Tsunehiro Takahashi

Gastric cancer: current status of diagnosis and treatment.

Gastric cancer is the second leading cause of death from malignant disease worldwide and most frequently discovered in advanced stages. Because curative surgery is regarded as the only option for cure, early detection of resectable gastric cancer is extremely important for good patient outcomes. Therefore, noninvasive diagnostic modalities such as evolutionary endoscopy and positron emission tomography are utilized as screening tools for gastric cancer. To date, early gastric cancer is being treated using minimally invasive methods such as endoscopic treatment and laparoscopic surgery, while in advanced cancer it is necessary to consider multimodality treatment including chemotherapy, radiotherapy, and surgery. Because of the results of large clinical trials, surgery with extended lymphadenectomy could not be recommended as a standard therapy for advanced gastric cancer. Recent clinical trials had shown survival benefits of adjuvant chemotherapy after curative resection compared with surgery alone. In addition, recent advances of molecular targeted agents would play an important role as one of the modalities for advanced gastric cancer. In this review, we summarize the current status of diagnostic technology and treatment for gastric cancer.

Gastric carcinogenesis and the cancer stem cell hypothesis

Normal stem cells (NSCs) are reported to exist in most tissues, including the brain, bone marrow, and probably the gastrointestinal tract. In the latter case, they are thought to possess both the self-renewal capacity and asymmetrical division capacity to generate progenitor cells which differentiate into epithelial cells. NSCs in the normal gastric mucosa are thought to be present in the proliferative zone of the neck/isthmus region, and to undergo a complex bipolar migration from the neck/isthmus region either upward or downward, becoming differentiated normal epithelial cells. NSCs in human gastric mucosa are difficult to identify due to the current lack of a useful marker. A precise definition of cancer stem cells (CSCs) is still under discussion. CSCs are generally defined as malignant cells with NSC capacity. However, many studies of CSCs have demonstrated their rapid growth and high metastatic potential, while NSCs are thought to be slow-growing and self-renewing, and to lack functional capacities such as cell migration and attachment. Recent evidence suggests the existence of CSCs in a wide variety of solid tumors. In this review, we will discuss the existence and cell biology of gastric NSCs and CSCs. We will also discuss whether gastric CSCs originate as organ-specific stem cells or as bone marrow-derived cells (BMDCs). Under certain conditions, the local microenvironment may promote the development of gastric cancer. Thus, Helicobacter pylori infection and the accompanying chronic inflammatory processes will supply critical initiators inducing cell growth and the tissue repair response, leading to carcinogenesis. This mechanism will be discussed in light of stem cell research. Progress in stem cell research in the gastric field is still limited to experimental animal models. However, recent studies should enhance our understanding of human cancer biology, and provide novel tools for the treatment of incurable gastric cancer.

Borderline cases between benignancy and malignancy of the duodenum diagnosed successfully by endoscopic submucosal dissection

Abstract Objective. Due to advances in endoscopic equipment, primary duodenal tumors are found more frequently than in the past. We performed endoscopic submucosal dissection (ESD) to diagnose and treat four non-ampullary duodenal tumors. Material and methods. During endoscopic treatment, marks were placed around the circumference of the tumor and sufficient amounts of physiological saline with epinephrine were injected into the submucosal layer to elevate the lesion. An incision was made around the lesion using a long-type needle knife and the isolated lesion was resected completely “en bloc”. In this procedure, a cylindrical transparent hood was attached to the endoscopy apparatus to allow for satisfactory visualization of the procedure. Results. The mean age of the patients was 69 years. The patients consisted of two males and two females. Gross examination showed three flat, elevated lesions and one polypoid lesion. Tumor size ranged from 10 to 31 mm in maximum diameter. Histological examination revealed two cases of well-differentiated adenocarcinomas and two cases of tubular adenomas with severe atypia. Procedure-related complications consisting of perforation occurred in two cases and were resolved under close postoperative observation including antibiotics, use of a nasogastric tube and nil per oral feeding status. The mean follow-up period was 18 months and none of the patients experienced tumor recurrence after the treatment. Conclusions. Since tissue obtained from endoscopic biopsies can sometimes prove difficult for definitive histological diagnosis, ESD may play an important role in the management of cases appearing to border on malignancy. In addition, ESD allows for minimally invasive treatment without sacrificing the possibility of cure for duodenal carcinoma.

The Impact of Postoperative Complications on Survivals After Esophagectomy for Esophageal Cancer.

AbstractThe aim of this study was to assess the impact of postoperative complications after esophagectomy on long-term outcome.The treatment of esophageal cancer has recently been improved; however, esophagectomy with thoracotomy and laparotomy carries considerable postoperative morbidity and mortality. The real impact of postoperative complications on overall survival is still under evaluation.A retrospective analysis was performed on patients with esophageal cancer who underwent esophagectomy with thoracotomy and laparotomy, with R0 or R1 resection between January 1997 and December 2012. Of 402 patients, we analyzed the following parameters 284 patients who could be followed up for over 5 years: stage of disease, neoadjuvant therapies, surgical approaches, surgical complications, postoperative medical complications, and overall and relapse-free survivals using medical records.Of the 284 patients, 64 (22.5%) had pneumonia, 55 (19.4%) had anastomotic leakage, and 45 (15.8%) had recurrent laryngeal nerve paralysis (RLNP). Pneumonia had a significant negative impact on overall survival (P = 0.035); however, anastomotic leakage and RLNP did not affect overall survival. Multivariate analysis revealed that the presence of pneumonia was predictive of poorer overall survival; the multivariate hazard ratio was 1.456 (95% confidence interval 1.020–2.079, P = 0.039).Pneumonia has a negative impact on overall survival after esophagectomy. Strategies to prevent pneumonia after esophagectomy should improve outcomes in this operation.

Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment.

Among multidisciplinary therapies developed for advanced esophageal cancer, neoadjuvant chemotherapy and chemoradiotherapy have been established as standard treatments. To deliver cautious follow up and intense treatment for high-risk patients, a simple and instructive biomarker for the postoperative recurrence needs to be identified. Fibrinogen, a common component of hemostasis, has been suggested to not only play an important role in cancer metastasis, but also correlate with tumor recurrence. We aim to clarify the validity of plasma fibrinogen as a marker for predicting the postoperative recurrence of esophageal squamous cell carcinoma patients who received neoadjuvant treatment. We reviewed 72 consecutive patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy at the Keio University Hospital from 2001 to 2010. Of them, we retrospectively examined 68 patients who underwent plasma fibrinogen examination before and after neoadjuvant treatment and underwent transthoracic radical esophagectomy. We investigated patient characteristics, clinicopathological factors, neoadjuvant treatment effects, postoperative course, and plasma fibrinogen levels. We investigated pretreatment and preoperative (postneoadjuvant treatment) plasma fibrinogen levels, as well as changes in fibrinogen levels before and after neoadjuvant treatment. Patients with preoperative hyperfibrinogenemia (>350 mg/dL) and patients with increased plasma fibrinogen levels during neoadjuvant treatment showed significantly shorter postoperative disease-free survival (DFS) (P = 0.002 and P = 0.037, respectively). Moreover, we classified these patients into three classes on the basis of their preoperative fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment. Patients who had both high preoperative plasma fibrinogen and increased fibrinogen levels showed significantly shorter DFS than others. In contrast, patients who had normal preoperative plasma fibrinogen and decreased fibrinogen levels showed significantly longer DFS. Based on this fibrinogen classification, we could differentiate between significantly favorable and poor prognosis patients group. Overall, this classification (hazard ratio = 1.812, P = 0.013) and the response to neoadjuvant treatment (hazard ratio = 0.350, P = 0.007) were found to be significant determining factors for postoperative DFS. With the validity of preoperative plasma fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment, the plasma fibrinogen level was found to be a possible biomarker for postoperative recurrence in advanced esophageal cancer patients who received neoadjuvant treatment. Moreover, plasma fibrinogen classification could be a simple and valuable predictive marker for postoperative follow up.

Factors Affecting Cytokine Change After Esophagectomy for Esophageal Cancer

AbstractBackgroundEsophagectomy for esophageal cancer is one of the most invasive operative procedures. Surgical stress induces the release of proinflammatory cytokines, and overproduction induces a systemic inflammatory response syndrome, which may lead to acute lung injury and multiple organ dysfunction syndrome. In addition, surgical stress may cause immunosuppression, which may affect not only perioperative mortality but also long-term survival.Methods Between 2006 and 2013, levels of perioperative serum cytokines were evaluated in 90 patients who underwent esophagectomy for esophageal carcinoma. The serum interleukin (IL)-6, IL-8, and IL-10 levels were measured by enzyme-linked immunosorbent assays. We reviewed and assessed medical records, including cytokine profiles, and determined the factors affecting postoperative serum cytokine levels.ResultsThese cytokine levels peaked on postoperative day 1 and decreased gradually. Of the clinicopathologic factors, a thoracoscopic approach was a significant factor in attenuating IL-6 and IL-8 levels on postoperative day 1 in multivariate analysis, and a longer operative time was a significant factor in increasing these levels. During postoperative days 3–7, the thoracoscopic approach and early enteral nutrition were significant factors in attenuating serum cytokine changes in multivariate analysis, and postoperative infectious complications were significant factors in increasing these levels.ConclusionsThe thoracoscopic approach and early enteral nutrition could attenuate the cytokine change after esophagectomy, and a longer operative time and postoperative infectious complication could increase it. We should undertake strategies to minimize the surgical stress to reduce potential short-term and long-term consequences for patients.

Morphologic analysis of gastroesophageal reflux diseases in patients after distal gastrectomy

The precise mechanisms that cause gastroesophageal reflux after distal gastrectomy remain unclear. We analyzed the endoscopic findings of the cardia and the position of the remnant stomach, which are related to gastroesophageal reflux. We retrospectively examined the records of 45 patients with Billroth I (B-I) and 39 patients with Roux-en-Y (R-Y) procedure for gastric cancer. Esophagitis was evaluated by the Los Angeles (LA) classification. The endoscopic findings of hiatus hernia were classified according to the criteria of the Keio Cancer Detection Center form (K-form). The valvular appearance of the cardia was classified according to V-grades. The height of the remnant stomach was measured on computed tomography scans. The postoperative findings of esophagitis in the B-I group were significantly worse than the preoperative findings, but no significant change was observed in the R-Y group. The postoperative V-grades and K-forrn findings in the B-I group were worse than their preoperative findings. In the R-Y group, however, there was no significant change in the V-grades or K-form findings. In addition, the height of the remnant stomach was significantly higher in the B-I group than in the R-Y group. This study suggested that an aggravated cardia is associated with the B-I procedure and that the position of the remnant stomach may therefore play an important role in the occurrence of postoperative reflux esophagitis. In contrast, the R-Y operation was shown to preserve the cardia and the position of the remnant stomach better. As a result, R-Y might help prevent not only duodenogastric reflux but also gastroesophageal reflux.

Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in gastric cancer (GC) and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting agents and cytotoxic agents are considered to be a potential therapeutic option for EGFR-overexpressing GC. Herein, we have investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the EGFR-targeting agent cetuximab in GC cells with or without EGFR overexpression. EGFR expression was determined by FACS and quantitative PCR in GC cells. Experimental 5-fluorouracil (5FU) was used instead of S-1 for in vitro experiments. The efficacy of 5FU or cetuximab monotherapy or combination 5FU/cetuximab therapy was examined in vitro and in vivo. Clinical specimens were examined for EGFR by immunohistochemistry (IHC). EGFR expression score was defined as strong membrane and cytoplasmic staining in at least 50–75% of cells. The combination of 5FU and cetuximab synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in GC cells with EGFR overexpression. Cetuximab also induced down-regulation of phosphorylation of EGFR and AKT, leading to diminished signaling. The antitumor effect of the combination of S-1 and cetuximab in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and EGFR-targeting therapy is a promising treatment option for GC with EGFR overexpression.

Successful endoscopic submucosal dissection for mucosal cancer of the duodenum

We report a case of mucosal duodenal cancer in a 62‐year‐old woman, which was successfully removed en bloc by endoscopic submucosal dissection (ESD). The patient underwent an upper gastrointestinal endoscopy at our hospital, which revealed an elevated flat mucosal lesion (type IIa) measuring 10 mm in diameter in the second portion of the duodenum. Histopathological examination of a biopsy specimen revealed features suggestive of a tubulovillous adenoma with severe atypia. As the findings suggested that the lesion had an adenocarcinoma component but was confined to the mucosal layer, we decided to carry out ESD and successfully removed the tumor in one piece. The resected tumor was 20 × 15 mm in size. Histopathological examination revealed that the lesion was a well‐differentiated mucosal adenocarcinoma with no lymphovascular invasion. Mucosal duodenal cancer is extremely rare, and ESD of a lesion in the duodenum requires a high level of skill. To the best of our knowledge, this case is the first report of successful ESD carried out in a case of mucosal duodenal cancer.

Clinical outcome of transthoracic esophagectomy with thoracic duct resection Number of dissected lymph node and distribution of lymph node metastasis around the thoracic duct

AbstractThe number of dissected lymph nodes (LNs), surgical outcomes, and postoperative recurrence-free survival (RFS) were compared between thoracic duct (TD)-preserved and TD-resected groups. The distribution of metastasis in LNs around TD (TDLN) was reviewed. Transthoracic esophagectomy (TTE) with TD resection for esophageal cancer patients has been one of the standard procedures. Because the adipose tissue surrounding the TD contains LNs, TD resection might be necessary for radical LN dissection. However, few studies have investigated the oncological outcome of TTE with TD resection. Two hundred fifty-six consecutive patients who underwent TTE between 2004 and 2015 were retrospectively reviewed and classified into TD-preserved or TD-resected groups. The number of dissected LNs for each LN station and surgical outcomes were compared. RFS was analyzed in 155 patients who underwent TTE before December 2012. Since 2013, the TDLN number was prospectively examined, independent of the regional LNs (n = 72). Of these, the TDLN number for each location (TDLN-Ut/Mt/Lt) was investigated and the correlation between TDLN metastasis and clinicopathological factors was analyzed. The TD was preserved in 89 patients and resected in 167 patients. Patients with TD resection showed significant advanced stage. There was no significant difference in the incidence of postoperative complications, including pneumonia, anastomotic leakage, and chylothorax. The number of dissected mediastinal LNs was significantly increased in the TD-resected group. The 5-year RFS rate of cStage I patients was 67.3% in the TD-preserved group against 90.3% in the TD-resected group, showing a tendency towards RFS extension that did not quite reach statistical significance (P = 0.055). The mean TDLN-Ut/Mt/Lt numbers were 0.89/0.56/0.44, respectively. Eight of 72 (11%) patients displayed TDLN metastasis. Metastatic TDLNs were observed on the same or cranial level of the primary lesion in 7 of 8 patients. Transthoracic esophagectomy with TD resection could increase the number of dissected mediastinal LNs without increase of postoperative complication. TDLN metastasis was observed in patients with advanced disease. A prospective trial, investigating the survival between TD-preserved and TD-resected groups, should be conducted to clarify if TD should be resected in TTE.