Yoshiaki Kajiyama

Radical lymph node dissection for cancer of the thoracic esophagus.

ObjectiveThe authors documented the localization and frequency of lymphatic spread in squamous cell carcinoma of the thoracic esophagus and evaluated the influence of radical systematic lymph node dissection on patient survival. Summary Background DataFrom accumulated surgical experience, it was suggested that some of the patients with lymph nodal involvement from cancer could be cured by its clearance. However, it is only recently that cancer of the esophagus has been evaluated in terms of analyzing lymphatic spread and results of lymphadenectomy. MethodsAmong 1298 patients admitted to the Toranomon Hospital between 1973 and 1993,913 (70.3%) had resections, including curative and palliative procedures. For this study, 717 patients with TNM RO (resection with no residual tumor at operation in TNM classification) were analyzed. Survival was compared between groups of patients with less extensive thoracoabdominal (two-field) dissections and extensive collothoracoabdominal (three-field) dissections. ResultsComparative study revealed that 5-year survival rate for TNM RO patients after three-field dissection (55.0%) was significantly better (log rank test, p = 0.0013) than the rate after two-field dissection (38.3%). The results were particularly significant in subgroups with stage III and IV (because of nodal factor). Overall 5-year survival rate after all resections was 42.4%. ConclusionsThe role of radical lymph node dissection in cancer of the thoracic esophagus was evaluated. Long-term survival was compared between two groups with two-and three-field dissection. It was concluded that survival rate was significantly better in patients with extensive three-field dissection.

c-erbB-2 oncoprotein expression related to chemoradioresistance in esophageal squamous cell carcinoma

PURPOSE Esophageal carcinoma is a challenging target for radiotherapy. To improve treatment efficacy, an investigation of a predictive factor is desirable. In this study, we evaluated the significance of apoptosis and immunohistochemical staining for p53, Ki-67, c-erbB-2 (HER-2/neu), Ku (p70/p80), and DNA-PKcs for predictive markers of the responsiveness to chemoradiotherapy in esophageal squamous cell carcinoma. MATERIALS AND METHODS This retrospective analysis consisted of 34 patients with esophageal squamous cell carcinoma in whom tumor biopsy was performed before treatment. They were divided into chemoradiosensitive (n = 13) and chemoradioresistant (n = 21) groups according to the tumor response evaluated at a total radiation dose of 40 Gy. The biopsy samples were examined with immunohistochemical staining for various factors and with an in situ nick end labeling method for apoptosis. The examined data were compared between the two groups. RESULTS The difference in the Ki-67, p53, Ku (p70/p80), DNA-PKcs labeling indexes and the apoptosis index in tumor cells between the chemoradiosensitive and chemoradioresistant groups was not statistically significant. The expression of c-erbB-2 oncoprotein was statistically significant in the chemoradioresistant group (p = 0.02), although it did not correlate with survival. CONCLUSIONS c-erbB-2 immunostaining is useful for the prediction of chemoradioresistance in esophageal squamous cell carcinoma.

Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles

Background Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis. Objective To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors. Methods A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed. Results Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10−40 and OR=4.13, p=8.4×10−76, respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk. Conclusions Analysis of ADH1B and ALDH2 variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the ADH1B and/or ALDH2 risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC.

Polyglycolic acid sheet application to prevent esophageal stricture after endoscopic submucosal dissection for esophageal squamous cell carcinoma

BACKGROUND AND STUDY AIM Esophageal stricture following endoscopic submucosal dissection (ESD) can be a serious complication in patients with large mucosal defects. This preliminary study examined the efficacy of using a polyglycolic acid (PGA) sheet with fibrin glue for the prevention of esophageal stricture after ESD. PATIENTS AND METHODS A total of 15 patients were enrolled. After resection, PGA sheets were placed over the surgical wound. The size of the mucosal defect was estimated by dividing the circumference of the esophagus into 12 parts of equal size. The occurrence of esophageal stricture at 6 weeks, along with the proportion of patients who had PGA sheet remaining in place 1 week and 2 weeks after ESD, and the occurrence of adverse events were investigated. RESULTS The size of mucosal defects in the 15 patients were 7/12 (n = 4), 8 /12 (n = 5), 9/12 (n = 4), 10/12 (n = 1) and 11/12 (n = 1). Esophageal stricture occurred in 1/13 patients (7.7 %; two patients were not included in the analysis because they had required surgical resection during the follow-up period). The PGA sheet remained at 1 week after ESD in 13/15 patients (86.7 %) and at 2 weeks after ESD in 6/15 patients (40 %). No adverse events were observed. CONCLUSION PGA sheets may have the potential to prevent esophageal stricture.

Prognostic factors in adenocarcinoma of the gastric cardia: pathologic stage analysis and multivariate regression analysis.

PURPOSE To clarify the pathologic stages of adenocarcinoma of the gastric cardia in which the prognosis is worse than in adenocarcinoma of the middle or distal part of the stomach, and to determine prognostic factors in these stages by multivariate analysis. PATIENTS AND METHODS We analyzed 2,536 cases of surgically resected gastric adenocarcinoma of all pathologic stages. Four hundred seventy-two cases of gastric carcinoma, in which cumulative survival of gastric cardia was poor, were subjected to Cox regression analysis for prognostic factors, and to logistic regression analysis for factors influencing venous or lymphatic invasion. RESULTS The prognosis of adenocarcinoma of the gastric cardia was inferior when compared with similarly staged carcinomas of the middle or lower part of the stomach when there was invasion of proper muscle layer or subserosal layer, with no lymph node metastasis or with only adjacent (group 1) lymph nodes metastases (T2N0 or T2N1, according to the Japanese classification). In these stages, the prognostic factors were age, histologic type, venous invasion, and location of the tumor in the upper part of the stomach. Tumor location in the upper stomach was also a predictor for the presence of venous invasion. CONCLUSION The prognosis of adenocarcinoma of the gastric cardia is poor in patients with T2 tumors with no or few lymph node metastases. Additional treatment after surgery may be necessary to improve the survival of this population.

Immunohistochemical and oncogenetic analyses of the esophageal basaloid squamous cell carcinoma in comparison with conventional squamous cell carcinomas.

Basaloid squamous cell carcinoma of the esophagus is a rare variant of squamous cell carcinoma. We reviewed 878 cases of esophageal squamous cell carcinoma and detected 22 cases (3%) of basaloid squamous cell carcinoma. These tumors and stage-matched paired conventional squamous cell carcinomas were investigated for clinicopathologic features and immunoreactivity of cytokeratin subtypes, p53, B-cell lymphoma 2 (bcl-2), β-catenin, and epidermal growth factor receptor. Molecular aberrations in p53, CTNNB1 (the gene encoding β-catenin), and epidermal growth factor receptor (EGFR) were also determined. Patients with basaloid squamous cell carcinomas demonstrated a 5-year survival rate of 42%, significantly worse than those with well-differentiated squamous cell carcinoma (P<.01). Histologically, solid nests with central necrosis and a cribriform pattern were identified in almost all (≥95%) cases, and ductal differentiation was less frequent (45%) but associated with significantly better survival (P<.05). Compared with conventional squamous cell carcinomas, the basaloid squamous cell carcinomas were less immunoreactive for cytokeratin 14, cytokeratin 903, and membranous β-catenin (P<.01-.001) but more reactive for bcl-2, nuclear β-catenin, epidermal growth factor receptor, and Ki-67 (P<.05-.001). Direct sequencing showed mutations of p53 (36%), EGFR (14%), but not CTNNB1; fluorescent in situ hybridization detected amplification of the epidermal growth factor receptor gene (22%). In basaloid squamous cell carcinomas, low-level expression of cytokeratin 14/cytokeratin 903 and mutations of p53 and EGFR had a significant influence on worse survival (P<.05-.001). We conclude that the esophageal basaloid squamous cell carcinoma, a neoplasm with particularly aggressive biologic behavior, should be differentiated from conventional squamous cell carcinomas. In this context, immunohistochemical assessment of several markers might provide a useful adjunct diagnostic tool. Aberrations of p53 and epidermal growth factor receptor genes are possibly involved in progression of esophageal basaloid squamous cell carcinoma.

Lymphatic invasion according to D2-40 immunostaining is a strong predictor of nodal metastasis in superficial squamous cell carcinoma of the esophagus: Algorithm for risk of nodal metastasis based on lymphatic invasion

In squamous cell carcinoma (SCC) of the esophagus, D2‐40 immunostaining has recently been used to detect lymphatic invasion, but invasion detected using D2‐40 immunostaining for a predictor of nodal metastasis was controversial. Therefore, the usefulness of detecting lymphatic invasion by D2‐40 immunostaining as a predictor of nodal metastasis was examined in superficial (mucosal and submucosal) SCC of the esophagus. A total of 115 superficial SCC of the esophagus were examined on immunohistochemistry using D2‐40. It was found that lymphatic invasion demonstrated on D2‐40 immunostaining was mainly detected in the lamina propria mucosa. Lymphatic invasion was found in 37 cases and the invasion detected in the entire tumor tissue was statistically correlated with nodal metastasis. Based on the lymphatic invasion according to D2‐40 immunostaining, an algorithm was devised for the risk (low, intermediate and high) of nodal metastases in superficial SCC in the esophagus. In conclusion, the detection of lymphatic invasion on D2‐40 immunostaining in tumor tissue is a strong predictor for nodal metastasis in superficial SCC of the esophagus. Lymphatic invasion was found mainly in the lamia propria mucosa, thus the devised algorithm is useful for determining the optimal treatment strategy after endoscopic mucosal resection for esophageal SCC.

Study of abnormal chromosome regions in esophageal squamous cell carcinoma by comparative genomic hybridization: relationship of lymph node metastasis and distant metastasis to selected abnormal regions

Squamous cell carcinoma of the esophagus (ESCC) has a poor prognosis among digestive tract cancers. Lymph node metastasis and distant metastasis are the major factors determining its prognosis. We used comparative genomic hybridization (CGH) to evaluate primary tumor lymph nodes and metastatic areas from ESCC patients in order to determine the relationship between abnormal chromosome regions and outcome. Tumor tissues and lymph nodes were collected from 51 patients with ESCC, and abnormal chromosome regions were detected by CGH. We searched for regions that were significantly more common in patients with lymph nodes metastases (n>/= 6) or distant metastases, and correlated those chromosomal changes with survival. Regions showing amplification in more than 65% of esophageal squamous cell cancers were as follows: 17q12 (90.2%), 17q21 (86.3%), 3q29 (82.4%), 3q28 (78.4%), 8q24.2 (76.5%), 22q12 (76.5%), 3q27 (74.5%), 8q24.3 (74.5%), 1q22 (70.6%), 5p15.3 (70.6%), 22q13 (70.6%), 3q26.3, 8q23, 8q24.1, 9q34, 11q13, 17p12, 17q25, 20q12, 20q13.1 (68.6%), 1q32, 1q42, and 20q13.2 (66.7%). Regions showing deletion in more than 50% of the tumors were as follows: Yp11.3 (62.7%), 3p26 (56.9%), Yq12 (54.9%), 13q21 (52.9%), 4q32 (51.0%), and 13q22 (51.0%). When Fishers test was used to assess associations of these regions with metastases to lymph nodes, amplification at 2q12-14 (P= 0.012), 3q24-26 (P= 0.005), and 7q21-31 (P= 0.026) were significant. Survival was worse for patients with amplification at all 3 regions. In patients with distant organ metastases, amplification at 7p13-21 was significant (P= 0.008), and survival was worse. Chromosomal amplifications in ESCC at 2q12-14, 3q24-26, and 7q21-31 were associated with lymph node metastasis, while amplification at 7p13-21 was related to distant metastasis. Amplification at these regions correlated with worse survival. Genes involved in the phenotype of ESCC may exist in these regions. Identification of these genes is a theme for future investigation.

High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy.

Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in 22 cases of esophageal squamous cancer, 79 cases of esophageal adenocarcinoma, and 16 cases of Barretts esophagus with high-grade dysplasia - a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in 77 % of the squamous cancers, 96% of the adenocarcinomas, and 94% of the Barretts lesions with high-grade dysplasia, when compared to levels in normal esophageal epithelium and non-dysplastic Barrett mucosa. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N esophageal squamous cell carcinoma cell line using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer, and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in high-risk, pre-invasive lesions of the esophagus, leading us to propose considering FAS-inhibitors for purposes of esophageal cancer chemoprevention.

Cologastric fistula and colonic perforation as a complication of percutaneous endoscopic gastrostomy.

Cologastric fistula has rarely been reported as a complication of percutaneous endoscopic gastrostomy (PEG). We encountered a patient in whom this problem went unrecognized for 2 years. After the initial PEG tube was changed, the second PEG tube was advanced into the colon, causing severe diarrhea. When a third PEG tube was inserted, acute peritonitis occurred because of colonic perforation. We discuss the mechanism of this complication and technical points related to its prevention.