FR-167653, a selective p38 MAPK inhibitor, exerts salutary effect on liver cirrhosis through downregulation of Runx2.

Liver cirrhosis remains a difficult-to-treat disease with a substantial morbidity and mortality rate. There is an emerging body of data purporting a pivotal role of the activated p38 mitogen-activated protein kinase (MAPK) in the process of cirrhosis. Several anticirrhotic agents have been developed over the past few years, and most of them exert their effects by indirectly inhibiting the p38 pathway. Effect of a selective p38 inhibitor is yet to be reported. In this study, we evaluated the salutary effect of FR-167653 (FR), a selective p38 inhibitor, in a carbon tetrachloride (CCl(4))-induced rat cirrhotic model. Twenty rats were assigned into four groups: Sham, olive oil only; Control, CCl(4) in olive oil; FR50, FR 50 mg/kg/day and CCl(4); and FR100, FR 100 mg/kg/day and CCl(4). FR dose-dependently inhibited activation of p38 and had an ameliorating effect on cirrhosis formation. Significant dose-dependent reduction in alpha-smooth muscle actin immunostaining and hydroxyproline content of the liver was noticed in the FR-treated rats. Also densitometric analysis showed a significant reduction in azan-stained area in the FR-treated rats. These fibrotic changes were observed in the myofibroblasts including the hepatic stellate cells and portal fibroblasts. mRNA expression of runt-related protein 2 (Runx2), a profibrogenic transcription factor, was significantly low in FR-treated livers, indicating that Runx2 might be a key downstream regulator of the p38 pathway. A similar reduction in expression of Smad4 and tissue inhibitor of metalloproteinase-1 was noticed in the FR-treated rats. In conclusion, FR treatment exerted a significant beneficial effect in a CCl(4)-induced rat cirrhotic model. The ameliorating effect of FR could be partially attributable to an inhibition of the Smad4/p38/Runx2 axis in the cirrhotic liver.

Appraisal of a revised lymph node classification system for esophageal squamous cell cancer.

BACKGROUND: Node-positive patients with esophageal carcinoma constitute a heterogeneous population with a variable prognosis, which the current staging system insufficiently addresses. To that end, 863 patients with a curative resection for esophageal squamous cell carcinoma were analyzed to evaluate a useful and simple nodal classification system. METHODS: Along with standard conventional clinicopathologic factors, data for metastatic lymph node (MLN) number, metastatic to examined LN ratio (MLN ratio), and MLN size were evaluated. The greatest microscopic dimension of the metastatic tumor inside the largest MLN (MLN size) was measured on histopathologic slides. Patients with MLNs were classified into n1 (< 9 mm) and n2 (> or = 9 mm) groups, according to size of MLNs (n-stage). RESULTS: The paratracheal LNs most frequently contained the largest MLN and among them the right recurrent laryngeal LNs were the most common site (81.8%). Patients were stratified into significant groups by all the nodal criteria. In multivariable analysis, MLN size n-stage and MLN ratio N-stage were the best independent predictors for disease-free and overall survival, respectively. In the disease-free survival, MLN ratio N-stage subcategories were divided into prognostic groups according to the n-stage. A combined nodal staging strategy combining the n-stage and N-stage had the strongest prognostic value and was used for the tumor-node-metastasis classification with distinct separation of patients into prognostic groups. CONCLUSIONS: Results of this study indicate that the MLN size may serve as an accurate metric to classify node-positive patients and a combination of the MLN ratio and size may have synergism in classifying node-positive patients into prognostically homogenous groups.

Differential expression of RUNX genes in human esophageal squamous cell carcinoma: downregulation of RUNX3 worsens patient prognosis.

BACKGROUND: The RUNX proteins are a family of transcriptional factors that have essential functions during embryogenesis and development, whereas deregulation in expression of RUNXs is often linked to tumor formation. To date, there has been no study describing the precise expression, prognostic impact and methylation status of RUNXs in esophageal squamous cell carcinoma. METHODS: Resected specimens from 61 patients with esophageal SCC were used to identify the expression of RUNX1, RUNX2 and RUNX3 by real-time RT-PCR. Localization of mRNA was done by in situ hybridization, expression of Smad4 was evaluated by immunohistochemistry, and the methylation status of RUNX3 was analyzed by methylation-specific PCR. RESULTS: RUNX3 had a significant impact on patient prognosis with worse survival in the RUNX3-negative group. In early tumors (T1/T2), the prevalence of lymph vessel invasion and the number of metastatic lymph nodes were significantly higher in RUNX3-negative tumors. Furthermore, RUNX3 became a strong prognostic factor only in Smad4-positive tumors. Also, the methylation status of the RUNX3 promoter had a significant correlation with the loss of RUNX3 expression. CONCLUSION: Downregulation of RUNX3 may play a role in disease progression of esophageal SCC, and hypermethylation of the promoter region might be one of the crucial pathways to silence RUNX3 gene.

Surgical treatment of superficial esophageal cancer.

OBJECTIVE: The worldwide incidence of superficial esophageal cancer (SEC) is increasing. The aim of this study is to review the systematic surgical outcomes of esophagectomy for SEC. DATA SOURCES: Only manuscripts written in English and written between 1980 and 2003 were selected from MEDLINE. The keywords consisting of superficial esophageal cancer, early esophageal cancer, and early stage or superficial stage or stage I in esophageal cancer were searched. STUDY SELECTION: There were no exclusion criteria for published information relevant to the topics. The most representative articles were selected when there were several articles from the same institution. Case reports were excluded. DATA EXTRACTIONS: Thirty-two manuscripts were finally collected from MEDLINE and eight articles were also added from reference lists of the pertinent literatures. In evaluating the statistical analysis of the complications of the reported literature, collective method was used. DATA SYNTHESIS: The collected information was organized. CONCLUSIONS: The conclusions drawn from those articles showed that the overall prevalence of SEC accounted around 10% and increased to 25% in the 2000s. The overall incidence of lymph node metastasis of SEC was about 25% and its incidences in mucosal and submucosal cancer were 5 and 35%, respectively. The percentage of the cases of squamous cell carcinoma (SCC) vs adenocarcinoma (AC) widely varied depending on the geographic locations reported; most SCC cases were from the Asian countries and most AC cases were from the European countries. Clinical significance of multimodal treatment for SEC has dramatically developed in the recent era and could provide various potential therapeutic options for SEC. These concepts make it possible to individualize surgical management of SEC as part of various multimodal treatments. The operative approaches for SEC varied from minimally invasive thoracoscopic esophagectomy, limited transabdominal distal esophagectomy, conventional transthoracic esophagectomy, transhiatal esophagectomy without thoracotomy, en bloc esophagectomy, and to extended esophagectomy with a complete three-field lymph node dissection. A 5-year overall survival rate of SEC after esophagectomy was good (46 to 83%) to excellent (71 and 100%) for mucosal SEC, but far from satisfactory (33 and 78%) for submucosal SEC. Early diagnosis, development of multimodal treatment, standardization of the surgical procedure including routine lymph node dissection, and improved perioperative management of patients have led to a better survival for patients with SEC.

Inherent potential for production of tumor necrosis factor-alpha by human intestinal macrophages.

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) production by the macrophages in intestines appears to play a critical role in the pathogenesis of Crohn's disease (CD). However, it is reported that resident intestinal macrophages (both colonic and small-bowel) do not produce TNF after lipopolysaccharide (LPS) stimulation. It has not yet been proven whether or not intestinal macrophages have an inherent potential to produce TNF. The purpose of this study is to answer this question. MATERIALS AND METHODS: Colonic macrophages were isolated from lamina propria of human large intestine and stimulated with a variety of substances: LPS, a lipid A derivative (ONO-4007), killed Streptococcus bacterial body (OK-432), phorbol 12-myristate 13-acetate, and lectins (pokeweed mitogen and Sarcophaga lectin). RESULTS: Colonic macrophages were phenotypically negative for CD14 and positive for CD68 and produced very little TNF in response to LPS, as reported previously. Of the substances tested, only Sarcophaga lectin, which is a defense protein of fleshflies (Sarcophaga peregrina), induced TNF production by the intestinal macrophages. In addition, when the colonic macrophages were cultured on immunoglobulin-A-coated dishes, their characteristic response to LPS was altered, and they produced TNF at a level 6.6 times higher than when on collagen-coated dishes. CONCLUSION: Colonic macrophages have an inherent ability to produce TNF. Activation of colonic macrophages by unknown substances may contribute to the induction of TNF production, which causes the intestinal inflammation of CD.

Expression of trefoil factor family members correlates with patient prognosis and neoangiogenesis.

PURPOSE: Trefoil factor family (TFF) peptides are thought to contribute to epithelial protection and restitution by virtue of their protease-resistant nature and their strong affinity for mucins. However, they are often overexpressed in tumors, where they seem to be negative prognostic factors, possibly contributing to tumor spread, although the precise mechanisms have not been defined. EXPERIMENTAL DESIGN: Tissue sections from 111 patients with curatively resected advanced gastric carcinoma were immunohistochemically stained for TFF2, ITF (TFF3), and CD34. Microvessel density was expressed as number and area of microvessels. Results were correlated with clinicopathological characteristics and patient survival. RESULTS: Forty-nine (44.1%) and 41 (36.9%) tumors were immunohistochemically positive for TFF3 and TFF2, respectively. Among the various clinicopathologic variables, overexpression of TFF3 had a significant correlation with patient age only. In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis. The number of microvessels had a significant correlation with both TFF3 and TFF2 staining, whereas the area of microvessels had a significant correlation only with TFF3 staining. Both TFF3 and TFF2 were independent predictors of a worse disease-free survival. TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma. CONCLUSIONS: Induction of increased tumor vascularity might be one of the mechanisms by which TFFs confer metastatic phenotype and frequent disease recurrence in gastric carcinomas. Female patients with TFF3-negative advanced gastric carcinoma have comparable survival as that reported for patients with early gastric carcinoma.

Clinical outcomes of extended esophagectomy with three-field lymph node dissection for esophageal squamous cell carcinoma.

OBJECTIVE: Opinions are conflicting about 3-field lymph node dissection (3FLND) during esophagectomy for esophageal cancer. In the current study, we sought to determine the prevalence of cervical and upper thoracic lymph node metastasis in patients with squamous cell carcinoma of the thoracic esophagus and to determine the impact of 3FLND on mortality, morbidity, survival, and recurrence rate. MATERIALS AND METHODS: Among 287 patients with squamous cell carcinoma of the thoracic esophagus seen between November 1985 and December 2001, 141 (49%) underwent extended esophagectomy with 3FLND (cervical, mediastinal, and abdominal lymph node dissection). Patients were observed and clinicopathologic information collected prospectively on all patients until death or August 2002. The median follow-up was 41 months, ranging from 10 to 173 months. RESULTS: Hospital mortality and morbidity rates were 6.4% and 80%, respectively. Thirty-four of 70 node-positive patients had cervicothoracic nodal involvement. Sixteen patients (11%) had nodal involvement confined only to the cervicothoracic nodes, and no patients with lower thoracic esophageal carcinoma showed cervicothoracic involvement alone. The frequency of cervical nodal disease was correlated with nodal status within the mediastinum (P <0.01). The 1-, 3-, and 5-year overall survival rates for all 141 patients were 76%, 58%, and 48%, respectively. Among significant variables verified by univariate analysis, independent prognostic factors for overall survival determined by multivariate analysis were number of lymph node metastasis (P <0.01), amount of blood transfusion (P <0.05), length of operation (P <0.05), and presence of pulmonary complications (P <0.05). CONCLUSIONS: Extended esophagectomy with 3FLND can be performed with an acceptable mortality. Metastases frequently involved the upper thoracic and cervical lesions, and cervical nodal disease was correlated with thoracic nodal status. 3FLND proved to be an important staging system in 11% of patients. An excellent overall survival suggests a superiority of 3FLND when performed at experienced centers.

En-bloc esophagectomy for esophageal cancer.

BACKGROUND: The operative approach for esophageal cancer varies from simple palliative resection to extended esophagectomy with 3-field lymph-node dissection or en-bloc esophagectomy (EBE) depending on tumor and patient status and surgical strategy of the surgeon. The merits and demerits of such EBE are yet to be determined. METHODS: A literature review was done regarding EBE for esophageal cancer. RESULTS: Twenty articles describing EBE were reported from experienced institutions during the last 20 years and were selected for this study. The conclusions drawn from those articles showed that EBE would be a safe procedure with acceptable morbidity and low mortality rates when performed by an experienced surgeon. When strict patient selection criteria were maintained, this procedure decreased locoregional recurrence and improved long-term survival rates. CONCLUSIONS: EBE would be the treatment of choice in selected patients presenting with esophageal cancer. Development of meticulous preoperative risk assessment and optimum postoperative care may further improve the acceptability of this procedure with minimum morbidity and acceptable mortality rates.

Downregulation of KiSS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma.

KiSS-1 is a promising candidate tumor-suppressor gene and may play a key role in the metastatic cascade. The expression profile and the role of KiSS-1 in cancer progression are largely unknown in most of the cancers, including gastric cancer. In this study, KiSS-1 expression was evaluated by RNase protection assay and localization was done by in situ hybridization in 40 gastric cancers and their adjacent normal gastric mucosa. For comparison with clinicopathologic characteristics and patient prognosis, all patients were divided into 2 groups having high and low KiSS-1 expression by using the median as the cutoff value of KiSS-1 expression as determined by the RNase protection assay. Gastric cancers with low KiSS-1 had frequent venous invasion, distant metastasis and tumor recurrence. Accordingly, patients with low KiSS-1-expressing tumors had a significantly worse overall and disease-free survival. In multivariate analysis, KiSS-1 became the strongest independent prognostic factor among the conventional prognosticators for gastric cancer patients. Collectively, these findings suggest that KiSS-1 may play a crucial role in gastric cancer invasion and could be a useful target for therapeutic intervention.