Primary CD56+ NK/T-cell lymphoma of the rectum accompanied with refractory ulcerative colitis.

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.

Increased proliferation of middle to distal colonic cells during colorectal carcinogenesis in experimental murine ulcerative colitis.

Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. This association is widely attributed to colonic inflammation. However, the severity of colonic inflammation necessary for the development of dysplasia and/or cancer remains unknown. In this study, we investigated the pattern of cell proliferation in colorectal carcinogenesis in an experimental murine model of UC. Chronic colitis was induced by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% or 2% DSS for 7 days and then distilled water for 14 days). Mice were sacrificed after every cycle and at 120 days following the completion of the fourth cycle. Colonic cell proliferation was immunohistochemically evaluated using the thymidine analogue bromodeoxyuridine and the labeling index (LI) was determined. The incidence of dysplasia and/or cancer was 28%, 6.7%, and 0% in the 5% DSS, 2% DSS, and normal control groups respectively. All gross lesions were present in the middle to distal colon. Disease activity index and total LI after four cycles of DSS were significantly higher in the 5% DSS group compared to the 2% DSS group. In the 5% DSS group, the LI was significantly higher in the middle colon than in the proximal colon. Simple repeated administration of the non-genotoxic colon carcinogen DSS induced dysplasia and/or cancer. In addition, we have demonstrated the presence of regional differences in proliferation pattern between the middle and the proximal colon during carcinogenesis in experimental murine UC. These findings may provide insight into the development of colorectal cancer in humans with long-standing UC.

Epidermal growth factor receptor is a possible predictor of sensitivity to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma.

BACKGROUND: Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. METHODS: We reviewed 62 patients with T(3-4), N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. RESULTS: The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. CONCLUSION: Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.

Evaluation of prognostic factors of esophageal squamous cell carcinoma (stage II-III) after concurrent chemoradiotherapy using biopsy specimens.

BACKGROUND: Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. METHODS: The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. RESULTS: The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. CONCLUSIONS: PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT.

Evaluation of the effect of pyrrolidine dithiocarbamate in suppressing inflammation in mice with dextran sodium sulfate-induced colitis.

AIM: To evaluate the effect of pyrrolidine dithio-carbamate (PDTC; an NF-kappaB inhibitor) administered at low (50 mg/kg) and high (100 mg/kg) doses in suppressing colitis in mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice were divided into a DSS-untreated group (normal group), DSS-treated control group, DSS+PDTC-treated group I (low-dose group), and DSS+PDTC-treated group II (high-dose group). In each group, the disease activity index score (DAI score), intestinal length, histological score, and the levels of activated NF-kappaB and inflammatory cytokines (IL-1beta and TNF-alpha) in tissue were measured. RESULTS: The DSS+PDTC-treated group II exhibited suppression of shortening of intestinal length and reduction of DAI score. Activated NF-kappaB level and IL-1beta and TNF-alpha levels were significantly lower in DSS+PDTC-treated group II. CONCLUSION: These findings suggest that PDTC is useful for the treatment of ulcerative colitis.

HLA genotype and development of gastric cancer in patients with Helicobacter pylori infection.

BACKGROUND/AIMS: Helicobacter pylori (HP) infection is reported to be involved in gastric carcinogenesis. However, only a small percentage of HP-infected patients actually develop gastric cancer. In the present study, we assessed HLA antigen polymorphism and investigated its relationship with the development of gastric epithelial tumors in patients who had HP infection. METHODOLOGY: Among patients with serologically proven HP infection, 80 cases who underwent endoscopic mucosectomy for gastric epithelial tumors (24 adenomas and 56 carcinomas) were recruited in the study (the tumor group), and 20 cases without tumors were also included as controls (the nontumor group). HLA status (HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1) was determined by HLA-DNA typing. RESULTS: HLA-B*05401, HLA-DQB1*0601 and HLA-DRB1*1502 genes showed a significantly higher frequency in the control group than in the tumor group (0.225 vs. 0.088, P=0.015; 0.3 vs. 0.163, P = 0.047; 0.175 vs. 0.069, P = 0.036, respectively). CONCLUSIONS: It suggests that HLA-B*5401, HLA-DQB1*0601 and HLA-DRB1*1502 may contribute to the inhibition of gastric carcinogenesis. Thus, HP-infected patients without these genotypes should undergo HP eradication therapy and close follow-up.

How closely is Helicobacter pylori infection related to gastroduodenal lesions?

BACKGROUND/AIMS: Various studies have indicated a relationship between Helicobacter pylori infection and upper gastrointestinal lesions, but this relationship needs to be assessed in individuals not seeking medical treatment for complaints. METHODOLOGY: We screened community residents for H. pylori infection and upper gastrointestinal lesions during an annual mass health examination aiming to determine relationships between infection and lesions. In 932 examinees we performed a 13C-urea breath test for H. pylori infection, and assessed degree of gastric atrophy by measuring pepsinogen I and II in serum. In 738 subjects we also performed upper gastrointestinal radiography with or without endoscopy. RESULTS: Prevalence of H. pylori infection increased with age, and the ratio of serum pepsinogen I to II decreased with age. Prevalence of H. pylori infection did not differ significantly between subjects with and without radiographically or endoscopically evident lesions. Of H. pylori-positive subjects with peptic ulcer, 73.2% had no recurrence of ulcer despite absence of medical treatment. CONCLUSIONS: Prolonged H. pylori infection was associated with atrophy of the gastric mucosa, but little relationship was evident between H. pylori infection and development or recurrence of peptic ulcer.

Expression of gamma-aminobutyric acid and glutamic acid decarboxylases in rat descending colon and their relation to epithelial differentiation.

OBJECTIVE: To detect the expression of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylases (GADs; including two isoforms GAD65 and GAD67) in the epithelial growth zones of the descending colon in rats, and to investigate their relation to epithelial differentiation and proliferation. METHODS: The expression of GABA and GADs in rat descending colon was investigated by immunofluorescent staining and confocal laser scanning techniques, and goblet cells were further investigated by wheat-germ agglutinin histochemistry. In addition, GAD65 and GAD67 mRNAs were also detected by reverse transcription-polymerase chain reaction. Furthermore, evaluation of cell kinetics in colonic epithelia was conducted by ABC immunostaining using a monoclonal antibody against proliferating cell nuclear antigen (PCNA). RESULTS: Immunoreactive GABA and GADs were distributed in the upper third of the crypts and at the luminal surface in the rat descending colon. Strong staining for GABA and GADs was localized mainly in the cytoplasm of epithelial cells near the neck of the crypts and along the luminal surface. In addition, GABA and GAD65 were also detected at the lamina propria in colonic mucosa. No staining for GABA or GADs was found in goblet cells. GAD65 and GAD67 mRNAs were identified in homogenates of rat descending colon. PCNA labeled nuclei were found in the lower two-thirds of the crypts. CONCLUSIONS: The expression of GABA and GADs in the maturation and function zones of rat descending colon suggests that GABA may be involved in the differentiation of colonic epithelial cells.

[Principles of managing chemotherapy-induced nausea and vomiting].

Chemotherapy-induced nausea and vomiting (emesis) can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. For patients treated with emetogenic chemotherapy, it is very important to prevent nausea and vomiting completely. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by numerous factors, including: 1) the specific chemotherapeutic agents used; 2) their dosage; 3) the schedule and route of administration; and 4) individual patient variability. Approximately 70 to 80% of all cancer patients receiving chemotherapy experience emesis, whereas 10% to 44% experience anticipatory emesis. The following general principles are recommended. 1) A 5-HT3 receptor antagonist should be administered prior to each day's 1st dose of moderately or highly emetogenic chemotherapy. 2) Dexamethasone should be administered once daily either orally or intravenously for every day of moderately or highly-emetogenic chemotherapy and for 2-3 days after chemotherapy for regimens that are likely to cause significant delayed-emesis. 3) The most effective way to treat anticipatory nausea and/or vomiting is to prevent it by using optimal antiemetic therapy during every cycle of treatment.

[A case of gastric cancer with multiple liver metastases resistant to TS-1 responding to chemotherapy with paclitaxel plus doxifluridine].

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

[Weekly administration regimen of paclitaxel (PTX) in patient with inoperable or recurrent gastric cancer].

Paclitaxel is one of the new drugs against advanced/recurrent gastric cancer. We report its efficacy and toxicity with weekly administration for advanced/recurrent gastric cancer. We administered 26 patients (postoperative/non-operation=9/17) PTX 80 mg/m(2)by 1-hour intravenous infusion once a week for 3 weeks followed by one week rest. Median PTX administrations were 2.0 cycles (range:1-22). Characteristics of the patients were median age of 62 (range: 37-78) and PS 0/1/2:2/17/7, male/female:18/8. Over grade 3 toxicities did not occur. The overall response rate was 14.3%, and the non-PD rate was 66.8%. Median time to treatment failure was 61 days and median survival time was 221 days. These results suggest that weekly PTX has modest activity with a favorable toxicity profile in patients with advanced/recurrent gastric cancer, and so this regimen may thus might be recommended in an outpatient treatment setting.

Refractory ulcerative colitis accompanied with cytomegalovirus colitis and multiple liver abscesses: a case report.

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (UC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.

Gastric mucosal cell protection by epidermal growth factor in primary monolayer culture of guinea pig gastric mucous cells.

BACKGROUND: Epidermal growth factor (EGF) has an anti-ulcer effect, but the mechanisms of this gastric mucosal protection are incompletely understood. We have suggested the importance of mucin as a mucosal protectant. We investigated whether increased mucin biosynthesis might be involved in the gastric mucosal protection conferred by EGF. METHODS: EGF and then ethanol were added to primary monolayer cultures of guinea pig gastric mucous cells, in which factors such as gastric acid and gastrointestinal hormones were excluded. Mucin and prostaglandin E(2) (PGE(2)) were assayed. RESULTS: Cytoprotection induced by EGF was demonstrated. Mucin biosynthesis and PGE(2) release were both significantly increased by EGF. When endogenous PGE(2) synthesis was inhibited by pretreatment with 10(-5) M or 10(-4) M indomethacin (IND), mucin biosynthesis was still significantly increased by EGF. Ethanol-induced cell damage was concentration-dependent in cultures with no other additions (normal PGE(2) and mucin biosynthesis). Damage by ethanol was decreased by EGF pretreatment (increased PGE(2) and mucin biosynthesis). Damage by ethanol was increased by 10(-5) M IND pretreatment (decreased PGE(2); normal mucin biosynthesis) and by 10(-4) M IND pretreatment (decreased PGE(2) and mucin biosynthesis). Ethanol-induced damage was decreased by EGF pretreatment even in the presence of 10(-5) M and 10(-4) M IND (decreased PGE(2); increased mucin biosynthesis). CONCLUSIONS: Increased mucin biosynthesis, induced by EGF independently of PGE(2), protects gastric mucous cells.

Differences in endoscopic classification of early colorectal carcinoma between China and Japan: a comparative study.

AIM: To compare the differences in the endoscopic classification of early colorectal carcinoma (CRC) between Japan and China. METHODS: Ten cases of early CRC were included in the study. After reviewing the color pictures of these cases, 5 Japanese endoscopists and 5 Chinese endoscopists made their classificatory diagnosis individually using the current Japanese classification, and indicated their findings on which the diagnosis was based. RESULTS: Some lesions diagnosed by the Japanese endoscopists as IIa or IIa plus IIc, were classified as Is or Isp by the Chinese endoscopists. For superficial lesions consisting of elevation plus central depression, IIa plus depression, IIa plus IIc or IIc plus IIa were classified according to the ratio of elevated area/depressed area. However, international as well as interobserver difference still existed in the classification of such lesions. In addition, most Chinese endoscopists overlooked slightly depressed part on the top of a protruded lesion. Laterally spreading tumor, a special type of IIa, was identified as LST by some Japanese endoscopists. CONCLUSION: Discrepancies on macroscopic classification for early CRC do exist between Japanese and Chinese endoscopists, which are found not only in terminology but also in recognition of some lesions. In order to develop a universal classification, it needs for international communication and cooperation.

Inhibition of Helicobacter pylori infection by orally administered yolk-derived anti-Helicobacter pylori antibody.

BACKGROUND/AIMS: We studied highly specific chicken egg yolk-derived anti-Helicobacter pylori antibody, and examined efficacy in inducing passive immunity and a bacteriostatic effect on H. pylori. METHODOLOGY: Heat-killed H. pylori were administered orally to hens, and specific anti-H. pylori antibody was purified from the yolk of eggs laid by these hens. The antibody's ability to inhibit H. pylori growth, urease activity, ammonia production, the cytopathic effects, and its effects on serum anti-H. pylori immunoglobulin G (IgG) production were investigated in vitro and in vivo. In addition, H. pylori-infected volunteers received the antibody orally and underwent repeated 13C-urea breath test after antibody ingestion. RESULTS: Anti-H. pylori antibody derived from egg yolk strongly inhibited growth of H. pylori and increased agglutination of H. pylori in vitro. It also strongly inhibited H. pylori-associated urease activity and ammonia production as well as the cytopathic effect of H. pylori on cultured cells. The antibody also inhibited serum anti-H. pylori IgG production and the incidence of acute gastritis in H. pylori-infected Mongolian gerbils. In volunteers, urea breath testing showed decreased urease activity after antibody ingestion. CONCLUSIONS: Anti-H. pylori antibody derived from egg yolk was specific for H. pylori. The antibody had a bacteriostatic effect on H. pylori, inhibited H. pylori urease activity, and inhibited H. pylori infection in Mongolian gerbils and humans.

[A case of advanced gastric cancer with DIC treated by sequential MTX and 5-FU].

A 75-year-old man was admitted to our hospital complaining of gastric fatigue. Endoscope and CT scan revealed type 3 gastric cancer with paraaortic lymph nodal metastasis. Histological examination of the endoscopic biopsy revealed poorly differentiated adenocarcinoma. A blood examination and bone marrow biopsy revealed DIC causing bone marrow carcinosis. Chemotherapy with sequential therapy consisting of MTX and 5-FU was performed. Stretch of the fold and flatness of the ulcer were obtained against the gastric primary lesion observed endoscopically. Complete response was obtained against the lymph node around the abdominal aorta. Reduction of low back pain and DIC were observed. He was thus able to be discharged and sequential therapy was performed again over 2 months in outpatient care.

Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer.

PURPOSE: To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. MATERIALS AND METHODS: TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. RESULTS: In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. CONCLUSION: This study suggests that, via down-regulation of TS by irinotecan treatment, combination chemotherapy with S-1 and irinotecan could be effective in gastric cancer patients with high TS levels.