Methylation of 14-3-3σ gene and prognostic significance of 14-3-3σ expression in non-small cell lung cancer.

Loss of 14-3-3σ expression through DNA methylation has been associated with carcinogenesis and the prognosis for various cancer types. Detection of methylation of the gene in serum may be useful for diagnostic utility. The present study aimed to investigate the correlation between 14-3-3σ methylation level in 36 paired tumor tissues of non-small cell lung cancer (NSCLC) and matched serum using methylation-specific polymerase chain reaction. The prognostic significance of 14-3-3σ expression in 167 NSCLC was also evaluated using immunohistochemistry. Methylation of the 14-3-3σ gene was identified in all samples. The methylation level in the serum (mean 87.7%, range 64.6-100%) was higher compared with tumor (mean 46.7%, range 25.3-56.3%). However, no significant correlation between methylation levels in tissues and serums was observed (Spearman's correlation, -0.036; P=0.837). In the 167 tumor tissues, the majority of the cases (83.8%) exhibited negative expression. Adenocarcinoma is more likely to exhibit negative expression (91.4%) compared with squamous cell carcinoma (70.2%). No significant difference was identified in the overall survival according to 14-3-3σ expression status and 14-3-3σ expression did not demonstrated independent prognostic significance. In conclusion, NSCLC harbors certain levels of 14-3-3σ methylation in the tumor and the sera of patients. The clinical value of serum 14-3-3σ methylation should be further elucidated. Immunohistochemical expression 14-3-3σ protein has limited value on prognostic significance.

Prognostic significance of 14-3-3γ overexpression in advanced non-small cell lung cancer.

The 14-3-3 protein has been shown to be involved in the cancer process. However, there is no understanding of the relationship between 14-3-3γ (14-3-3 gamma) expression and prognosis in advanced non-small cell lung cancer. In this study, we therefore investigated the association between protein levels by immunohistochemistry and clinicopathological features of advanced NSCLC patients. Survival curves were estimated using the Kaplan-Meier method and tested by log-rank. Multivariate analysis was conducted with the Cox's regression model to determine independence of factors. p values less than 0.05 were considered significant. A total 153 patients were studied, with 54.3% being stage III and 45.8% stage IV. Fifty-one cases (33.3%) were squamous cell carcinomas, and 98 cases (64.1%) were adenocarcinomas. High 14-3-3γ expression was seen in 59.5% and significantly correlated with lymph node metastasis (p=0.010) and distant metastasis (p=0.017). On Kaplan-Meier analysis, high 14-3-3γ expression was associated with poorer survival with a marginal trend toward significance (p=0.055). On multivariate analysis, age, treatment, and 14-3-3γ expression proved to be independent prognostic parameters. In vitro experiments indicated that 14-3-3γ overexpression also played a potential role in cancer invasion. In conclusion, our data suggest that 14-3-3γ overexpression is associated with invasion and a poor prognosis. Therefore, 14-3-3γ may be a potential prognostic marker of advanced non-small cell lung cancer.

Cytomorphologic and clinical factors of having high-grade cervical intraepithelial neoplasia/invasive carcinoma in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) smears.

OBJECTIVE: To determine the predictors for high-grade cervical intraepithelial neoplasia (CIN)/invasive carcinoma in women with atypical squamous cells, cannot exclude the high-grade squamous intraepithelial lesion (ASC-H) smears. MATERIAL AND METHOD: All women with ASC-H, who underwent colposcopy and had histolopathologic diagnosis between January 2004 and December 2011, were recruited. Clinical and cytomorphologic features were correlated with final histological diagnosis. Univariate and multivariate analysis were used to determine predicting factors for high-grade CIN/ invasive cancer RESULTS: Among 136,638 smears performed, 193 (0.14%) smears were reported as ASC-H and 121 smears were available for review. The underlying pathology were negative/reactive (N/R) 57 (47.1%), CIN 1 23 (19.0%), CIN 2-3 39 (32.0%), and invasive cancer 2 (1.6%). On univariate analysis, predicting factors of having high-grade CIN included a high N/C ratio, greater nuclear hyperchromasia, nuclear membrane irregularities, and the coarse chromatin. The multivariate analysis showed that a high nuclear-to-cytoplasmic (N/C) ratio (OR = 8.6, 95% CI = 1.1-70.1) and greater nuclear hyperchromasia (OR = 5.8, 95% CI = 1.6-20.8) were the independent predictors for high-grade CIN or invasive carcinoma. CONCLUSION: The presence of a high N/C ratio and greater nuclear hyperchromasia could be used to predict high-grade CIN or invasive carcinoma in ASC-H smears.

Free survival time of recurrence and malignant transformation and associated factors in patients with supratentorial low-grade gliomas.

OBJECTIVE: To determine the recurrence and malignancy free survival time and associated factors with recurrence and malignant transformation of patients with low-grade gliomas after primary surgical resection. MATERIAL AND METHOD: The present study was retrospective. Patients who underwent surgery and were diagnosed with low-grade gliomas between January 2000 and October 2009 were recruited. Time to recurrence and malignant transformation were analyzed using Kaplan-Meier method and multivariate Cox proportional hazard regression models. RESULTS: Seventy-seven patients underwent surgery for low-grade glioma. The pathological reports were diffuse astrocytoma in 55 patients (71%), oligodendroglioma in 19 patients (25%), and oligoastrocytoma in three patients (40%). The types of tumor resection were biopsy in 39 patients (50%), subtotal resection 34 patients (44%), and total resection in four patients (5%). The overall mean time to follow-up was 40 months, the median recurrence and malignant transformation times were 14 and 24 months. The 5-year recurrence-free and malignant-free survival rate was 50% and 68%. Factors associated with tumor recurrence were age, sex, presenting symptoms, preoperative Karnofsky performance status (KPS) score, tumor volume, and contrast enhancement. None of these factors showed statistically significant association with malignant transformation. CONCLUSION: One fourth of the patients had tumor recurrence and malignant transformation in a short period of time. Delayed recurrence and malignant transformation after primary resection are associated with several factors. The type of surgery especially total-subtotal resection might favor prognosis.

Fetal cardiac rhabdomyoma with hydrops fetalis: report of 2 cases and literature review.

Rhabdomyoma is the most common cardiac tumor in fetuses, often associated with the tuberous sclerosis complex, especially when multiple tumors and a positive family history of tuberous sclerosis are noted. The tumor is often benign and has a tendency to regress but may increase in size until the early third trimester. Fetal cardiac rhabdomyoma complicated by hydrops fetalis and leading to fetal death is rare. We report 2 cases of fetal cardiac rhabdomyoma with hydrops fetalis and provide a review of the literature.

Prognostic significance of tissue inhibitor of metalloproteinase-1 in breast cancer.

Introduction. Despite advances in breast cancer systemic treatment, new prognostic and predictive factors are still needed. Tissue inhibitor of metalloproteinase-1 (TIMP-1), a physiologic inhibitor of matrix metalloproteinases (MMPs), can act in both pro- and antitumoral effects. As role of TIMP-1 in breast cancer is controversial, we aimed to determine the prognostic significance of TIMP-1 in breast cancer. Methods. A single center-based case-control study was applied. Primary breast cancers from women with early stage disease treated with standard adjuvant therapy were analyzed by gene expression microarrays and immunohistochemistry for TIMP-1. Results. At the optimized cut-point, patients with high TIMP-1 RNA levels had a significantly shorter time to relapse, with a hazard ratio (HR) of 1.64 (P = 0.04), but without significant differences in overall survival (HR 1.29, P = 0.37). Although cytoplasmic overexpression of TIMP-1 protein was not correlated with early relapse (HR 1.0, P = 0.92), there was a tendency for short overall survival in patients with high expression (HR 1.41, P = 0.21). Conclusions. Our data indicate that elevated TIMP-1 RNA levels are independently prognostic for early recurrence, and there is a tendency for association of high cytoplasmic TIMP-1 protein levels with short survival in primary breast cancer.

Impact of lymph node retrieval on surgical outcomes in colorectal cancers.

BACKGROUND: Adequacy of lymph node sampling is fundamental to the accuracy of nodal status (N-status) assessment in colorectal cancers (CRCs). This study aimed to determine the minimum sampling number to achieve reliable prognosis and to look for any association between the positive lymph node ratio (LNR) and overall survival (OS). Pathological reports of 533 stages I-III CRC patients who underwent curative resection during the period from January 1998 to December 2007 were retrospectively reviewed with regard to the number of lymph nodes obtained for pathological diagnosis (nLN) and number of positive nodes. RESULTS: The median nLN was 10 nodes and the mean number of positive nodes was 1.7 nodes. On the N-status attribution plot, the cut-off point where the converging curves turned parallel was at 12 nodes. This cut-off was supported by the significant difference in OS between cases with nLN ≥ 12 (5-year OS 73.0%) and those with nLN < 12 (5-year OS 62.7%), (P-value < 0.01). Multivariate analysis showed that both nLN-12 and LNR were independent factors predicting survival probability. CONCLUSION: Our data emphasize the importance of lymph node harvesting during the surgical resection of CRCs. In addition, LNR is a strong independent factor associated with CRC survival.

WT1 expression as an independent marker of poor prognosis in colorectal cancers.

WT1 has been proven to be a prognostic marker and molecular target in various human cancers. In this study, we aimed to investigate the prognostic role of WT1 in colorectal cancers (CRCs). Archival tissue samples from 157 CRC cases who underwent curative surgery in our institute from February 1999 to May 2004 were subjected to WT1 expression studies using an immunohistochemistry technique. Number of positive staining per 500 tumor cells and staining intensities were analyzed against overall survival. Of 157 CRCs, 83 were colonic and 74 were rectal cancers. The mean follow-up period was 116 (range 77-145) months. Five-year and seven-year OS rates were 60.9% and 52.8%, respectively. WT1 immunostaining was positive in 143 cases (91%). The median number of positive cells was 120 (range 0-420). Univariate analysis by Log-rank test showed that AJCC stage, tumor site (rectal cancer), number of positive cells > 120 and high staining intensity (score ++/+++) were significantly associated with poorer survival (p-value < 0.01). Five-year survival rates in cases with positive cells of ⩽ 120 cells and > 120 cells were 72.2% and 49.4%, respectively. Five-year survival in cases with staining intensity of ++ or more was 45.3%, compared with 69% in cases with intensity of less than ++. Multivariate regression analysis demonstrated that the staining intensity, high tumor stage and rectal site were independent factors indicating poorer survival. Our findings indicate that WT1 expression is a marker of poor prognosis in CRCs, independent of AJCC staging.

Immunohistological evidence for Wnt-signaling activation in Peutz-Jeghers polyposis.

OBJECTIVE: Molecular pathogenesis of gastrointestinal polyposis in Peutz-Jegher's syndrome (PJS) has been linked to the loss-of-function mutation of LKB1. Recent functional genetic studies have pointed out that LKB1 plays a physiological role in controlling the Wnt-signaling pathway and activation of the pathway as a consequence of LKB1 haploinsufficiency might be responsible for the development of harmatomatous polyps. This study aimed to look for immunohistochemical evidence of Wnt-signaling activation in PJS polyps. METHOD: Beta-catenin immunohistochemistry patterns were evaluated in gastrointestinal polyps from five cases of PJS. All patients were also evaluated for germline mutations of LKB1 and somatic mutations of beta-catenin in the polyps. RESULTS: Four of the five cases had germline mutations of LKB1, including two novel mutations, a one-base insertion at codon 53 and a large deletion encompassing exon 3 (codon 136-155). PJS polyps from all patients showed generalized membrane and cytoplasmic localizations of beta-catenin along the mucosal endothelium. Polyps from two cases with LKB1 mutations revealed moderate-intensity nuclear staining in approximately 20 and 70% of the polyps. CONCLUSION: The study offers additional evidence of Wnt-signaling activation in PJS polyp development at the tissue level, although the degree of up-regulation was not as high as has been found in Wnt-associated neoplasms.