JGES guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection

Colorectal endoscopic submucosal dissection (ESD) has become common in recent years. Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also many types of precarcinomatous adenomas. It is important to establish practical guidelines in which the preoperative diagnosis of colorectal neoplasia and the selection of endoscopic treatment procedures are properly outlined, and to ensure that the actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with the guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society has recently compiled a set of colorectal ESD/endoscopic mucosal resection (EMR) guidelines using evidence‐based methods. The guidelines focus on the diagnostic and therapeutic strategies and caveat before, during, and after ESD/EMR and, in this regard, exclude the specific procedures, types and proper use of instruments, devices, and drugs. Although eight areas, ranging from indication to pathology, were originally planned for inclusion in these guidelines, evidence was scarce in each area. Therefore, grades of recommendation were determined largely through expert consensus in these areas.     

Colorectal endoscopic submucosal dissection: present status and future perspective,including its differentiation from endoscopic mucosal resection

Endoscopic submucosal dissection (ESD) allows en bloc resection of a lesion, irrespective of the size of the lesion. ESD has been established as a standard method for the endoscopic ablation of malignant tumors in the upper gastrointestinal (GI) tract in Japan. Although the use of ESD for colorectal lesions has been studied via clinical research, ESD is not yet established as a standard therapeutic method for colorectal lesions because colorectal carcinoma has unique pathological, organ specific characteristics that differ radically from those of the esophagus and stomach, and scope handling and control is more difficult in the colorectum than in the upper GI tract. Depending on the efficacy of endoscopic mucosal resection (EMR) and the clinicopathological characteristics of the colorectal tumor, the proposed indications for colorectal ESD are as follows: (1) lesions difficult to remove en bloc with a snare EMR, such as nongranular laterally spreading tumors (particularly the pseudo depressed type), lesions showing a type VI: pit pattern, and large lesions of the protruded type suspected to be carcinoma; (2) lesions with fibrosis due to biopsy or peristasis; (3) sporadic localized lesions in chronic inflammation such as ulcerative colitis; and (4) local residual carcinoma after EMR. Colorectal ESD is currently in the development stage, and a standard protocol will be available in the near future. We hope that colorectal tumors will be efficiently treated by a treatment method appropriately selected from among EMR, ESD, and surgical resection after precise preoperative diagnosis based on techniques such as magnifying colonoscopy.     

Rectal cancer in a 13-year-old boy without a detectable germline mutation in FAP and HNPCC genes

Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by familial clustering and early onset. It is unclear, however, whether the early onset of colorectal cancer necessarily represents HNPCC. A 13-year-old patient had rectal cancer and underwent curative surgery. DNA from this patient was examined for replication errors (RER) and genes related to familial colorectal cancer (APC, hMSH2, and hMLH1). The patient had a negative family history of colorectal cancer, did not show the RER phenotype, and had no germline mutation of the APC, hMSH2, and hMLH1 genes. The present case suggests that an unusually young patient with colorectal cancer is not always an HNPCC proband. Observation over time, however, will be needed, as a first mutator of familial colorectal cancer could be missed. Received: May 14, 1998/Accepted: November 27, 1998     

Number of aberrant crypt foci in the rectum is a useful surrogate marker of colorectal adenoma recurrence

Aim: Endoscopic screening and removal of colorectal adenomas can reduce the incidence of colorectal cancer. However, given the possibility of adenoma recurrence, surveillance colonoscopy is currently recommended after the initial screening and removal of colorectal adenomas. Aberrant crypt foci (ACF) have been shown to serve as a reliable surrogate marker of colorectal carcinogenesis. In this study, the relationship between the number of ACF at the initial endoscopic polypectomy and the likelihood of colorectal adenoma recurrence after polypectomy were investigated. Methods: High‐magnification chromoscopic colonoscopy was performed in 82 subjects who underwent endoscopic polypectomy to identify ACF in the lower rectum. Surveillance colonoscopy was then performed 3 years after the baseline polypectomy at Yokohama City University Hospital. Results: The number of ACF was greater in patients who showed adenoma recurrence (7.88 ± 6.35) than in those who did not (2.19 ± 2.95) (P < 0.001). Receiver–operating curve analysis showed that the number of ACF was a highly specific predictor of the risk of adenoma recurrence. Conclusions: This is the first study conducted to investigate the relationship between the number of ACF after endoscopic polypectomy and the likelihood of recurrence of colorectal adenomas. These results suggest that the number of ACF is a useful predictor of the likelihood of colorectal adenoma recurrence.     

Immunohistochemical study of colorectal adenocarcinomas and adenomas with antibodies against carcinoembryonic antigen (CEA), CA19-9, keratin, α-tubulin and secretory component (SC)

The immunohistochemical localization of five antibodies against carcinoembryonic antigen (CEA), CA19-9, keratin, α-tubulin and secretory component (SC) was investigated in 14 lesions of adenocarcinoma (AC), 22 of adenoma with high-grade atypia (AH), 50 of adenoma with low-grade atypia (AL), and 15 of non-neoplastic mucosa (NNM) of the large intestine. The positive patterns for each staining were divided into three categories (patterns 1,2, and 3). All neoplastic lesions (AC, AH and AL) were positive for CEA, while 85.7% of AC, 36.4% of AH and 6.0% of AL showed strongly positive staining (pattern 3). 78.6% of AC and 54.5% of AH were positive for CA19-9 in comparison to 20.0% of AL. For keratin, more than 95% ofthe neoplastic lesions were positive, while 78.6% of AC, 27.3% of AHand 22.0% of AL showed strongly positive staining (pattern 3). For a-tubulin, more than 85% of neoplstic lesions were positive, while 50.0% of AC, 36.3% of AH and 26.0% of AL showed strongly positive staining (pattern 3). For SC, in contrast, 42.9% of AC, 27.3% of AH and 8.0% of AL were negative, but 93.3% of NNM were positive. It was concluded that the positive staining rate, especially the rate of pattern 3 for each antibody correlated with the degree of atypia of the colorectal neoplastic lesions (AC, AH and AL).     

Time course of changes in phenotypes of cultured tumor-infiltrating lymphocytes isolated from human colorectal cancer

A study was conducted to investigate the time course of changes in phenotypes of cultured tumor-infiltrating lymphocytes (TIL) isolated from 5 patients with colorectal cancer. Following initial incubation with protein phytohemagglutinin (PHA-P, final concentration 0.1w/v%), one of the inducers of interleukin-2 (IL-2) receptor, and recombinant interleukin-2 (rIL-2, 1000U/ml) for 3 days, TIL was further cultured with rIL-2 alone for another 46 to 79 days. Phenotypes of cultured TIL were analyzed by a two color flow-cytometry. The following results were obtained: 1) Yields of TIL isolated from cancerous tissues were 1.0 × 10⁶ to 1.6 × 10⁶ cells/g wet weight, and TIL grew 31 to 3700 folds in the entire period of culture. These growth rates were significantly higher than those obtained by the conventional method of culture with rIL-2 alone (1 to 720 folds). 2) The population of cytotoxic T cells (CD8 (+), CDU (−)) reached the maximum (92%, median value) at 5 weeks of culture, and thereafter gradually decreased to 61% at 9 and 10 weeks. In contrast, the population of activated natural killer cells (CD 16 (+) and Leu7 (+) or (−)) remained below 4% for the entire period of culture. 3) Maximum enhancement of specific cytotoxic activities of cultured TIL was observed during 3 to 4 weeks in culture, using K562 cells as well as Daudi cells as target cells. In conclusion, addition of PHA-P seems to beneficially affect the growth rate of TIL in culture. Moreover, time course of changes in phenotypes as well as cytotoxic activities suggest that TIL thus obtained is recommended to be used for adoptive immunotherapy during 3 to 5 weeks of culture when the highest killer activity is achieved. This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan (1–7).     

SELF‐EXPANDABLE METALLIC STENT FOR PATIENTS WITH NON‐RESECTABLE MALIGNANT COLORECTAL STRICTURE: REVIEW OF 102 CASES IN THE JAPANESE LITERATURE

Alternative procedures using endoscopy have been developed, one of which is treatment with self‐expandable metallic stents (SEMS). In Japan, as SEMS for colorectal stricture has not been approved by the public insurance system, esophageal stent is used for colon and rectum exceptionally as a colonic SEMS after obtaining informed consent from the patient. This situation is very different to other countries. In the present study, we review the Japanese medical literature to determine the current status, feasibility, and challenges remaining for SEMS to show the current status of SEMS usage for colonic strictures in Japan. We investigated SEMS for patients with non‐resectable malignant colorectal stricture in 102 Japanese case reports. Primary colorectal cancer comprised half of the cases. The insertion success rate was 100% and the clinical effectiveness rate was 93%. Restricture occurred in 12 cases (12%), and half of those cases were treated by stent in stent. Stent migration occurred in eight cases (8%) and perforation in two cases (2%). The range of SEMS insertion duration was 1 to 576 days (mean: 132 days, median 142 days). There were no deaths related to the procedure. This procedure allows patients to forgo colostomy and is cheap, safe and effective, with a short treatment time. This procedure is a viable palliative alternative to colostomy for patients with inoperative malignant colorectal stricture. Widespread application of the procedure has been hampered.     

Warning for unprincipled colorectal endoscopic submucosal dissection: Accurate diagnosis and reasonable treatment strategy

Piecemeal endoscopic mucosal resection (EMR) is generally indicated for laterally spreading tumors (LST) >2 cm in diameter. However, the segmentation of adenomatous parts does not affect the histopathological diagnosis and completeness of cure. Thus, possible indications for piecemeal EMR are both adenomatous homogenous‐type granular‐type LST (LST‐G) and LST‐G as carcinoma in adenoma without segmentalizing the carcinomatous part. Diagnosis of the pit pattern using magnifying endoscopy is essential for determining the correct treatment and setting segmentation borders. In contrast, endoscopic submucosal dissection (ESD) is indicated for lesions requiring endoscopic en bloc excision, as it is difficult to use the snare technique for en bloc excisions such as in non‐granular‐type LST (LST‐NG), especially for the pseudodepressed type, tumors with a type V_I pit pattern, shallow invasive submucosal carcinoma, largedepressed tumors and large elevated lesions, which are often malignant (e.g. nodular mixed‐type LST‐G). Other lesions, such as intramucosal tumor accompanied by submucosal fibrosis, induced by biopsy or peristalsis of the lesion; sporadic localized tumors that occur due to chronic inflammation, including ulcerative colitis; and local residual early carcinoma after endoscopic treatment, are also indications for ESD. In clinical practice, an efficient endoscopic treatment with segregation of ESD from piecemeal EMR should be carried out after a comprehensive evaluation of the completeness of cure, safety, clinical simplicity, and cost–benefit, based on an accurate preoperative diagnosis.     

Double cancer (lung and colon cancer) that showed complete remission with irinotecan and cisplatin combined chemotherapy

We report a rare case of double (colon and lung) cancer which showed complete remission with chemotherapy with irinotecan (CPT-11) and cisplatin (CDDP). The patient was a 67-year-old man who was diagnosed as having double cancer (stage IIIb pulmonary adenocarcinoma and stage 0 [or 1] well-differentiated adenocarcinoma of the ascending colon). Two courses of chemotherapy (CPT-11, 60 mg/m², days 1 and 8; CDDP, 30 mg/m², days 1 and 8) were performed. The combination therapy of CPT-11 and CDDP was very effective. In Japan, there have been few published reports describing the use of CPT-11 for the treatment of gastrointestinal cancer. We think that the use of CPT-11 in gastrointestinal cancer is promising. Received: August 18, 1999 / Accepted: March 24, 2000     

逍遥散对腹腔注射卵清清蛋白致肠易激综合征大鼠内脏敏感性的作用

[目的]研究腹腔注射鸡卵清清蛋白(Alb)致肠易激综合征(IBS)大鼠内脏敏感性的变化及逍遥散的调节作用。[方法]采用腹腔注射鸡卵清Alb法建立IBS大鼠模型。实验动物随机分为正常组,模型组,阳性对照(匹维溴胺)组,逍遥散高、中、低剂量组,观察各组大鼠引起腹部收缩反射的最小容量阈值及不同扩张容量下腹壁肌电活动的变化,研究逍遥散的干预作用。[结果]腹腔注射鸡卵清Alb致IBS大鼠内脏敏感性明显增高(P<0.01)。而逍遥散能降低结、直肠扩张引起IBS大鼠腹部收缩反射的最小容量阈值,降低IBS大鼠不同扩张容量下的腹壁肌电活动(P<0.05,<0.01),且有一定的量-效关系。[结论]腹腔注射鸡卵清Alb致IBS大鼠内脏敏感性增高,逍遥散可降低IBS大鼠的内脏高敏感性。     

RELATION BETWEEN OBESITY AND ADENOMATOUS POLYPS OF THE LARGE BOWEL

Background: We compared the prevalence of colorectal adenoma (polyps) in men and women and examined the role of body mass index (BMI) on polyp risk according to patient age and gender. Methods: The risk of developing colorectal polyps was studied in 15 380 subjects (7155 men and 8225 women) who underwent colonoscopy for the first time from April 1998 to March 2006 at our ‘Human Dry Dock’, which is the check‐up service provided in Japan. Eligible subjects were 20–86 years old (mean age ± SD, 47.3 ± 8.5) and were free of invasive cancer, hyperplastic polyps and familial polyposis. Polyps were found in 1590 subjects (1062 men and 528 women). The odds ratio (OR) of detection of polyps in relation to obesity was determined in all cases by multivariate logistic regression analysis after making an adjustment for gender and age. Results: The OR of polyp detection in obese subjects (BMI ≥ 25) versus non‐obese subjects (BMI < 25, OR = 1) was 1.34 (P < 0.001) in men and 1.13 (P = 0.26) in women. As the BMI increased in increments of one, the OR in men increased significantly to 1.01 (P < 0.001), whereas the OR in women was unchanged at 1.00 (P = 0.23), which was without significance. Conclusions: We conclude that obesity in men is a risk factor for the development of polyps. These results must be confirmed by additional epidemiological studies.     

Transforming growth factor-β during carcinogenesis: the shift from epithelial to mesenchymal signaling

Transforming growth factor-β (TGF-β) activates not only TGF-β type I receptor (TβRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). While the TβRI/pSmad3C pathway inhibits growth of normal epithelial cells, JNK/pSmad3L-mediated signaling is involved in invasion by activated mesenchymal cells. During sporadic human colorectal carcinogenesis, TGF-β signaling confers a selective advantage on tumor cells by shifting from the TβRI/pSmad3C pathway characteristic of mature epithelial cells to the JNK/pSmad3L pathway, which is more characteristic of the state of flux shown by the activated mesenchymal cells. JNK acts as a regulator of TGF-β signaling by increasing the basal level of pSmad3L available for action in the nuclei of the invasive adenocarcinoma, in the meantime shutting down TGF-β-dependent nuclear activity of pSmad3C. Loss of epithelial homeostasis and acquisition of a migratory, mesenchymal phenotype are essential for tumor invasion. From the viewpoint of TGF-β signaling, a key therapeutic aim in cancer would be restoration of the lost tumor suppressor function observed in normal colorectal epithelial cells at the expense of effects promoting aggressive behavior of the adenocarcinoma. Specific inhibitors of the JNK/pSmad3L pathway might prove useful in this respect. In the case of molecularly targeted therapy for human cancer, pSmad3L and pSmad3C could be assessed as biomarkers to evaluate the likely benefit from specific inhibition of the JNK/pSmad3L pathway.     

Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study

Background Depth of submucosal invasion (SM depth) in submucosal invasive colorectal carcinoma (SICC) is considered an important predictive factor for lymph node metastasis. However, no nationwide reports have clarified the relationship between SM depth and rate of lymph node metastasis. Our aim was to investigate the correlations between lymph node metastasis and SM depth in SICC.Methods SM depth was measured for 865 SICCs that were surgically resected at six institutions throughout Japan. For pedunculated SICC, the level 2 line according to Haggitts classification was used as baseline and the SM depth was measured from this baseline to the deepest portion in the submucosa. When the deepest portion of invasion was limited to above the baseline, the case was defined as a head invasion. For nonpedunculated SICC, when the muscularis mucosae could be identified, the muscularis mucosae was used as baseline and the vertical distance from this line to the deepest portion of invasion represented SM depth. When the muscularis mucosae could not be identified due to carcinomatous invasion, the superficial aspect of the SICC was used as baseline, and the vertical distance from this line to the deepest portion was determined.Results For pedunculated SICC, rate of lymph node metastasis was 0% in head invasion cases and stalk invasion cases with SM depth <3000µm if lymphatic invasion was negative. For nonpedunculated SICC, rate of lymph node metastasis was also 0% if SM depth was <1000µm.Conclusions These results clarified rates of lymph node metastasis in SICC according to SM depth, and may contribute to defining therapeutic strategies for SICC.     

Estimation of glycogen levels in human colorectal cancer tissue: relationship with cell cycle and tumor outgrowth

In this study, we quantitatively measured glycogen levels in tissue samples obtained from tumors, regions adjacent to tumor, and regions of normal colorectum to determine whether the levels were related to cell cycle and cancer growth. Glycogen levels were analyzed in relation to histopathological factors, (tumor size and stage of disease) and cell cycle progression. The glycogen level was found to be highest in the cancer tissue, lower in normal tissue, and lowest in the adjacent tissue. The difference in glycogen level between the cancer tissue and the other two regions was significant (P < 0.05). There was a negative correlation between glycogen level and tumor size, but it was not significant. The level of glycogen in cancer tissues decreased as the stage of the disease progressed, but a significant difference was not found between stages. There was a negative correlation between the glycogen level and the proliferation index. There was a positive correlation between the glycogen level and the proportion of cancer cells in G₁ phase, while there was a negative correlation with S and G₂M phases. Glycogen levels were highest in cancers with a high proportion of cells in G₁, and decreased with progression to S phase. It may be that glycogen is utilized in the progression to S phase, and the cancer tissues are supplied with glycogen from the tumors themselves as well as their adjacent tissues. Cancer growth may be inhibited by artificial control of the glycogen level in the G₁ phase of cancer cells. Received: July 17, 1998 / Accepted: February 26, 1999     

Paired tumor marker of soluble E-selectin and its ligand sialyl Lewis A in colorectal cancer

BACKGROUND: Better diagnosis of metastatic disease has been pursued by oncologists: however, many of the tumor markers have been still controversial. Our purpose was to estimate the usefulness of soluble E-selectin and its ligand sialyl Lewis A for more accurate diagnosis as a combined tumor marker for metastases in colorectal cancer. METHODS: E-selectin and sialyl Lewis A, collected from preoperative blood, were measured of its levels in 54 patients with colorectal cancer classified according to Dukes' stage. E-selectin was assayed by enzyme-linked immunosorbent assay, whereas sialyl Lewis A was quantified by enzyme immunoassay using immunoclone kit. RESULTS: The elevation in the level of E-selectin was significantly higher in Dukes' D group than that of healthy volunteers (P < 0.001, Fisher's procedure of least significance test), Dukes' A (P = 0.01), B (P = 0.025) and C (P < 0.01). Significantly higher level of sialyl Lewis A was shown in the group of metastases than that of non-metastases (P < 0.0068. Student's t-test). Paired elevation of E-selectin and sialyl Lewis A was significantly higher in the hematogenous metastases than non-metastases (P < 0.001, Fisher exact test). CONCLUSIONS: These results suggest that E-selectin could play some role in the progress of hematogenous metastases. The elevation of E-selectin alone or both E-selectin and sialyl Lewis A may be one of the useful indexes for more precise diagnosis of hematogenous metastases of human colorectal cancer.