Marie Washio

The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios

We previously demonstrated that the lymph node ratio (LNR) is a prognostic factor associated with EGFR expression, among first priority genes amplified or overexpressed in cancer. Here, we investigated the associations between high LNR and second, third, and fourth priority genes. We performed mRNA expression microarray analysis of tumor tissue from patients with stage III gastric cancer and high or low LNRs. Candidate high LNR-associated genes were further evaluated in 39 patients with stage III gastric cancer. The functional relevance of these genes was evaluated in gastric cancer cell lines. We focused on five genes: H19,PEG10, IGF2BP3, CD177, and PGA3. H19 and PEG10 were confirmed as high LNR-associated genes. H19, PEG10, and IGF2BP3 were found to promote each other’s expression. Knocking down H19 or PEG10 using RNAi decreased cell proliferation, invasion, anchorage-independent growth, and chemoresistance. These genes had a mutual relationship in MKN7 cells. H19 knockdown decreased expression of epithelial-mesenchymal transition-associated genes in MKN74 cells to suppress transformation. Thus, H19 promotes epithelial-mesenchymal transition in gastric cancer and is a potential therapeutic target.

Esophagogastric junction cancer successfully treated by laparoscopic proximal gastrectomy and lower esophagectomy with intrathoracic double-flap technique: A case report

A 66‐year‐old man was referred to our hospital for treatment of esophagogastric junction cancer. He was diagnosed as cT2N0M0, and the esophageal invasion was found to be 1 cm from the esophagogastric junction. He underwent laparoscopy‐assisted proximal gastrectomy and lower esophagectomy with esophagogastrostomy using the intrathoracic double‐flap technique through the transhiatal approach. The operative time was 662 min (suturing time was 198 min), and blood loss was 200 mL. The operative time was much longer for this procedure than for esophagogastrostomy with the conventional (intra‐abdominal) double‐flap technique. The postoperative course was uneventful. No abnormal gastroesophageal reflux, esophageal motility, or lower esophageal sphincter (LES) pressure was demonstrated 3 months after the operation. Laparoscopic proximal gastrectomy and lower esophagectomy with esophagogastrostomy using the double‐flap technique through the transhiatal approach is safe and feasible. It may be recommended for patients with esophagogastric junction cancer with esophageal invasion of about 1 cm.

Prognostic relevance of FGFR2 expression in stage II/III gastric cancer with curative resection and S‑1 chemotherapy

Curative gastrectomy and adjuvant chemotherapy using S-1 is a standard treatment for stage II/III gastric cancer in Japan. The purpose of the present study was to evaluate the prognostic relevance of fibroblast growth factor receptor (FGFR)2 expression in patients with stage II/III gastric cancer that underwent postoperative adjuvant chemotherapy with S-1. Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 167 patients with stage II/III gastric cancer that underwent curative gastrectomy followed by adjuvant S1 chemotherapy. FGFR2 expression was measured using immunohistochemistry (IHC) staining. The IHC results for FGFR2 were as follows: Grade 1+, 32; grade 2+, 80; grade 3+, 55 patients. The FGFR2 expression level was not significantly associated with relapse-free or overall survival rates. However, in the diffuse type, the FGFR2 expression level tended to be negatively correlated with relapse-free survival. In particular, the proportion of patients who recurred >5 years following surgery was significantly larger in the FGFR2 grade 3+ group than in the grade 1+, 2+ group (4/22 vs. 1/35; P=0.047). The recurrent sites of long-term failure were mostly peritoneum among the diffuse type. To the best of our knowledge, the present study indicated for the first time that FGFR2 could predict long-term failure of adjuvant S-1 chemotherapy in curative advanced gastric cancer. There was no interaction between FGFR2 expression and patient survival outcomes in stage II/III gastric cancer. Patients with FGFR2 3+ in stage II/III gastric cancer should carefully be followed-up for >5 years after surgery.

Robust vascular invasion concurrent with intense EGFR immunostaining can predict recurrence in patients with stage IB node-negative gastric cancer

PurposeThe prognosis of most patients with stage IB node-negative gastric cancer is good without postoperative chemotherapy; however, about 10% suffer recurrence and inevitably die. We conducted this study to establish the optimal indications for postoperative adjuvant chemotherapy in patients at risk of recurrence.MethodsThe subjects of this retrospective study were 124 patients with stage IB node-negative gastric cancer, who underwent gastrectomy at the Kitasato University East Hospital, between 2001 and 2010. We reviewed EGFR immunohistochemistry (IHC) as well as clinicopathological factors.ResultsOf the 124 patients, 47 (38%) showed intense EGFR IHC (2+ or 3+), with significantly less frequency than in stage II/III advanced gastric cancer (p < 0.001). According to univariate analysis, intense EGFR IHC was significantly associated with relapse-free survival (RFS) (p = 0.023) and associated with overall survival (OS) (p = 0.045) as well as vascular invasion (p = 0.031). On the multivariate Cox proportional hazards model, intense EGFR IHC(p = 0.016) was an independent prognostic predictor for RFS, and both vascular invasion (p = 0.033) and intense EGFR IHC (p = 0.031) were independent prognostic predictors for OS. The combination of both factors increased the risk of recurrence (p = 0.001).ConclusionsIn stage IB node-negative gastric cancer, vascular invasion and intense EGFR IHC increase the likelihood of recurrence. We recommend adjuvant chemotherapy for such patients because of the high risk of metachronous recurrence.

Optimized lymph node dissection range during progression of lower thoracic esophageal squamous cell carcinoma in the latest therapeutic surgical strategy: A retrospective analysis

The distribution of lymph node metastases, including recurrences, remains elusive in lower thoracic esophageal squamous cell carcinoma (LtESCC). The present study was a retrospective investigation into the optimized lymph node dissection range during LtESCC. Esophagectomies were performed on 163 patients with ESCC between 2009 and 2016, among whom 41 patients with LtESCC were examined. The rates of pathological and potential (including recurrences) metastases to lymph nodes and the prognosis (median, 34 months) were determined. Preoperative Docetaxel, Cisplatin and 5-fluorouracil chemotherapy was administered in >60% of cStage II/III LtESCC. During stage progression, abdominal lymph node metastasis rapidly becomes aggressive in LtESCC and lymph node metastases to the para-aortic area were more dominant than cervical and recurrent laryngeal nerve (RLN) areas. There were few control failures of regional lymph node metastases in LtESCC with surgery, if 1 unique case with cStage III who had metastases and recurrences of multiple lymph nodes during the clinical course was excluded. Defective lymph node dissection around the RLN did not worsen LtESCC prognosis with no RLN palsy. In the context of the potent preoperative chemotherapy and esophagectomy, lymph node dissection of cervical, para-aortic and RLN areas are putatively not mandatory to all LtESCC patients.

Carcinosarcoma of the esophagus: A report of 6 cases associated with zinc finger E‑box‑binding homeobox 1 expression

Esophageal carcinosarcoma (ECS) has been suggested to result from an epithelial mesenchymal transition (EMT) phenomenon. However, knowledge on its underlying molecular features is limited. The clinical and pathological features, and the prognosis of ECS require further investigation. In the present study, a total of 325 patients with esophageal tumors were observed between January 2004 and December 2014, of which 6 patients were diagnosed pathologically with ECS. The clinicopathological features were compared with those of corresponding cases with the identical pathological T stage (pT) of esophageal squamous cell carcinoma (ESCC). In terms of the clinical T stage (cT), the 6 cases were composed of cT1, cT2, cT3 and cT4 in 1, 1, 3 and 1 case, respectively. Nevertheless, pT was eventually diagnosed as pT1 in all cases. There was a large discrepancy between clinically diagnosed depth of tumor invasion prior to surgery and depth of tumor invasion following surgery. Zinc finger E-box-binding homeobox 1 (ZEB1), an EMT-associated transcription factor, was expressed only in the sarcoma component in all 6 cases of ECS. The ECS cases had a significantly poorer prognosis compared with the 115 pT1 ESCC cases. The present study suggests that the depth of invasion of ECS lesions does not correspond with their respective size, and the EMT of the carcinoma component may affect the prognosis by overexpression of the ZEB1 gene.

Patients’ preoperative background causes gastric stasis after laparoscopy-assisted pylorus-preserving gastrectomy: Cause of stasis in LAPPG

Despite technical improvements in laparoscopic gastrectomy, gastric stasis is still a serious problem in laparoscopy‐assisted pylorus‐preserving gastrectomy (LAPPG). The aim of this study was to investigate the factors that might cause gastric stasis in LAPPG.

Video-assisted thoracic surgery and jejunal reconstruction in a case of situs inversus totalis with esophageal cancer

A 78‐year‐old man with situs inversus totalis who had a previous history of distal gastrectomy for gastric cancer was referred to our hospital for treatment of esophageal cancer. He was diagnosed as cT2N0M0 and underwent video‐assisted thoracic surgery and open completion gastrectomy with jejunal reconstruction via the ante‐thoracic route. The postoperative period was uneventful except for transient palsy of the right recurrent laryngeal nerve. Based on a preoperative assessment of anatomical abnormality and an intraoperative adaptation to the mirror image of the standard procedure, video‐assisted esophagectomy was considered safe and feasible. It can be recommended for patients with esophageal cancer complicated by situs inversus totalis. This is the first case report of a patient with situs inversus totalis who underwent video‐assisted esophagectomy with jejunal reconstruction. Relevant literature is also discussed and reviewed.