Trends in surgical results of hepatic resection for hepatocellular carcinoma: 1,000 consecutive cases over 20 years in a single institution.

BACKGROUND: Surgical results have been reported to be improved in hepatic resections for hepatocellular carcinoma (HCC) in recent years, but the detailed trends in surgical results for HCC in a single high-volume center are still not clear. METHODS: Surgical results in 1,000 hepatic resections for HCC performed at a single medical center from 1989 to 2011 were analyzed. Patients were divided into 3 groups: those performed in the early period (1989 to 1995, n = 181), the middle period (1996 to 2004, n = 391), and the late period (2005 to 2011, n = 428). RESULTS: Hospital mortality (3.9%, 1.0%, and .5%; P = .0027) and morbidity (45%, 24%, and 15%; P < .0001) rates were significantly decreased. The overall survival rates were significantly improved (50%, 72%, and 78% at 5 years; P = .0021), but there was no significant difference in the disease-free survival (29%, 34%, and 31% at 5 years; P = .7823). CONCLUSIONS: Surgical results of hepatic resections for HCC were significantly improved, with the mortality rate nearly reaching 0%. The 5-year survival rate after hepatic resections for HCC was also improved to 78%, but the consistently high rate of HCC recurrence after hepatic remains a problem.

Body mass index influences long-term outcome in patients with colorectal cancer.

BACKGROUND/AIMS: The influence of high Body Mass Index (BMI) on long-term outcome is scarcely known in patients with colorectal carcinoma. METHODOLOGY: In the present study was analysed 356 consecutive patients with colorectal carcinoma, in order to address the impact of BMI on patients' characteristics, surgical procedures, and clinical outcomes following radical resection. Patients were divided into the following 3 categories according to BMI; high BMI group (BMI > or = 24.0 kg/m2), middle BMI group (21.0 < or = BMI < 24.0 kg/ m2), and low BMI group (BMI < 21.0 kg/m2). RESULTS: Low BMI was significantly correlated with advanced tumor stage compared with middle BMI group (p < 0.05). The mean number of lymph node dissected per patients of the high BMI group was significantly lower than the middle BMI group (p < 0.05). The 5-year disease-free survival rates of both high and low BMI groups were significantly lower than middle BMI group, respectively. Low and high BMI also became worse independent prognostic factors by multivariate analysis, respectively (p < 0.01; low vs. middle, p < 0.05; high vs. middle). CONCLUSIONS: Both high and low BMI became independent prognostic factors of disease recurrence in patients with colorectal carcinoma, as low BMI was correlated with tumor progression and high BMI influenced the number of lymph node dissected.

Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats.

BACKGROUND AND AIM: Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration. METHODS: Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators. RESULTS: The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group. CONCLUSIONS: These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.

A resected case of liver metastasis from colon cancer that occurred 13 years after a colectomy.

A 73-year-old man, who underwent a potentially curative resection of cancer of the descending colon 13 years before, was found to have a well-defined hepatic tumor on ultrasonography. A lateral segmentectomy was performed for a solitary hepatic tumor. Histopathological examination of the tumor indicated well differentiated adenocarcinoma compatible with the metastasis from the previous descending colon cancer. There have been no signs of recurrence for 5 years after the hepatic resection. This case suggests that distant metastasis from colorectal could be found several years after operation like in this case, and consequently long-term and strict follow-up is required after curative resection of the primary lesion.

Experimental investigation of the role of endothelin-1 in idiopathic portal hypertension.

BACKGROUND AND AIM: The authors' previous report revealed that endothelin-1 might be released from B lymphocytes in cirrhotic patients with hypersplenism. Other investigators have shown that persistent exposure to environmental contaminants including arsenic might induce idiopathic portal hypertension. The aim of this study was to experimentally identify how endothelin-1 is involved in the development of idiopathic portal hypertension and which cells produce endothelin-1 in the spleen. METHODS: Portal pressure and venous endothelin-1 concentrations were measured in rats that were given sodium arsenate orally for long periods, and endothelin-1 expression levels in the spleen were assessed by staining. In a second experiment, B and T lymphocytes and monocyte-derived macrophages cultured from healthy human peripheral blood were stimulated with sodium arsenite, sodium arsenate, lipopolysaccharide and interferon-gamma. Endothelin-1 concentrations in the supernatants were measured by ELISA. RESULTS: Arsenic exposure gradually increased portal pressure and venous endothelin-1 levels in rats. Endothelin-1 concentration in the supernatant did not change in every cell type stimulated with arsenic, but it increased in B lymphocytes and monocyte-derived macrophages treated with lipopolysaccharide and interferon-gamma. CONCLUSIONS: The in vivo study indicated that arsenic might elevate portal pressure through mechanisms involving endothelin-1. In the in vitro study, lipopolysaccharide and interferon-gamma clearly induced endothelin-1 synthesis not only in monocyte-derived macrophages but also in B lymphocytes, although arsenic treatment did not affect those cells. This study partially supports the hypothesis that idiopathic portal hypertension might be promoted by endothelin-1 overproduction from splenic B lymphocytes in response to certain substances.

Our experiences in surgical treatment for hilar cholangiocarcinoma.

BACKGROUND/AIMS: Although resection for hilar cholangiocarcinoma usually requires difficult surgical manipulations, it is only one therapeutic modality for a permanent cure or a desirable prognosis. We verified our own experiences after surgical treatment for hilar cholangiocarcinoma. METHODOLOGY: This study included 24 patients with hilar cholangiocarcinoma from 1981 to 2002. The current study mainly evaluated postoperative complications and overall prognosis after resection. RESULTS: Twenty-one patients received tumor resection. Hepatic resection including extended hepatectomy was required in 19 patients (90.5%). Postoperative morbidity was observed in 16 (71.2%), and motality in 2 (9.5%). The overall 5-year survival rate was 33.7%, and median survival was 35.7 months. Tumor extent in the TNM stage (p = 0.011) and the existence of lymph node metastases (p = 0.038) were identified as significant prognostic factors in overall survival after operation by univariate analysis. Postoperative adjuvant radio-chemotherapy after resection improved their prognosis (p = 0.010). CONCLUSIONS: Our results suggest that aggressive resection and appropriate adjuvant therapies for hilar cholangiocarcinoma might make a better prognosis possible, especially in patients without lymph node metastases excluding advanced tumor.

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.

Fractalkine-CX3CR1 axis regulates tumor cell cycle and deteriorates prognosis after radical resection for hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Fractalkine is the only CX3C chemokine, and its receptor, CX3CR1, is expressed on NK cells, CD8+ T cells, monocytes, and dendritic cells (DC). Although studies have reported that fractalkine regulates the host immune response, the roles of the fractalkine-CX3CR1 axis in tumor biology and the clinical results of hepatocellular carcinoma (HCC) remain unknown. METHODS: Fractalkine and CX3CR1 expression in HCC were evaluated and compared with the clinicopathologic features, including tumor progression determined by proliferating cell nuclear antigen (PCNA) antibody and patient prognosis after surgery. RESULTS: Tumors with high expression of both fractalkine and CX3CR1 had significantly fewer intra- and extrahepatic recurrences, a low PCNA labeling index (PCNALI), and different histological grades. Patients with tumors that expressed both had a significantly better prognosis in terms of disease-free (DFS) and overall survival (OAS), and this finding was identified as one of the independent prognostic factors in the multivariate analysis. CONCLUSIONS: Our results suggest that the fractalkine-CX3CR1 axis plays a pivotal role in the prognosis of patients with HCC, which might arise from the known modulation of the host immune response, and that of the cell cycle in HCC.

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.

Simplified hepatic resections with the use of a Chang's needle.

OBJECTIVE: To demonstrate the use of Chang's needle for hepatic resections. SUMMARY BACKGROUND DATA: Specialized instruments, fine surgical skills, and good control of hepatic inflow and backflow are essential for hepatic resections. This needle was specifically designed to simplify these requirements. METHODS: Whole-thickness interlocking sutures of the liver can first be made along the designed resection line with a Chang's needle; then parenchyma transection can follow without inflow or backflow control. This was consecutively performed on 69 patients with primary (41), metastatic (10), and benign (18) diseases since 1997. RESULTS: Blood loss during parenchyma transection was reduced in 11 right lobectomies (652 mL), 1 3-segmentectomy (300 mL), 14 bisegmentectomies (252 mL), 7 segmentectomies (104 mL), 12 subsegmentectomies (19 mL), 5 wedge resections (7 mL), 18 left lateral segmentectomies (110 mL), and 1 hepatorrhaphy (minimal). There was no procedure-related mortality. A mild bile leakage occurred in 1 case (1.5%) but healed spontaneously. CONCLUSIONS: The preliminary results demonstrate that this maneuver is a simple, easy, and safe method for performing hepatic resections.

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.

Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells.

Tetracycline analogues (TCNAs) possess cytotoxic activities as well as matrix metalloproteinase (MMP) inhibitory properties. Previously, we demonstrated that doxycycline (DOXY) could induce apoptosis in human HT29 colon cancer cells. In present study, the molecular apoptotic mechanisms induced by two kinds of TCNAs, designated as DOXY and COL-3 (chemically modified tetracycline-3; 6-demethyl, 6-deoxy, 4-dedimethylamino tetracycline), were evaluated in cultured HT29 cells. Both TCNAs inhibited the proliferation of 6 different colorectal cancer cell lines in a dose-dependent manner. Especially, COL-3 had a stronger effect on cancer cells than DOXY. Apoptotic changes were actually observed by 10 mug/ml COL-3 and 20 mug/ml DOXY in a time-dependent manner. COL-3 produced the increase in cytosolic cytochrome c and the loss of mitochondrial membrane potential after 3 hr treatment, and thereafter activated caspases. In case of DOXY, these changes were observed after 24 hr. Bax translocation was not a prerequisite for cytochrome c releasing in COL-3 treatment. Pretreated pancaspase inhibitor (Z-VAD-FMK) reduced COL-3 and DOXY mediated apoptosis up to 81.3 and 35.3%, as compared with nontreated cells, respectively. These data indicated that TCNAs could induce mitochondria-mediated apoptosis through both caspase-dependent and -independent pathway. In fact, endonuclease G and apoptosis-inducing factor were released into cytosol after the treatment of TCNAs, which indicated that caspase-independent apoptotic pathway is also one of the key mechanisms for the treatment of TCNAs. Taken together, we believe that TCNAs could have strong potentials for clinical application in treating colorectal cancers and improve cancer chemotherapy.

Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats.

BACKGROUND/AIMS: It has been well established that hypoxia inducible factor-1alpha (HIF-1alpha) transcribes essential factors in cell preservation, including angiogenesis, during hypoxia. However, the transition of HIF-1alpha expression during liver regeneration remains unknown. In this study, a role of HIF-1alpha was experimentally elucidated in relation to sinusoidal endothelial reconstruction during liver regeneration. METHODS: Expression of HIF-1alpha was evaluated in the regenerating liver following 70% hepatectomy in rats. Expressions of nuclear HIF-1alpha, vascular endothelial growth factor (VEGF) and fms-like tyrosine kinase-1 (flt-1) were measured by Western blot and liver blood flow by a laser Doppler. Sinusoidal endothelial cell area (SECA) and HIF-1alpha were localized by immunohistochemistry. HIF-1alpha mRNA was measured by reverse transcription-polymerase chain reaction. RESULT: Liver blood flow and SECA were lowest 36 and 72 h following hepatectomy, respectively. Nuclear HIF-1alpha peaked at 24 h and continuously increased 72-120 h following hepatectomy. This transition was fully supported by histological HIF-1alpha expression and HIF-1alpha mRNA up-regulation. VEGF and flt-1 peaked at 120 and 12 h, respectively. CONCLUSIONS: A significant evaluation in HIF-1alpha expression was revealed in regenerating rat livers. HIF-1alpha expression was preceded by VEGF and flt-1 expression and thus may be related to sinusoidal endothelial reconstruction.

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.

Role of tumor-associated macrophages (TAM) in advanced gastric carcinoma: the impact on FasL-mediated counterattack.

BACKGROUND: Exactly what role does tumor-derived Fas ligand (FasL) play in cancer: maintaining the immune privilege site or inducing a pro-inflammatory effect? One possible hypothesis is that tumor-associated macrophages (TAM) act as the mediator that enables apoptosis of anti-tumor immune cells without FasL-related inflammation. We have evaluated the tumor FasL expression and TAM along the tumor margin and/or in cancer stroma, and their impact on the infiltration of immune-competent cells into the tumor nest. PATIENTS AND METHODS: Tissue specimens from consecutive 84 advanced gastric carcinoma patients, who had undergone a curative resection, were evaluated for TAM (CD68+ cells), tumor FasL expression and immune status (CD8 + T cells). RESULTS: A high number of TAM significantly correlated with lymph node metastasis, intestinal type tumor and FasL expression. Although TAM had a tendency for an inverse correlation with the number of CD8+ T cells within the tumor nest (nest CD8) (p=0.0592), there was no correlation between FasL expression and nest CD8 (p=0.2158). This inverse association was found to be stronger in cases with both FasL-positive and high TAM tumors than in others (p=0.0139). The combination parameter of FasL-positive and high TAM became an independent prognostic factor in Cox's multivariate analysis, along with the pT status, nest CD8 and tumor cell apoptosis. CONCLUSION: We suggest that TAM works harmoniously with tumor-derived FasL and serves as a barrier against the infiltration of CD8+ T cells into the cancer nest.

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.

Metastatic lymph node size and colorectal cancer prognosis.

BACKGROUND: Colorectal cancer patients with lymph node metastasis constitute a heterogeneous population with variable prognoses. In this study, my colleagues and I propose a simpler lymph node (LN) staging system for colorectal cancer. STUDY DESIGN: Four-hundred and twenty-three consecutive colorectal cancer patients were studied. Of these, 36 were excluded because another carcinoma was present. The remaining 387 patients entered the TNM staging analysis. In the survival analysis, 76 patients with distant metastasis were excluded and the remaining 311 patients (LN(-) = 204 and LN(+) = 107) were studied. The diameter of the largest metastatic LN (MLN) was measured on histopathological slides. After examination of various cutpoints and survival outcomes, patients with MLNs were classified into n1 (< or = 9 mm) and n2 (> or = 10 mm) groups, according to size of MLNs (n-stage). RESULTS: Using disease-free survival (DFS) and overall survival (OS) as outcomes, patients were separated into significant prognostic groups by MLN size (univariate, p < 0.0001) (5-year survival, DFS: n0 = 91.5%, n1 = 62.2%, and n2 = 34.4%; OS: n0 = 85.1%, n1 = 63.5%, and n2 = 42.5%) and International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) (N-stage) (univariate, p < 0.0001) (5-year survival, DFS: N0 = 91.5%, N1 = 60.5%, and N2 = 36.8%; OS: N0 = 85.1%, N1 = 65.3%, and N2 = 38.0%). But in patients with fewer than 15 LNs examined (n = 31), only the new nodal stage stratified patients into significant groups (OS: p = 0.003 and DFS: p = 0.001). Only the UICC/AJCC N-stage subcategories were further split into significant prognostic groups by MLN size (UICC/AJCC N1: DFS, p = 0.048 and OS, p = 0.11; N2: DFS, p = 0.04 and OS, p = 0.04). n-stage was an independent important factor both in the DFS and OS in multivariable analysis. CONCLUSIONS: MLN size is a strong prognostic variable in colorectal carcinoma. This new metric may help clinicians treating colorectal cancer patients, but additional studies are required before clinical application.

Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pivotal cytokine that regulates inflammatory and immune responses. Recently, many investigators reported that MIF is expressed highly in several tumors, including hepatocellular carcinoma (HCC). However, the role of MIF in tumor angiogenesis and patient prognosis has not been examined in patients with HCC. METHODS: The authors evaluated MIF expression in 56 samples of HCC by Western blot analysis, and the results were correlated with clinicopathologic factors and patient prognosis. MIF localization was determined by immunohistochemical methods, and the results were compared with tumor microvessel density (MVD), as assessed by anti-CD34 antibody. Furthermore, to validate the role of MIF in angiogenesis, both MIF expression during culture of HCC cells (using the Hep3B, HepG2, and Huh7 cell lines) under hypoxic condition and the angiogenic potential of recombinant MIF in an in vitro angiogenic model were examined. RESULTS: Tumors with high MIF expression had high alpha-fetoprotein levels (P = 0.049) and frequent intrahepatic recurrence (P = 0.043). Immunohistochemical MIF scores had a significant correlation with MVD (P = 0.007). Patients who had tumors with high MIF expression levels had a significantly worse (P = 0.025) disease-free survival, and this finding remained significant as an independent prognostic factor in the multivariate analysis. Hep3B cells had high expression of MIF at 6 hours and 12 hours after hypoxic stress and exogenous MIF stimulated endothelial tube formation in in vitro angiogenesis. CONCLUSIONS: The current findings suggest that MIF expression may play a pivotal role in the dismal prognosis of patients with HCC that may be attributable to the modulation of angiogenesis.