Inhibition of intestinal polyp growth by oral ingestion of bovine lactoferrin and immune cells in the large intestine.

Studies using animal models have demonstrated that ingestion of bovine lactoferrin (bLF) inhibits carcinogenesis in the colon and other organs of experimental animals. As a result of these studies, a blinded, randomized, controlled clinical trial was conducted in the National Cancer Center Hospital, Tokyo, Japan to determine whether ingestion of bLF had an effect on the growth of colorectal polyps in humans. Patients with colorectal polyps ≤5 mm diameter and likely to be adenomas ingested 0, 1.5, or 3.0 g bLF daily for 1 year. Ingestion of 3.0 g bLF suppressed the growth of colorectal polyps and increased the level of serum human lactoferrin in trial participants 63 years old or younger. The purpose of the present study was to investigate correlations between immune parameters and changes in polyp size. Trial participants with regressing polyps had increased NK cell activity, increased serum hLF levels (indicating increased neutrophil activity), and increased numbers of CD4+ cells in the polyps. These findings are consistent with a correlation between higher immune activity and suppression of colorectal polyps. In addition, participants with regressing polyps had lower numbers of PMNs and increased numbers of S100A8+ cells in the polyps, consistent with a correlation between lower inflammatory potential in the colon and suppression of colorectal polyps. Trial participants ingesting bLF had increased serum hLF levels, a possible increase in systemic NK cell activity, and increased numbers of CD4+ and CD161+ cells in the polyps. Taken together, our findings suggest that bLF suppressed colorectal polyps by enhancing immune responsiveness.

Cancer prevention by bovine lactoferrin: from animal studies to human trial.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and, despite improved colonoscopic screening, CRC is a leading cause of death from cancer. Administration of bovine lactoferrin (bLF) suppresses carcinogenesis in the colon and other organs of test animals, and recently it was shown that ingestion of bLF inhibits the growth of adenomatous polyps in human patients. Here we review work which established bLF as an anti-carcinogenic agent in laboratory animals and the results of a clinical trial which demonstrated that bLF can reduce the risk of colon carcinogenesis in humans.

Narrow-band imaging endoscopy with magnification is useful for detecting metachronous superficial pharyngeal cancer in patients with esophageal squamous cell carcinoma.

BACKGROUND AND AIMS: Head and neck cancers, especially pharyngeal cancers, as well as esophageal cancers frequently coexist either synchronously or metachronously, but most cases of pharyngeal cancer are detected at an advanced stage resulting in poor prognosis. The aim of this study is to evaluate the effectiveness of using narrow-band imaging (NBI) endoscopy with magnification for early detection of pharyngeal cancer on patients following their treatment for esophageal squamous cell carcinoma (SCC). METHODS: This case series was conducted at the National Cancer Center Hospital in Tokyo between April and October 2005 and included 424 consecutive patients for surveillance endoscopy who had previously undergone chemoradiotherapy (CRT) and/or surgery for esophageal SCC. Observation of the pharyngeal region was randomly conducted on 91 patients using NBI endoscopy with magnification (NBI group) and 333 patients using conventional white light endoscopy (control group). RESULTS: The detection rate for pharyngeal cancer was significantly higher using NBI endoscopy with magnification (10.9%; 10/91) compared with conventional endoscopy (1.2%; 4/333) (P < 0.0001). In particular, the detection rate in CRT patients was significantly higher in the NBI group (12.9%; 7/54) than the control group (0.5%; 1/191) (P < 0.0001). In addition, diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value for the NBI group were 100% (10/10), 97.5% (79/81), 97.8% (89/91), 83.3% (10/12) and 100% (79/79), respectively. CONCLUSION: NBI endoscopy with magnification is a promising technique for detecting superficial pharyngeal cancer at an early stage in patients previously treated for esophageal SCC.

Lymph node staging in esophageal squamous cell carcinoma: a comparative study of endoscopic ultrasonography versus computed tomography.

BACKGROUND AND AIM: Endoscopic ultrasonography (EUS) is established as a standard approach for locoregional staging of esophageal cancer. However, only a few published studies have attempted to correlate the station of the abnormal lymph nodes detected by EUS with the definitive histology. We compared EUS and computed tomography (CT) in the initial staging of esophageal squamous cell carcinoma. METHODS: Consecutive patients with esophageal cancer undergoing EUS were evaluated. EUS findings and patient data including histopatology were collected prospectively and analyzed retrospectively. Lymph node locations were divided into three groups; abdominal (A), paraesophageal (B), and thoracic paratracheal (C). RESULTS: A total of 365 consecutive patients underwent EUS and 159 patients underwent esophagectomy without neoadjuvant chemotherapy. Thirty-eight patients were excluded (insufficient EUS, etc.), and 121 patients were enrolled. The overall accuracy of EUS was 64% (sensitivity 68%, specificity 58%, positive predictive value [PPV] 68%), CT was 51% (sensitivity 33%, specificity 75%, PPV 64%), and CT + EUS was 64% (sensitivity 74%, specificity 50%, PPV 66%). The accuracy of EUS was higher than CT in Groups A and C. Sensitivity of CT was lower than that of EUS alone and CT + EUS. CONCLUSIONS: This study has demonstrated that EUS is a more accurate technique than contrast-enhanced CT for detecting abnormal lymph nodes. Sensitivity of CT was lower than that of EUS alone and CT + EUS. But some metastatic lymph nodes in neck and abdominal fields are only detectable by CT. Therefore, both EUS and CT should be undertaken for routine examination prior to treatment of esophageal cancer.

Effect of orally administered bovine lactoferrin on the growth of adenomatous colorectal polyps in a randomized, placebo-controlled clinical trial.

Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps

Usefulness and safety of 0.4% sodium hyaluronate solution as a submucosal fluid "cushion" for endoscopic resection of colorectal mucosal neoplasms: a prospective multi-center open-label trial.

BACKGROUND: Sodium hyaluronate (SH) solution has been used for submucosal injection in endoscopic resection to create a long-lasting submucosal fluid "cushion". Recently, we proved the usefulness and safety of 0.4% SH solution in endoscopic resection for gastric mucosal tumors. To evaluate the usefulness of 0.4% SH as a submucosal injection solution for colorectal endoscopic resection, we conducted an open-label clinical trial on six referral hospitals in Japan. METHODS: A prospective multi-center open-label study was designed. A total of 41 patients with 5-20 mm neoplastic lesions localized in the colorectal mucosa at six referral hospitals in Japan in a single year period from December 2002 to November 2003 were enrolled and underwent endoscopic resection with SH. The usefulness of 0.4% SH was assessed by the en bloc complete resection and the formation and maintenance of mucosal lesion-lifting during endoscopic resection. Safety was evaluated by analyzing adverse events during the study period. RESULTS: The usefulness rate was high (82.5%; 33/40). The following secondary outcome measures were noted: 1) steepness of mucosal lesion-lifting, 75.0% (30/40); 2) intraoperative complications, 10.0% (4/40); 3) time required for mucosal resection, 6.7 min; 4) volume of submucosal injection, 6.8 mL and 5) ease of mucosal resection, 87.5% (35/40). Two adverse events of bleeding potentially related to 0.4% SH were reported. CONCLUSION: Using 0.4% SH solution enabled sufficient lifting of a colorectal intramucosal lesion during endoscopic resection, reducing the need for additional injections and the risk of perforation. Therefore, 0.4% SH may contribute to the reduction of complications and serve as a promising submucosal injection solution due to its potentially superior safety in comparison to normal saline solution.

Detection of colorectal cancer cells from feces using quantitative real-time RT-PCR for colorectal cancer diagnosis.

Early detection of colorectal cancer (CRC) is desired for reducing its mortality rate. Recently, the feasibility of a new method for isolating colonocytes from feces was demonstrated, followed by direct sequencing analysis for detecting colorectal cancer. In the present study, gene expression analysis was conducted using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). One hundred and sixty-six patients with CRC and 134 healthy volunteers were enrolled. Messenger RNA expressions of CEA, MMP7, MYBL2, PTGS2 and TP53 in the colonocytes isolated from feces were analyzed by quantitative real-time RT-PCR. Beta-2-microglobulin, used for internal control, could not be detected in approximately 25% each of the CRC patients (39/166) and healthy volunteers (33/134). CEA expression did not differ significantly between CRC patients and healthy volunteers (P = 0.21). MMP7, MYBL2, PTGS2 and TP53 gene expressions were significantly higher in CRC patients than in healthy volunteers (P < 0.001). The overall sensitivity and specificity using these gene expressions were 58.3% (74/127, 95% CI; 49.2-67.0) and 88.1% (89/101, 95% CI; 80.2-93.7), respectively. The sensitivity was dependent on the tumor location (P = 0.01) and tumor size (P = 0.02), but not the tumor depth (P = 0.06) or cancer stage (P = 0.37). Gene expression analysis of colonocytes isolated from feces may be a useful method for CRC screening, if the number of isolated colonocytes is sufficiently high for analysis by quantitative real-time PCR. Therefore, improvement of the colonocyte retrieval system from feces may be necessary for the technique to be developed for clinical use.

Endoscopic submucosal resection with a ligation device is an effective and safe treatment for carcinoid tumors in the lower rectum.

BACKGROUND AND AIMS: Various methods for complete endoscopic resection of rectal carcinoid tumors have been reported; however, the number of cases investigated in each study has been limited. The aim of the present study was to clarify the clinical usefulness of a novel technique named endoscopic submucosal resection with a ligation device (ESMR-L) in a large number of rectal carcinoid tumors. PATIENTS AND METHODS: Between January 1999 and March 2005, a total of 61 patients with 63 rectal carcinoid tumors estimated at 10 mm or less in diameter, without atypical features and resected by ESMR-L were recruited for this analysis. The complete resection rate, complications associated with the procedure, local recurrence, and distant metastases were evaluated. RESULTS: Sixty-one patients were 36 males and 25 females with a mean age of 59 +/- 11 years (24-76 years). Tumor size ranged from 2 to 12 mm in diameter, with an average size of 6.4 +/- 2.4 mm. Fifty-nine lesions (93.6%) were located in the lower rectum (Rb), three in the upper rectum (Ra) and one in the recto-sigmoid colon (Rs). In total, 60 out of 63 lesions (95.2%) were histologically determined to be completely resected. The complete resection rate for lesions located in the Rb was 98.3%, which was significantly higher than that for lesions in Ra and Rs (50%). Minor bleeding associated with the procedure occurred in five lesions (7.9%), but all cases were successfully managed with hemoclips. Histopathologically, all tumors were located in the submucosal layer, and all were classified as classical-type carcinoids without lymphovascular invasion. Neither local recurrence nor distant metastasis was detected during a median follow-up period of 24 months. CONCLUSION: In a large number of cases, ESMR-L proved to be a useful and safe procedure to resect rectal carcinoid tumors 10 mm or less in diameter, especially for those located in the Rb.

A pilot study to assess the safety and efficacy of carbon dioxide insufflation during colorectal endoscopic submucosal dissection with the patient under conscious sedation.

BACKGROUND: Endoscopic submucosal dissection (ESD) is accepted as one of the treatments for en bloc resection of large superficial colorectal lesions. This procedure is performed by using air insufflation, is time consuming, and is associated with severe abdominal discomfort. The safety and efficacy of carbon dioxide (CO(2)) insufflation during colonoscopy already has been assessed in some trials. OBJECTIVE: To assess the safety and efficacy of CO(2) insufflation instead of air insufflation during colorectal ESD with the patient under conscious sedation. DESIGN: A case-control series with a historical control. PATIENTS: A total of 35 consecutive patients were enrolled in this study. Another 35 consecutive patients who previously received colorectal ESDs by using air insufflation were included as a historical control. INTERVENTIONS: Arterial partial pressure of CO(2) (pCO(2)) was measured before and after each procedure with the total dose of midazolam used as an index of abdominal discomfort. MAIN OUTCOME MEASUREMENTS AND RESULTS: The mean (standard deviation [SD]) operation time was 90 +/- 57 minutes in the CO(2) group and 100 +/- 80 minutes in the control group (not significant). In the CO(2) group, the mean (SD) dose of midazolam was significantly lower than that of the control group; 5.6 +/- 4.9 mg and 9.7 +/- 5.9 mg, respectively (P = .005). Blood analysis revealed a slight pCO(2) elevation in the CO(2) group; however, only 2 patients complained of mild abdominal discomfort. LIMITATIONS: Abdominal discomfort and pCO(2) were not evaluated in the control group. CONCLUSIONS: This study strongly suggests that CO(2) insufflation is safe and effective during lengthy colonic endoscopic procedures, eg, ESD, with the patient under conscious sedation.

Serum triglycerides and colorectal adenoma in a case-control study among cancer screening examinees (Japan).

OBJECTIVE: Most epidemiologic studies have shown serum triglycerides to be associated with colorectal adenoma. However, whether the association can be modified by smoking is unknown. We cross-sectionally investigated the association of serum triglycerides with the risk of adenoma by smoking status. METHODS: We identified 782 newly diagnosed adenoma cases from the examinees of a colorectal cancer screening program. All cases were diagnosed by a magnifying colonoscopy with dye spreading. We determined 738 controls without present illness or past history of adenoma from among the examinees. They provided their lifestyle information and fasting blood samples to measure their serum triglycerides. We calculated odds ratios (OR) and 95% confidence intervals (CI) of colorectal adenoma for serum triglycerides. RESULTS: High serum triglycerides were associated with colorectal adenoma (OR 1.5; 95% CI 1.1-2.0 for the highest versus the lowest quartile, P (trend, )0.030). A stronger association was observed between three or more adenoma cases and study controls (OR 2.3; 95% CI 1.3-4.2, P (trend,) < 0.0010). After classifying the study subjects by smoking status, a significant linear risk trend was found in ever-smokers (P (trend), 0.0018) but not in never-smokers (P (trend), 0.94; P (interaction), 0.067). CONCLUSIONS: Our results suggested that a higher serum triglyceride level may be related to a larger number of adenomas. Adenoma development involving an elevated serum triglyceride level may be modified by smoking.

Detection and treatment of early cancer in high-risk populations.

In this paper we describe how to more efficiently detect and treat early gastric cancer (EGC) in high-risk populations. For detection, we first assess the value of known risk factors from the viewpoint of availability for cancer screening. Serum pepsinogen appears to be the most useful and realistic of the factors examined, although its adequacy needs to be assessed in high-risk populations other than those in Japan. Helicobacter pylori infection is known to be a universal risk factor (or gastric carcinogen), and several interventional studies have recently shown positive results. However, H. pylori infection can be eradicated from at-risk populations, thereby decreasing its availability for cancer screening. Smokers are thought to be at risk epidemiologically, but the efficacy of screening in this population has yet to be elucidated, and further studies are warranted. Gender and aging can be risk factors in Japanese populations; male gender and old age are predominant in the intestinal type of carcinoma which is dominant in Japan, although this is not the case in the West. As for early diagnosis of cancer, only endoscopy can be commonly used for the detection of gastritis-like EGC, seen as a faint mucosal irregularity or discoloration. To make early diagnosis more accurate, it is indispensable to carry out detailed endoscopy together with careful scrutiny of the mucosa using dye-spraying techniques. The remarkable progress of early diagnosis in Japan prompted the endoscopic treatment for less invasive EGCs. The first success was with endoscopic mucosal resection (EMR). Although convenient, its therapeutic efficacy is inadequate, particularly for larger lesions. Endoscopic submucosal dissection (ESD) has no limitation on resection size and is expected to replace surgery, although it needs a high level of skill and there are several technical problems to be solved.

A new method for isolating colonocytes from naturally evacuated feces and its clinical application to colorectal cancer diagnosis.

BACKGROUND & AIMS: The early detection of colorectal cancer is desired because this cancer can be cured surgically if diagnosed early. The purpose of the present study was to determine the feasibility of a new methodology for isolating colonocytes from naturally evacuated feces, followed by cytology or molecular biology of the colonocytes to detect colorectal cancer originating from any part of the colorectum. METHODS: Several simulation studies were conducted to establish the optimal methods for retrieving colonocytes from any portion of feces. Colonocytes exfoliated into feces, which had been retrieved from 116 patients with colorectal cancer and 83 healthy volunteers, were analyzed. Part of the exfoliated colonocytes was examined cytologically, whereas the remainder was subjected to DNA analysis. The extracted DNA was examined for mutations of the APC, K-ras, and p53 genes using direct sequence analysis and was also subjected to microsatellite instability (MSI) analysis. RESULTS: In the DNA analysis, the overall sensitivity and specificity were 71% (82 of 116) of patients with colorectal cancer and 88% (73 of 83) of healthy volunteers. The sensitivity for Dukes A and B was 72% (44 of 61). Furthermore, the sensitivity for cancers on the right side of the colon was 57% (20 of 35). The detection rate for genetic alterations using our methodology was 86% (80 of 93) when the analysis was limited to cases in which genetic alterations were present in the cancer tissue. CONCLUSIONS: We have developed a new methodology for isolating colonocytes from feces. The present study describes a promising procedure for future clinical evaluations and the early detection of colorectal cancers, including right-side colon cancer.

Percutaneous traction-assisted EMR by using an insulation-tipped electrosurgical knife for early stage gastric cancer.

BACKGROUND: EMR now is accepted as a minimally invasive treatment for early stage gastric cancer. However, the endoscopic approach sometimes is limited by the size and location of the tumor. The technique and early results of percutaneous, traction-assisted EMR for resection of larger early stage gastric cancers is described. METHODS: EMR, by using an insulation-tipped electrosurgical knife, was performed with the simultaneous assistance of laparoscopy devices. A small snare was introduced into the gastric lumen through a gastric port (2-mm diameter) to grasp and pull the EGC away from the muscularis propria to facilitate resection. RESULTS: The technique was performed successfully in our endoscopic suite in the first patient under general anesthesia and the remaining seven under conscious sedation. Tumors situated in any part of the stomach could be reached with percutaneous assistance, and this facilitated en bloc resection of large specimens (mean size 50 mm). The procedure was performed in about 60 minutes. Seven patients (88%) resumed eating 1 or 2 days after surgery. All patients were discharged after 1 week without complication. CONCLUSIONS: Percutaneous, traction-assisted EMR is useful for resection of large lesions en bloc and can be performed easily and safely under direct vision.