Kyoko Nohara

Left-sided approach for suprapancreatic lymph node dissection in laparoscopy-assisted distal gastrectomy without duodenal transection

Laparoscopy-assisted distal gastrectomy (LADG) with extended lymph node dissection has not yet been widely adopted for the treatment of gastric cancers because of the perceived complexity of the procedure. Suprapancreatic lymph node dissection is one of the most important and demanding procedures in this approach. The techniques of duodenal transection within the abdominal cavity or taping of the common hepatic or splenic artery had traditionally been adopted for suprapancreatic nodal dissection during open surgery. In 2005, we developed a new laparoscopic procedure to safely and simply perform suprapancreatic lymph node dissection in LADG. We introduced a left-sided approach for the dissection of lymph nodes in the left gastropancreatic fold, where the body of the stomach is turned over and lifted ventrally to expose the left gastropancreatic fold through the opened lesser sac, without duodenal transection, and the suprapancreatic lymph nodes are resected en bloc in reverse order, i.e., including the lymph nodes along the proximal splenic artery (station 11p), around the celiac artery (station 9), and along the common hepatic artery (station 8a). Between April 2005 and December 2007, a total of 391 patients with cT1,2 gastric cancer underwent this surgical approach. In all patients, surgery was completed safely with favorable outcomes; mean operating time was 239 min and mean blood loss was 63 ml. The complication rate was 4.6% (18/391); there were ten conversions (2.6%) and no mortality. The aim of the present study was to describe the surgical technique of our new approach for LADG with extended lymph node dissection and to evaluate the treatment outcomes achieved by this technique.

Expression of kallikrein-related peptidase 13 is associated with poor prognosis in esophageal squamous cell carcinoma

ObjectiveOur previous differential transcriptome analysis between a paired specimen of normal and esophageal squamous cell carcinoma (ESCC) tissues found aberrant expression of kallikrein-related peptidase 13 (KLK13) in tumors. In this study, we evaluated the expression of KLK13 in many ESCC cases in relation with clinical features, and the prognosis.MethodsEighty-eight ESCC cases were subjected to immunohistological staining for KLK13 and classified into KLK13-negative and KLK13-positive groups. Difference of clinical features and the prognosis between the groups was analyzed.ResultsIn normal esophageal mucosa, KLK13 expression was evident but limited in the stratum granulosum in all cases. By contrast, only 27 of 88 ESCC samples showed KLK13 expression, whereas the remaining 61 tumors showed no KLK13 expression. The KLK13-positive group was significantly associated with pT classification (deeper tumor invasions; P = 0.0282), pN classification (lymph node metastasis; P = 0.0163), and advanced TNM stage (P = 0.0198). In KLK13-positive samples, KLK13-expressing cells often expressed Ki67, a proliferation marker, unlike normal mucosa, in which Ki67-expressing cells were limited to the basal layer and did not express KLK13. Compared with patients with KLK13-negative group, KLK13-positive group showed poorer postoperative prognosis.ConclusionRelatively high levels of KLK13 expression in ESCC were associated with cell proliferation and correlated with tumor progression, advanced cancer stage, and poor prognosis.

DNA hypermethyation and silencing of PITX1 correlated with advanced stage and poor postoperative prognosis of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is associated with the accumulation of genetic and epigenetic changes in the background mucosa. Dysregulated DNA methylation is known to lead to the inactivation of tumor suppressor genes and the activation of oncogenes. To identify the genes whose expression is perturbed by abnormal DNA methylation in ESCC, integrative transcriptomics by serial analysis of gene expression (SAGE) and methylome sequencing by methyl-DNA immunoprecipitation (MeDIP) analysis were performed. We found 159 genes with significantly decreased expression in ESCC compared to that in noncancerous esophageal mucosa. MeDIP-seq analysis identified hypermethylation in the promoter region of 56 of these genes. Using surgically resected tissues of 40 cases, we confirmed that the paired-like homeodomain 1 (PITX1) gene was hypermethylated in ESCC compared to that in normal tissues (P < 0.0001) by pyrosequencing. PITX1 overexpression in ESCC cell lines inhibited cell growth and colony formation, whereas PITX1 knockdown accelerated cell growth. A PITX1-transfected ESCC cell line, KYSE30, formed smaller tumors in nude mice than in mock-transfected cells. Hypermethylation of PITX1 was associated with tumor depth (P = 0.0011) and advanced tumor stage (P = 0.0052) and predicted poor survival in ESCC (hazard ratio, 0.1538; 95% confidence interval, 0.03159–0.7488; P = 0.0169). In this study, we found a novel tumor suppressor gene of ESCC, PITX1, which is silenced by DNA hypermethylation. Downregulation of PITX1 contributes to the growth and progression of ESCC. Hypermethylation of the PITX1 in ESCC correlated with tumor progression and advanced stage cancer, and may predict a poor prognosis.

Expression of the desmosome-related molecule periplakin is associated with advanced stage and poor prognosis of esophageal squamous cell carcinoma

Background: Our previous report showed that periplakin (PPL), a member of the plakin family of proteins, was expressed in all the normal esophageal squamous cells, except the Ki67+ basal cell layer; however, PPL-negative cells were observed in esophageal squamous cell carcinoma (ESCC) tissue samples and the proportion of PPL-positive areas in tumors showed considerable variation. In this study, we analyzed the relationships between PPL expression in tumors and the clinicopathological features of ESCC. Methods: PPL expression was evaluated by immunostaining ESCC samples from 70 patients who underwent surgery and we classified the samples into PPL-negative and PPL-positive groups based on the proportion of PPL-positive areas in tumors, and the relationships among PPL expression, clinical features, and the ESCC prognosis were analyzed. ESCC cell line KYSE270 cells were stably transfected with the PPL expression vector and their growth was assessed by colony formation assay and subcutaneous xenografts in athymic mice. Results: As found in our previous study, decreased PPL staining intensity was observed in all of the cancer tissues analyzed, compared with that observed in paired normal esophageal mucosae; however, the PPL-positive group (the percentage of PPL-positive tumor cells was >20% on immunostaining) exhibited positive associations with the pT classification (larger primary tumor) (P=0.029), pN classification (lymph node metastasis) (P=0.0462), and advanced stages of cancer (P=0.0253). High PPL expression was observed in all of 26 lymph node metastases analyzed. Furthermore, patients with PPL-positive tumors showed poor postoperative prognosis compared to those with PPL-negative ones. Forced expression of PPL in the KYSE270 ESCC cell line induced a stratified structure and colony formation. In addition, PPL-transfected cells formed larger tumors in nude mice than mock-transfected cells, suggesting that relatively high PPL expression in tumors may facilitate cell-cell adhesion by desmosome formation and eventual cell growth in vivo. Conclusions: PPL expression was generally reduced in ESCC compared with paired non-cancer tissue; however, relatively high levels of PPL expression in tumors correlated with tumor progression, lymph node metastasis, advanced stage cancer, and a poor prognosis.