Satoshi Aiko

Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous-cell carcinoma

Although we have identified two putative targets, ATF3 and CENPF, for a frequently gained/amplified region around 1q32-q41 in esophageal squamous cell carcinoma (ESCC), it is possible that other amplification targets remain to be identified. In this study, we tested whether SET and MYND domain-containing protein 2 (SMYD2), located between those two genes and encoding a lysine methyltransferase for histone H3K36 and p53K370 that regulates transcription and inhibits transactivation activity, respectively, acts as a cancer-promoting gene through activation/overexpression in ESCC. Frequent overexpression of SMYD2 messenger RNA and protein was observed in KYSE150 cells with remarkable amplification at 1q32-41.1 and other ESCC cell lines (11/43 lines, 25.6%). Overexpression of SMYD2 protein was frequently detected in primary tumor samples of ESCC (117/153 cases, 76.5%) as well and significantly correlated with gender, venous invasion, the pT category in the tumor-lymph node-metastases classification and status of recurrence. Patients with SMYD2-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and SMYD2 positivity was independently associated with a worse outcome in the multivariate analysis. Knockdown of SMYD2 expression inhibited and ectopic overexpression of SMYD2 promoted the proliferation of ESCC cells in a TP53 mutation-independent but SMYD2 expression-dependent manner. These findings suggest that SMYD2 plays an important role in tumor cell proliferation through its activation/overexpression and highlight its usefulness as a prognosticator and potential therapeutic target in ESCC.

ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis

Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress‐induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress‐activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1‐dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.

Beneficial Effects of Immediate Enteral Nutrition After Esophageal Cancer Surgery

Abstract This study was conducted to determine the effects of immediate enteral nutrition (EN) on nutritional status, immunological competence, and the suppression of excessive inflammatory responses in patients following esophageal cancer surgery. Twenty-four patients who underwent the same elective operation for thoracic esophageal carcinoma were randomized into an immediate enteral nutrition (IEN) group who received EN from postoperative day (POD) 1 and a parenteral nutrition (PAN) group. Both groups received comparable volumes and calories on the same POD. Laboratory studies were carried out preoperatively and on PODs 1–7. Other nutritional and immunological assessments were repeated on PODs 1 and 7. Plasma concentrations of nitrate and nitrite were also measured. All of the patients in the IEN group tolerated enteral feeding well. There were no significant differences in the results of nutritional assessments, lymphocyte function, or plasma nitrate and nitrite levels between the two groups. The IEN group showed a significantly earlier recovery of the total lymphocyte count. The serum levels of total bilirubin and C-reactive protein were significantly attenuated in the IEN group. These results indicate that immediate EN may have beneficial effects on immunological competence and the suppression of excessive inflammatory responses in patients following esophagectomy. Patients undergoing radical esophageal surgery who are subjected to severe surgical stress might benefit the most from early EN.

Expression of hypoxia-inducible factor-1α in esophageal squamous cell carcinoma

Hypoxia‐inducible factor‐1 (HIF‐1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis. Elevated levels of HIF‐1α, a subunit of HIF‐1, are noted in various malignant tumors, but it is unclear whether this is so in esophageal carcinoma. The purpose of this study was to evaluate the implications of HIF‐1α expression in esophageal squamous cell carcinoma. In 215 patients with esophageal carcinoma, we examined immunoreactivity for HIF‐1α protein, vascular endothelial growth factor (VEGF) protein and p53 protein. In 38 patients, we examined the expression of HIF‐1α messenger ribonucleic acid (mRNA) (using the semiquantitative reverse transcriptase‐polymerase chain reaction [RT‐PCR]). A positive HIF‐1α protein expression was recognized in 95% of the patients, and was strongly apparent within both the nuclei and/or cytoplasm of tumor cells. The proportion of patients in the ‘high score’ group for HIF‐1α protein expression increased significantly with increasing VEGF protein expression. Immunoreactivity for HIF‐1α protein was found to have a significant effect on disease‐free survival rate in our univariate analysis, but no effect on overall survival rate. In RT‐PCR, HIF‐1α mRNA scores correlated significantly with scores for HIF‐1α protein expression, but not with any clinicopathologic factor or either of the survival rates. The detection of HIF‐1α protein and mRNA would appear to offer limited information as to progression and prognosis in esophageal carcinoma. (Cancer Sci 2005; 96: 176–182)

Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma.

Epigenetic alterations and the resulting inactivation of tumor suppressor genes often contribute to the development of various cancers. To identify novel candidates that may be silenced by aberrant methylation in esophageal squamous-cell carcinoma (ESCC), we analysed ESCC cell lines by a recently developed method known as bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA), and selected candidates through BAMCA-assisted strategy. In the course of this program, we identified frequent CpG methylation-dependent silencing of the gene encoding cellular retinoic acid binding protein 1 (CRABP1) in our panel of ESCC cell lines. Expression of CRABP1 mRNA was restored in gene-silenced ESCC cells after treatment with 5-aza 2′-deoxycytidine. The DNA methylation status of the CRABP1 CpG island with clear promoter activity correlated inversely with expression of this gene. CpG methylation of CRABP1 was frequently observed in primary ESCC tissues as well. Restoration of CRABP1 expression in ESCC cells lacking the protein reduced cell growth by inducing arrest at G0–G1, whereas knockdown of the gene in cells expressing CRABP1 promoted cell growth. Among 113 primary ESCC tumors, the absence of immunoreactive CRABP1 was significantly associated with de-differentiation of cancer cells and with distant lymph-node metastases in the patients. These results indicate that CRABP1 appears to have a tumor-suppressor function in esophageal epithelium, and its epigenetic silencing may play a pivotal role during esophageal carcinogenesis. Its expression status in biopsies or resected tumors might serve as an index for identifying ESCC patients for whom combined therapeutic modalities would be recommended.

The effects of immediate enteral feeding with a formula containing high levels of ω-3 fatty acids in patients after surgery for esophageal cancer

BACKGROUND We investigated whether supplementation of enteral nutrition (EN) with ω-3 polyunsaturated acids (PUFAs) affected platelet aggregation, coagulation activity, and inflammatory response in the early stages after esophageal cancer surgery. METHODS Twenty-eight patients with esophageal cancer who underwent the same surgical procedure were selected for this study. All patients received EN, which was started immediately after the operation and was increased to a maximum volume of 1500 ml/day by the third postoperative day (POD). Eleven patients received a conventional EN formula (Ensure Liquid), while the remaining 17 patients received a different formula rich in ω-3 PUFAs (Racol [RAC]). Several markers of coagulation and fibrinolysis were determined in POD 2, while the concentrations of interleukin (IL)-6, IL-8, 6-keto-PGF1α and thromboxane B2 were determined on PODs 1, 3, and 5. RESULTS A total of 27 patients completed the study, 11 in the Ensure Liquid group and 16 in the RAC group. Administration of RAC significantly inhibited the postoperative decrease in platelet count. The level of D-dimer was attenuated significantly in the RAC group. Plasma IL-8 levels were decreased significantly in the RAC group on PODs 1 and 3. The anti-inflammatory effects of ω-3 PUFAs were confirmed by the clinical findings of lower body temperature. The plasma concentration of 6-keto-PFG1α also tended to decrease in the RAC group with a significant difference on POD 5. CONCLUSIONS Early EN with a large amount of ω-3 PUFAs in reduced platelet aggregation, coagulation activity, and cytokine production. All these effects would be expected to be beneficial in patients following esophageal cancer surgery. The clinical significance of the changes in eicosanoid production remains to be established.

Enteral immuno‐enhanced diets with arginine are safe and beneficial for patients early after esophageal cancer surgery

We previously reported that provision of immediate enteral nutrition (EN) with a certain amount of omega (omega)-3 fatty acids (FAs) in patients after esophageal cancer surgery resulted in reduced platelet aggregation, coagulation activity, and cytokine production. We investigated whether EN using immuno-enhanced diet (IED) containing a large amount of omega-3 FAs as well as arginine and RNA affected the above-described responses. We also attempted to reveal whether arginine in the IED can potentially harm patients who undergo esophageal cancer surgery. Twenty-nine patients with esophageal cancer who underwent similar surgical procedures were selected. All patients received EN starting immediately after surgery. Fourteen patients received the formula with fewer omega-3 FAs, and fifteen patients received the IED. Administration of the IED tended to inhibit postoperative decrease in platelet count. Prothrombin activity and thrombin-antithrombin III complex levels were significantly reduced in the IED group. Plasma IL-8 levels were significantly lower (P < 0.05) in patients without the IED on the fifth postoperative day (POD). The proportion of T-cells was significantly higher (P < 0.05) in the IED group on PODs 1 and 7. Nitrate/nitrite levels did not differ significantly between the two groups. Early EN with an IED may enhance the inhibitory effects on postoperative platelet aggregation and hypercoagulation, and appeared to be advantageous to T-cell proliferation. These effects are expected to be beneficial in patients at risk of developing infectious complications. This study also showed that the IED could be safely used without any adverse effects for patients early after a radical surgery for the esophageal cancer.

Duodenal gangliocytic paraganglioma with regional lymph node metastasis and a glandular component.

Gangliocytic paraganglioma (GP) is generally considered to be a benign periampullary lesion, although it is unclear whether it should be classified as a hamartoma or as a neoplasm. Here, we present a GP case with lymph node metastasis. A 16‐year‐old boy complained of exertional dyspnea. Upper endoscopy and imaging studies revealed a polypoid ampullary tumor. Pancreaticoduodenectomy with lymph node dissection was performed due to swelling of peripancreatic lymph nodes. Histologically, the tumor consisted of three cell types: epithelioid; spindle; and ganglion cells. In addition to these typical components of GP, a distinct glandular component was also present. There was substantial invasion of tumor cells into the lymphovascular vessels, associated with lymph node metastases. These lymph node metastases were histologically similar to the primary tumor. To judge from these findings GP may be a true neoplasm with metastatic capacity. Pre‐ and intraoperative investigations for lymph node or distant metastases are required for adequate resection of this kind of tumor.

Influences of thoracic duct blockage on early enteral nutrition for patients who underwent esophageal cancer surgery

OBJECTIVES We have previously reported the beneficial effects of immediate enteral nutrition (EN) after esophageal cancer surgery. This randomized control study was conducted to determine whether immediate EN is beneficial or not for patients whose thoracic ducts were ligated, as well as those whose thoracic ducts were preserved. PATIENTS AND METHODS Thirty-nine patients who underwent radical resection of the esophageal cancer entered this trial. After stratifying into two groups--patients whose thoracic ducts were preserved [D(+)] and those whose thoracic ducts were ligated [D(-)], they were randomly divided into two groups--the patients who received early EN and those who received parenteral nutrition (PN) followed by delayed enteral feeding. Thus, the number of patients in the D(+)-EN group, D(+)-PN group, D(-)-EN group and D(-)-PN group were 13, 12, 7 and 7, respectively. The mortality and morbidity rates, and several blood chemistries were compared between the EN groups and the PN groups. RESULTS Total lymphocyte count showed a significant early increase and serum c-reactive protein (CRP) was significantly decreased in the D(+)-EN group compared to the D(+)-PN group. However those differences were not observed between the D(-) groups. Serum total bilirubin was significantly decreased in the both EN groups compared to the PN groups. The mortality and morbidity rates were not different between the EN group and the PN group in the D(+) patients and also in the D(-) patients. CONCLUSIONS Patients whose thoracic ducts were ligated did not obtain any other benefit from early enteral feeding except for bilirubin metabolism. Early enteral feeding is not recommended for patients whose thoracic ducts are ligated during radical resection of a cancer in the thoracic esophagus.

Systemic inflammatory response syndrome as a predictor of anastomotic leakage after esophagectomy

PurposeEsophageal anastomotic leakage is still a major cause of morbidity and mortality after esophagectomy. We conducted this study to elucidate how anastomotic leakage affects the systemic inflammatory response syndrome (SIRS) criteria.MethodsThe subjects of this retrospective study were 61 patients who underwent esophagectomy. We evaluated their preoperative status, the surgical procedures, and postoperative systemic response, including white blood cell count, heart rate, respiratory rate, body temperature, and laboratory data up to postoperative day (POD) 4.ResultsAnastomotic leakage developed in nine patients (14.8%) and was found on POD 7 on average. These patients had a significantly longer hospital stay than those without leakage. Although no difference was observed in postoperative changes of any of the SIRS criteria, the postoperative incidence of SIRS was significantly higher in the patients with anastomotic leakage on POD 4. The number of positive criteria for SIRS was also significantly higher in patients with anastomotic leakage than in those without leakage on PODs 3 and 4.ConclusionsThe SIRS scoring system is valuable for evaluating the severity of systemic inflammatory response caused by anastomosis leakage, and may serve as an indicator for prompt management.