in correlation with molecular markers in a larger cohort of CN-AML patients.▪▪ Disclosures:No relevant conflicts of interest to declare.

Prognostic value of vascular endothelial growth factor A expression in gastric cancer: a meta-analysis

Vascular endothelial growth factor A (VEGF-A) is considered as a prime mediator of angiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF-A overexpression with the clinical outcome in patients with gastric cancer, but yielded conflicting results. Electronic databases updated to September 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF-A overexpression and survival of patients with gastric cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 20 studies that evaluated the correlation between VEGF-A overexpression and survival in patients with gastric cancer. Combined hazard ratios suggested that VEGF-A overexpression had an unfavorable impact on overall survival (OS) (hazard ratio [HR] = 1.57; 95% confidence interval [CI], 1.30–1.84) and disease-free survival (DFS) (HR = 1.85; 95% CI, 1.39–2.32) in patients with gastric cancer. No significant heterogeneity (P = 0.487) was observed among 16 studies for OS and among 7 studies for DFS (P = 0.435). VEGF-A overexpression indicates a poor prognosis for overall survival and disease-free survival in patients with gastric cancer.

Carcinoma of the Oral Tongue: A Case Series Analysis of Prognostic Factors and Surgical Outcomes

To identify factors affecting the clinical course and survival of patients with squamous cell carcinoma of the tongue. One hundred thirty-eight patients who were treated with surgical excision of primary tongue cancer and neck dissection were analyzed retrospectively. The study had a median follow-up period of 23 months. Univariate and multivariate statistical analyses for prognostic risk factors were performed using the Cox regression method. Survival curves were processed with the Kaplan-Meier method. The 138 patients (73 male, 65 female) had a median age of 60 years. The 5-year overall, disease-specific, and relapse-free survival rates were 81%, 73%, and 71%, respectively. Tumor thickness greater than 8 mm was the only independent prognostic factor indicating a poor prognosis in overall survival (P = .049). Presence of involved lymph nodes indicated a tendency toward a poorer prognosis in disease-specific survival (P = .026) and relapse-free survival (P = .043). The present findings indicated that tumor thickness greater than 8 mm and lymph node metastasis were independent predictors of worse survival in patients with squamous cell carcinoma of the tongue. Because similar regional recurrence rates were observed in selective and radical neck dissections, supraomohyoid neck dissection is supported as a primary treatment for patients with clinical N0 tumor.

Long non‐coding RNA HOTAIR is an independent prognostic marker for nasopharyngeal carcinoma progression and survival

Identification of new nasopharyngeal carcinoma (NPC) biomarkers is of great clinical value for the diagnosis and treatment of NPC. HOTAIR, a cancer-related long non-coding RNA, was tested and its prognostic value for NPC was evaluated. As determined using in situ hybridization (ISH), 91 of 160 (56.87%) paraffin-embedded NPC biopsies showed high expression levels of HOTAIR (staining index score ≥ 6). HOTAIR was upregulated in tumors with a large size (P=0.021), more advanced clinical stage (P=0.012) and increased lymph node tumor burden (P=0.005). Quantified using real-time PCR, HOTAIR expression levels in fresh tissue and paraffin-embedded samples were 5.2~48.4-fold higher compared with non-cancer tissue samples. Moreover, HOTAIR expression levels increased with clinical stage progression, which was consistent with ISH findings in the paraffin-embedded tissue. Most importantly, NPC patients with higher HOTAIR levels had a poor prognosis for overall survival using univariate and multivariate analysis. In addition, HOTAIR mediated the migration, invasion and proliferation of NPC cells in vitro. HOTAIR is a potential biomarker for the prognosis of NPC, and dysregulation of HOTAIR might play an important role in NPC progression.

Preoperative serum CYFRA 21-1 level as a prognostic factor in surgically treated adenocarcinoma of lung

BackgroundHigh preoperative serum CYFRA 21-1 has been reported as diagnostic marker and poor prognostic factor in non-small cell lung cancer, especially in squamous cell carcinoma. However, the prognostic value in adenocarcinoma of lung has not been reported. This study is performed to investigate the prognostic impact of CYFRA 21-1 in adenocarcinoma of lung. MethodsWe retrospectively reviewed 298 patients who underwent lobectomy or above with complete mediastinal lymph node dissection for adenocarcinoma of lung, between 2004 and 2009. The patients were divided into 2 groups, by receiver operating characteristic (ROC) curve analysis. ResultsThere were 145 male patients and mean age was 62.2±26.4 years. The median follow-up period was 43.3 months. Mean and median value of CYFRA 21-1 were 2.16±1.97ng/mL and 1.68ng/mL (range, 0.37–15.10), respectively. The optimal cut-off value of CYFRA 21-1 for overall survival was 1.95ng/mL which was determined by ROC curve analysis. One hundred fourteen (38.4%) patients showed high level of CYFRA 21-1. Preoperative serum CYFRA 21-1 was higher in advanced stage (p=0.004). The high CYFRA 21-1 was also correlated with bigger tumor size (p<0.001) and poor differentiation (p=0.008). The 5-year overall survival of low group and high group was 79.1% and 58.4% (p<0.001), respectively. Univariate and multivariate analysis showed that CYFRA 21-1 level was related to the poor prognosis for overall survival (hazard ratio=1.1, p=0.033) in adenocarcinoma of lung. The concordance index for Cox model was also higher in multivariate analysis model with CYFRA 21-1 level than in model without CYFRA 21-1 level (0.722, 95% CI 0.718–0.726 vs. 0.701, 95% CI 0.697–0.705). ConclusionsHigh preoperative CYFRA 21-1 may be a determinant for poor prognosis in operated adenocarcinoma of lung.

Significance of Clinical Factors As Prognostic Indicators for Mature T-Cell Non-Hodgkin Lymphoma Patients: A Retrospective Analysis of Chinese Cases

Abstract 5093 Objectives:To retrospectively analyze the significance of different clinical factors for predicting the prognosis of mature T-cell non-Hodgkin lymphoma (MTCL) patients. Methods:Two hundred and fifty-two MTCL patients admitted from 2005 to 2011 into the First Affiliated Hospital of the Zhejiang University were retrospectively reviewed. All diagnoses were confirmed by histopathological hematoxylin and eosin (HE) staining and prognostic values of β2-microglobulin (β2-MG) levels, lactate dehydrogenase (LDH) levels, B symptoms, Ann Arbor stages, international prognostic index (IPI), Eastern Cooperative Oncology Group (ECOG) performance status, bone marrow involvement (BMI) and extra nodal involvement (ENI) for the overall survival (OS) were evaluated. Additionally, we compared the OS of patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and patients treated with an alternative intensive chemotherapy. Results:At a median follow-up of 23 months, the OS rate was 23. 8%. Our results revealed that the presence of B symptoms (P <0. 001), ECOG score≥2 (P <0. 001), BMI (P <0. 001), elevated LDH levels (P <0. 001), elevated β2-MG levels (P<0. 001), Ann Arbor stages III/IV (P=0. 007) and IPI ≥3 (P=0. 001) were factors for a poor OS prognosis and intensive chemotherapy showed a better OS outcome than CHOP treatment. Conclusion:Elevated LDH and β2-MG levels, B symptoms, Ann Arbor stage III/IV, BMI, high IPI indexes and ECOG scores predict an unfavorable prognosis of MTCL patients. When compared with the classical CHOP regimen, the intensive chemotherapy treatment can improve the prognosis of patients with MTCL. Disclosures:No relevant conflicts of interest to declare.

A nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with oesophageal cancer

BackgroundThe presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality) in patients with oesophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesised that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality in EC patients. MethodsWe report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients. ResultsOf 293 patients, 91 (31.1%) had +ypNodes. OS (p=0.0002) and DFS (p<0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381–36.969; p=0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024–4.926; p=0.044), tumour length (OR, 1.178; 95% CI, 1.024–1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242–0.915; p=0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007–8.485; p=0.049) and enlarged node(s) on post-chemoradiation computerised tomography (OR, 3.465; 95% CI, 1.549–7.753; p=0.002). The nomogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756. ConclusionOur nomogram highly correlates with the presence of +ypNodes after chemoradiation, however, considerably more refinement is needed before it can be implemented in the clinic.

Impact of concurrent chemotherapy on definitive radiotherapy for women with FIGO IIIb cervical cancer

The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40–60 Gy in 20–30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m2/week). After a median follow-up period of 44.0 months (range 4.2–114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44–4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39–4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64–3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer.

A nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with esophageal cancer (EC).

e14547 Background: The presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality therapy) in patients with EC portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesized that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality therapy in EC patients. Methods: We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients. Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p=0.0002) and DFS (p&lt;0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumor length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007-8.485; p=0.049), and enlarged node(s) on post-chemoradiation computerized tomography (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The normogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756. Conclusions: Our nomogram highly correlates with the presence of +ypNodes after chemoradiation and upon validation; it could prove useful in individualizing therapy for EC patients. Supported by UTMDACC and generous donors.

Abstract 186: High-throughput microRNA (miRNAs) arrays unravel the prognostic role of miR211 in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal among solid tumors. Only a subset of patients benefit from chemotherapy, and identification of novel prognostic factors is warranted. Recently, miRNAs emerged as a pivotal class of regulators for multiple genes involved in cancer, including PDAC (Giovannetti et al, Cancer Res 2010), and miRNA expression pattern classified tumors better than mRNA data (Lu et al, Nature 2005), suggesting their use for diagnostic purposes. However, high-throughput arrays detecting more than 1000 miRNAs are opening new opportunities to evaluate whether their profiles can also predict clinical outcome. Therefore, the present study evaluated whether comprehensive miRNA expression profiling by microarray technology can predict overall survival (OS) in resected PDAC patients. High-resolution miRNA profiles were obtained with the Toray's 3D-GeneTM miRNA chip, detecting 1200 types of human miRNA. RNA was isolated from formaldehyde fixed paraffin embedded primary tumors of 26 stage-pT3N1Mx homogeneously treated patients (gemcitabine 1000 mg/m2/day on days 1/8/15, every 28 days), selected according to their outcome (OS &amp;lt;12 months vs. OS &amp;gt;30 months). Microarray slides of the 19 samples that passed RNA quality check were scanned using 3D-GeneTM Scanner 3000 with appropriate photomultiplier settings for red channel. Each microarray was scanned three times, and then merged into one dataset analyzed. Highly stringent statistics included t-test, Spearman ranked correlation to generate a distance matrix, and iterative approaches. Unsupervised hierarchical analysis revealed that the PDAC specimens clustered according to their long/short OS classification, while the feature selection algorithm RELIEF identified the top 10 discriminating miRNAs between the two groups. MiR211 emerged as the best discriminating miRNA, with significantly higher expression in long vs. short OS patients. The expression of this miRNA was subsequently assessed by quantitative RT-PCR in an independent cohort of laser microdissected tumors from 60 resected stage-pT3N1Mx PDAC patients treated with the same gemcitabine regimen. Patients with low miR211 expression, according to median value (12.8 a.u. calculated as ΔCt vs. RNU6), had a significantly shorter median OS (14.8, 95%CI=13.1-16.5, vs. 25.7 months, 95%CI=16.2-35.1, log-rank P=0.004). Multivariate analysis demonstrated that low miR211 expression was an independent factor of poor prognosis for OS (hazard ratio 2.3, P=0.03) after adjusting for all the factors influencing clinical outcome. In conclusion, through comprehensive microarray analysis and PCR validation we identified miR211 as prognostic factor in resected PDAC. This miRNA was already associated with melanoma invasiveness, but our results prompt further prospective studies as well as research on miR211 biological role in PDAC. 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 186. doi:1538-7445.AM2012-186

Pseudomyxoma peritonei treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results from a single centre

Pseudomyxoma peritonei (PMP) is a rare, slowly progressive disease whose prognosis depends primarily on the completeness of cytoreduction. The value of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and of additional factors predicting long-term outcome and disease-free survival (DFS) remains poorly understood. This study aims to analyse survival rates and prognostic factors in patients undergoing maximal cytoreduction and HIPEC. Thirty patients were selected from a prospective database of records for patients undergoing cytoreduction and HIPEC with mitomycin C or paclitaxel. Overall survival (OS), DFS, and the prognostic factors influencing them, were examined using multivariate analysis. Median follow-up was 44 months (range, 8-144). Histological classification of PMPs was DPAM in 6/30 of cases, PMCA-I in 10/30 and PMCA in 14/30. Complete cytoreduction (CC-0 and CC-1) was achieved in 28/30 of patients and CC-2 in 2/30. Median OS was 111 months (range 0-230) and five-year OS rate was 67%. Median DFS was 53.5 months (range 0-120) and 5-year DFS rate was 44%. Incomplete cytoreduction, lymph node involvement and PCI>20 were associated with poor prognosis for OS, while lymph node involvement, elevated CA-125 levels, unfavourable histology and previous chemotherapy were associated with poor outcomes for DFS. There was morbidity of Grade 3 or higher in 9/30. Post-operative mortality occurred in 1 case. Cytoreduction plus peritonectomy procedures combined with HIPEC is a safe treatment and could improve survival rates. Since the optimal cytoreduction is the primary prognostic factor, patients should be centralised under the care of experienced teams.

Evaluation of serum CXCL5 as a serum marker for prognosis of colorectal cancer patients.

442 Background: CXCL5 is known as CXC chemokine which promotes angiogenesis related to cancer. However, the function of serum level of CXCL5 (sCXCL5) has not been fully studied in colorectal cancer. The purpose of this study was to evaluate the relationships between preoperative sCXCL5 and clinicopathological features and prognosis in colorectal cancer. Methods: This was a single-institution, retrospective study. Preoperative serum samples of 250 colorectal cancer patients (between 1998 and 2007, median age: 65.3 years, male 159/female 91) were available for the study, and 33 normal serum was examined and used as a control. sCXCL5 level was assayed using a commercially available enzyme-linked immunosorbent assay kit, and analyzed statistically. Results: Mean level of sCXCL5 was significantly higher in colorectal cancer patients than in control group (p=0.013). Patients with liver metastases had significantly higher sCXCL5 level than those without metastases (p=0.0086), and in logistic analysis, sCXCL5 was an independent marker for predicting liver metastasis (p=0.040). Overall survival of patients with elevated sCXCL5 level was significantly worse than those with lower sCXCL5 (p=0.0006). Conclusions: Preoperative sCXCL5 level was increased in colorectal cancer patients compared to in healthy volunteer and elevated sCXCL5 was correlated with liver metastasis and poor prognosis for overall survival in colorectal cancer patients. Elevated sCXCL5 has been proposed as a useful predictive marker for liver metastasis and overall survival in colorectal cancer. No significant financial relationships to disclose.

Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma

Background:Stat3 is a member of the Janus-activated kinase/STAT signalling pathway. It normally resides in the cytoplasm and can be activated through phosphorylation. Activated Stat3 (p-Stat3) translocates to the nucleus to activate the transcription of several molecules involved in cell survival and proliferation. The constitutive activation of Stat3 has been shown in various types of malignancies, and its expression has been reported to indicate a poor prognosis. However, the correlation between the constitutive activation of Stat3 and the prognosis of cervical cancer patients has not been reported.Methods:The immunohistochemical analysis of p-Stat3 expression was performed on tissues from 125 cervical squamous-cell carcinoma patients who underwent extended hysterectomy and pelvic lymphadenectomy, and the association of p-Stat3 expression with several clinicopathological factors and survival was investigated.Results:Positive p-Stat3 expression was observed in 71 of 125 (56.8%) cases and was significantly correlated with lymph node metastasis, lymph vascular space invasion, and large tumour diameter (>4 cm) by Fisher's exact test. Kaplan–Meier survival analysis showed that p-Stat3 expression was statistically indicative of a poor prognosis for overall survival (P=0.006) and disease-free survival (P=0.010) by log-rank test.Conclusion:These data showed that p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis.

Dual Role of Sp3 Transcription Factor as an Inducer of Apoptosis and a Marker of Tumour Aggressiveness

BackgroundThe ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours.MethodologyWe generated normal and tumour cell lines conditionally expressing Sp3. Cell growth was analyzed in vitro and after inoculation in nude mice. Apoptosis was assessed by pan- caspase activity assays, by counting fragmented nuclei and by determination of caspase 9 cleavage. Gene expression was determined by quantitative PCR. Cleavage by different caspases was performed after in vitro translation of the Sp3 cDNA in the presence of [S35] labelled methionine. Different tumour cell lines and head and neck tumour samples were tested for the presence of Sp3 by western blots. Correlation between Sp3 expression and overall survival has been statistically determined.Principal FindingsConditional over-expression of Sp3 induces apoptosis and modifies expression of genes implicated in the regulation of cell cycle and pro and anti apoptotic genes. Sp3 over-expression strongly reduces the development of tumours in nude mice confirming its pro-apoptotic potential in vivo. However, cells can survive to apoptosis through selective Sp3 cleavage by caspase. Sp3 induction in established tumours resulted in transient regression then progression. Progression coincides with re-accumulation of the full length form of Sp3. Sp3 is over-expressed in tumour cell lines of different origins. The presence of high levels of the full-length form of Sp3 indicates a poor prognosis for overall survival of patients with head and neck tumours.ConclusionsFull length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness.

Correlation of Clinical Features with the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Children with Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal pathway, are thought to be involved in the pathogenesis of JMML. However, no information is available on the relationship between these mutations and clinical features of JMML. The impacts of these mutations on clinical outcome also remain unclear. We tested 49 Japanese children with JMML for N-RAS, K-RAS, and PTPN11 mutations and evaluated their clinical significance. We also assessed correlations between mutational status and clinical and laboratory findings, including age at diagnosis, fetal hemoglobin (HbF), platelet count, and cytogenetic abnormality, all which have been proposed as prognostic factors for JMML. Of the 49 JMML patients, cytogenetic abnormalities were detected in 13, including 8 with monosomy 7. For 2 patients, a clinical diagnosis of neurofibromatosis type 1 (NF1) was confirmed. PTPN11 and N-/K-RAS mutations were found in 22 (45%) and 8 (16%) patients, respectively. Neither PTPN11 nor RAS mutations nor NF1 were present in 17 (35%) patients, and no simultaneous aberrations in these genes were found. In patients with the PTPN11 mutation, age at diagnosis was older (35 vs 11 months; P=0.001, or 12 months; P<0.01) and HbF level was higher (31 vs 10%; P=0.03, or 16%; P<0.01) than for patients with the RAS mutation or without any aberration, suggesting that the clinical outcome for patients with the PTPN11 mutation might be poorer, because a higher HbF level and older age have been reported to be poor prognostic factors. In fact, overall survival (OS) at 5 years was lower for patients with the PTPN11 mutation than for those without (20±9% vs 58±9%; P=0.02). In addition to PTPN11 mutation, age older than 24 months (P<0.01) and abnormal karyotype (P=0.02) were also associated with poor prognosis for OS. Of the 49 patients, 33 received stem cell transplantation (SCT). OS probabilities for patients with and without a mutation in PTPN11 at 5 years after SCT were 25±10% and 64±12%, respectively (P=0.04). More importantly, mutation in PTPN11 was the only unfavorable factor for relapse after SCT (P<0.01). Seven patients died owing to relapse and 12 from complications. All patients who died after relapse had a PTPN11 mutation. In summary, our results suggest that PTPN11-mutated JMML might be a distinct subgroup with specific clinical characteristics and a poor outcome.