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Supplementary Table & Figure from An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis

Supplementary Table 2 from Dietary Induction of Colonic Tumors in a Mouse Model of Sporadic Colon Cancer

Mutations in the human DNA mismatch repair gene MSH2 are associated with hereditary nonpolyposis colorectal cancer as well as a significant proportion of sporadic colorectal cancer. The inactivation of MSH2 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of chemotherapeutic agents. Here we show that the DNA repair and DNA damage-induced apoptosis functions of Msh2 can be uncoupled using mice that carry the G674A missense mutation in the conserved ATPase domain. As a consequence, although Msh2G674A homozygous mutant mice are highly tumor prone, the onset of tumorigenesis is delayed as compared with Msh2-null mice. In addition, tumors that carry the mutant allele remain responsive to treatment with a chemotherapeutic agent. Our results indicate that Msh2-mediated apoptosis is an important component of tumor suppression and that certain MSH2 missense mutations can cause mismatch repair deficiency while retaining the signaling functions that confer sensitivity to chemotherapeutic agents.

Supplementary Table 1 from Dietary Induction of Colonic Tumors in a Mouse Model of Sporadic Colon Cancer

Purpose The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). Methods This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1–3); 1-day ART (ART-123: day 1, placebo: days 2–3); and 3-day ART (ART-123: days 1–3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. Results Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI −.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: −23.5 [95% CI −48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: −18.5 [95% CI −44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. Conclusion ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016

Introduction and importance The standard treatment for locally advanced colon cancer (LACC) without distant metastasis is curative surgery followed by adjuvant chemotherapy, but the long-term outcomes of this strategy are not satisfactory. Neoadjuvant chemotherapy (NAC) is a promising novel option to overcome this issue. Tumor regression is an expected effect of NAC for LACC, but pathological complete response (pCR) is rare. In this report, we present a rare case of pCR after NAC with FOLFOX for LACC in the sigmoid colon. Presentation of case A 66-year-old woman presented to our hospital with fever and abdominal pain. The diagnosis was LACC in the sigmoid colon with possible invasion of the uterus and pelvic wall, stage IIIC (T4bN1bM0). Furthermore, the tumor was complicated by diverticulitis. A colostomy was performed, followed by NAC with FOLFOX. Six cycles were completed without significant adverse events, and the lesion shrunk remarkably. We performed a curative sigmoidectomy without any postoperative complications. Pathological examination revealed no viable cancer cells, indicating pCR. Discussion To the best of our knowledge, this is the first report of pCR after NAC for LACC complicated by diverticulitis. Colostomy before NAC, regimen, and cycle of NAC may be the key to this favorable course. Conclusion We present a rare case of pathological complete after neoadjuvant chemotherapy with FOLFOX for locally advanced colon cancer in the sigmoid colon complicated by diverticulitis. Our experience may be valuable in determining the optimal treatment strategy for LACC complicated by diverticulitis., Highlights • Neoadjuvant chemotherapy is a promising novel option for locally advanced colon cancer. • Pathological complete response is rare. • Indications for cases complicated with diverticulitis are unknown. • We present a rare case of pCR after NAC for LACC complicated by diverticulitis.

The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN).This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators.Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred.ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.

Background and Aim Helicobacter pylori (H. pylori) infection is a strong risk factor for the development of gastric cancer. In 2013, the Japanese government approved H. pylori eradication therapy in patients with chronic gastritis as well as peptic ulcer. However, the continuing decline in eradication rates for first-line H. pylori eradication therapies is an urgent problem. In this study, we investigated changes in the first-line eradication rate from 2001 to 2010. Methods Eradication rates for 7-day triple therapy [proton pump inhibitor (rabeprazole 20 mg, lansoprazole 60 mg, or omeprazole 40 mg) + amoxicillin 1500 mg + clarithromycin (CAM) 400 or 800 mg, daily] were collated from 14 hospitals in the Tokyo metropolitan area. The urea breath test was used for the evaluation of eradication. The cut-off value was less than 2.5%. Results The yearly eradication rates (intention to treat/per protocol) were 78.5/79.5% (2001, n = 242), 71.2%/72.9% (2002, n = 208), 67.8%/70.5% (2003, n = 183), 75.6%/84.6% (2004, n = 131), 56.4%/70.5% (2005, n = 114), 70.5%/75.8% (2006, n = 271), 67.4%/82.0% (2007,n = 135), 64.0%/76.3% (2008, n = 261), 60.5%/74.3% (2009, n = 329), and 66.5%/78.8% (2010, n = 370), respectively. Examination of eradication rates according to CAM dosage revealed an eradication rate of 65.6% (383/584) for CAM 400 mg daily, and 68.5% (1124/1642) for CAM 800 mg daily, with no significant difference seen between dosages. Conclusion In recent years, eradication rates for first-line triple therapy have obviously decreased, but no noticeable decrease has occurred after 2001.

The reported patient was a 90-year-old woman with anorexia. She was diagnosed with advanced gallbladder cancer that occurred concurrently with stomach cancer. Subsequent to intestinal bypass surgery, S-1(80mg/day)was administered for 14 days, followed by 7 days of rest for one course. Tumor marker levels returned to normal after 4 months. Computed tomography results indicated that, in regard to the gallbladder cancer, the patient had stable disease after 8 months. In addition, gastroscopy revealed a complete response of the gastric cancer after a year. The patient was able to continue treatment as an outpatient until she experienced aspiration pneumonia. The administration of S-1 was terminated after 4 years and 4 months. Treatment with S-1 monotherapy is considered safe for elderly patients, and has the additional benefit that it is deliverable as an outpatient treatment.

Background: The environment surrounding Helicobacter pylori eradication treatment is dramatically changing. Recently, vonoprazan, a first-in-class potassium-competitive acid blocker (P-CAB), was introduced onto the market in 2015. The aging of Japan’s demographic structure is becoming pronounced. In this study, we examined the trend of the eradication rate of H. pylori in the metropolitan area and examined factors concerning successful eradication. Methods: We collected data from 20 hospitals in the Tokyo metropolitan area on patients who received first-line eradication therapy with a proton-pump inhibitor (PPI)/P-CAB, amoxicillin, and clarithromycin for 1 week and second-line eradication therapy with a PPI/P-CAB, amoxicillin, and metronidazole for 1 week from 2013 to 2018. The annual eradication rate and associated factors for successful eradication were analyzed. Results: We collected data of 4097 and 3572 patients in the first- and second-line eradication therapies, respectively. The eradication rate decreased from 2013 to 2014 and increased again from 2015 to 2018 with the first-line therapy [the eradication rates in 2013, 2014, 2015, 2016, 2017 and 2018 were 71.8%, 63.7%, 78.5%, 84.6%, 89.7 and 90.1%, respectively, in the per protocol (PP)]. The second-line eradication rates were 90.0%, 82.6%, 88.8%, 87.5%, 91.8% and 90.1% in 2013, 2014, 2015, 2016, 2017 and 2018, respectively, in PP. Vonoprazan was an independent factor for successful eradication in not only first-line, but also second-line eradication. Age over 75 years was an independent factor for eradication failure in both first- and second-line eradication therapies. Conclusion: The eradication rate improved from 2015 to 2018 with the first-line therapy because of the introduction of vonoprazan in the market. The eradication rates with first- and second-line regimens in elderly patients were lower than those in younger patients.

Background In Japan, the eradication rate of first-line therapy for Helicobacter pylori (H. pylori) with a proton pump inhibitor (PPI), amoxicillin (AMPC) and clarithromycin (CAM) has been decreasing because of a high prevalence of CAM resistance. A possible decrease of the eradication rate for second-line therapy with a PPI, AMPC and metronidazole (MNZ) is of concern. The aim of this study is to assess the trends in second-line eradication therapy for H. pylori in Japan. Materials and Methods We accumulated data retrospectively on patients administered second-line eradication therapy for Helicobacter pylori with a PPI, AMPC, and MNZ for 1 week after failure of first-line eradication therapy with a PPI, AMPC and CAM at 15 facilities in the Tokyo metropolitan area in Japan from 2007 to 2011. Trends for second-line eradication rates in modified intention-to-treat (ITT) analyses were investigated. Second-line eradication rates were categorized by three PPIs (rabeprazole (RPZ), lansoprazole (LPZ) or omeprazole (OMZ)) and evaluated. Results We accumulated data on 1373 patients. The overall second-line eradication rate was 92.4%. Second-line eradication rates in 2007, 2008, 2009, 2010 and 2011 were 97.7, 90.6, 94.5, 91.8 and 91.8%, respectively, with no significant trends revealed. Second-line eradication rates categorized by three PPIs for the entire 5-year period were 91.6, 93.4 and 92.4% (RPZ, LPZ and OPZ, respectively) with no significant differences among the three PPIs. Conclusions From 2007 to 2011, there were no significant trends in the second-line eradication rates and the rates remained consistently high. From the viewpoint of high prevalence of CAM resistance in Japan, triple therapy with PPI, AMPC and MNZ may be a better strategy for first-line therapy compared to triple therapy with PPI, AMPC and CAM.

Few cases of gastric carcinoma with infiltrating multi-nucleated giant cells (MGCs) have been reported, and giant cells infiltrating the gastric carcinoma were previously described as osteoclast-like giant cells (OGCs). However, hepatoid adenocarcinomas have never been reported previously, and the present case is extremely rare. A 100-year-old Japanese man with gastralgia was found to have a mass in his gastric body. Histological examination showed a poorly differentiated adenocarcinoma with infiltration of MGCs. Vascular and lymphatic invasion were noted but there were no metastases. Almost all the tumor comprised cells with hepatoid-like features. The MGCs proliferated, with infiltration of lymphoid cells. A few MGCs contained mucous material in their cytoplasm, indicating these were foreign-body giant cells. Immunohistochemically, the hepatoid-like components were positive for AFP, and staining with polyclonal antibodies against carcinoembryonic antigen (CEA) showed the canalicular pattern. We concluded that this component was hepatoid adenocarcinoma. The MGCs were positive for CD68, and surrounding infiltrating lymphoid cells were diffusely positive for CD3. Infiltration of MGCs in gastric cancer may represent a cellular immune response against gastric cancer invasion. Further studies are required to elucidate the etiology of MGCs in gastric cancer.

We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of Apc(Min/+) mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc(1638N/+) mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1(+/-) mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1(+/-)Apc(1638N/+) mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc(1638N/+) mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1(+/-)Apc(1638N/+) mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc(1638N/+) mice, but it increased inflammation in the small intestine of Mlh1(+/-) mice and Mlh1(+/-)Apc(1638N/+) mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.

A defined rodent “new Western diet” (NWD), which recapitulates intake levels of nutrients that are major dietary risk factors for human colon cancer, induced colonic tumors when fed to wild-type C57Bl/6 mice for 1.5 to 2 years from age 6 weeks (two-thirds of their life span). Colonic tumors were prevented by elevating dietary calcium and vitamin D3 to levels comparable with upper levels consumed by humans, but tumorigenesis was not altered by similarly increasing folate, choline, methionine, or fiber, each of which was also at the lower levels in the NWD that are associated with risk for colon cancer. The NWD significantly altered profiles of gene expression in the flat colonic mucosa that exhibited heterogeneity among the mice, but unsupervised clustering of the data and novel statistical analyses showed reprogramming of colonic epithelial cells in the flat mucosa by the NWD was similar to that initiated by inheritance of a mutant Apc allele. The NWD also caused general down-regulation of genes encoding enzymes involved in lipid metabolism and the tricarboxylic acid cycle in colonic epithelial cells before tumor formation, which was prevented by the supplementation of the NWD with calcium and vitamin D3 that prevented colon tumor development, demonstrating profound interaction among nutrients. This mouse model of dietary induction of colon cancer recapitulates levels and length of exposure to nutrients linked to relative risk for human sporadic colon cancer, which represents the etiology of >90% of colon cancer in the United States and other Western countries. [Cancer Res 2008;68(19):7803–10]

Summary Background Endoscopic classifications were reported to reflect the pathophysiology of gastric mucosa. However, relationship between gastric lesions and classifications has not been examined well. Aim To investigate the relationship between endoscopic classifications and cancers or ulcers. Methods In this study, 487 patients undergoing upper gastrointestinal endoscopy in Takahashi Clinic and 257 patients with early gastric cancer in Keio University Hospital were enrolled. Results Incidence of reflux oesophagitis was higher in Helicobacter pylori-negative patients. K-form was better in the H. pylori-positive patients. Most cancers in the patients with the closed-type or reflux oesophagitis were of undifferentiated types. Incidences of ulcers were highest in C-2 and C-3 in which the borders of atrophy cross the medial oblique muscle bundle, the border circular muscle bundle or both, and 94% of ulcers in C-2 and C-3 stomach were located along the lesser curvature. Conclusion The predominant existence of undifferentiated types in patients with reflux oesophagitis or closed-type stomach can be useful information for early diagnosis of cancers. The relationship between the Kimura–Takemoto classification and ulcer location may explain why H. pylori infection is related to ulcer formation along the lesser curvature.

Cronkhite-Canada syndrome is generally accepted to be a benign disorder, with 374 reported cases to the present. Worldwide, there have been 18 previously reported cases of Cronkhite-Canada syndrome associated with gastric cancer. In this report we describe a case of a 52-year-old man with the clinical features of Cronkhite-Canada syndrome combined with gastric cancer. Although the gastric tumor was located at the antrum of the stomach, we performed a total gastrectomy because of the edematous swelling and high risk of malignancy in the remnant stomach. As Cronkhite-Canada syndrome may be a premalignant condition for gastric cancer, as well as for colorectal cancer, we suggest periodic examination of the stomach, colon, and rectum for patients with Cronkhite-Canada syndrome.

Summary Background: Matrix metalloproteinases (MMPs), enzymes capable of degrading collagens and other extracellular matrix components, have been implicated in gastric ulcer formation. However, the effect on MMP expression of Helicobacter pylori, also implicated in these lesions, has not been studied to our knowledge. Aim: To seek links between H. pylori and MMP expression likely to affect gastric ulcer formation. After fibroblasts from human gastric wall were cocultured with H. pylori, concentrations of MMP-1 and -2 in the medium were determined by enzyme-linked immuno-sorbent assays. Results: Whereas MMP-1 was not detected in media from fibroblasts or H. pylori culture alone, MMP-1 was detected in cocultures (P

Background A clinicopathological study of early gastric cancer with submucosal invasion was carried out in relation to lymph node metastasis. Methods A retrospective study was conducted of 245 patients with submucosal gastric cancer treated by gastrectomy combined with D2 lymph node resection between 1985 and 1994 in a university hospital. Results Lymph node metastasis was observed in 34 patients (14 per cent). The mortality rate due to recurrence in patients with lymph node metastasis (three of 34) was significantly higher than in those without lymph node metastasis (five (2 per cent) of 211) (χ2 = 3·95, 1 d.f., P < 0·05). Tumour size, depth of invasion, lymphatic involvement of cancer cells and preoperative diagnosis of advanced cancer correlated significantly with the presence of lymph node metastasis. When the submucosal carcinomas were classified into three categories according to depth of invasion by dividing the submucosal (sm) layer into three equal parts, sm1, sm2 and sm3, the incidence of lymph node metastasis increased from 2 per cent to 12 and 20 per cent respectively. Conclusion When the pathological report reveals sm1 invasion after laparoscopic or endoscopic surgery, reoperation should not be necessary because sm1-carcinomas with diameters of less than 2 cm do not usually metastasize to the lymph nodes.

Undiferentiated carcinoma of the anal canal is rare. We report a case of extramucosal carcinoma of the anal canal in which pre-and post-operative diagnosis was difficult. An 81-year-old male was admitted with a complaint of constipation. Digital examination of the anal canal and rectum reveaeld annular stricture 5cm above the anal verge caused by an immobile hard mass. Colonoscopy showed annular stenosis between 3 and 6cm above the anal verge but no mucosal abnormalities. Endoscopic mucosal resection and peranal needle biopsy did not allows pathological diagnosis. After obtaining the patient's informed consent, abdominoperianal rectal excision was performed on suspicion of extramucosal anal cancer or malignant submucosal tumor. Microscopic examination of the resected specimen showed that undifferentiated tumor cells had spread in an annular extraluminal fashion around the anal canal and the lower rectum and infiltrated the external sphincter muscle in the anal canal. The tumor cells were demonstrated to express cytokeratin and epithelial membrane antigen by immunohistochemical staining. Based on these findings, a diagnosis of extramucosal undifferentiated carcinoma of the anal canal was made.

Adhesion of Helicobacter pylori to both human gastric carcinoma cell lines (MKN45, MKN28 and KATO III) and prepared primary human gastric epithelial cells were analyzed with flow-cytometry. All strains adhered to human gastric carcinoma cells. Especially, these strains strongly adhered to MKN45 cells. Adhesion of H. pylori strains to prepared primary human gastric epithelial cells was also observed. However, the adherence rates of H. pylori to these cells were different among the cells used. These results suggested that the host factor might be important for adhesion of the bacteria to human gasgric cells. In addition, H20 monoclonal antibody directed to H. pylori HSP60 inhibited the adhesion of H. pylori to both cells. These results indicate that H. pylori HSP60 might be associated with the adhesion of the bacteria to human gastric epithelial cells.

We encountered a case of pheochromocytoma as a complication of total heterotaxia in a 49-year-old female. The patient was hospitalized because of a chief complaint of nausea and headache. Significant fluctuations in blood pressure were observed. A chest x-ray revealed dextrocardia. Abdominal ultrasonography and computed tomography showed total heterotaxia and a right adrenal tumor about 6cm in size. MIBG scintigraphy revealed abdominal acumulation was observed in the region that coincided with the right adrenal gland, and urinary catecholamine levels were high. Based on the above findings, the case was diagnosed as right adrenal pheochromocytoma and total heterotaxia, and the right adrenal gland was excised. The surgical findings revealed that the intra-abdominal organs were a mirror-image of the normal arrangement because of the total heterotaxia. A tumor 6cm in size was observed in the right adrenal grand, and the excised specimen weighed 116.45g. As there have been no reports of cases of pheochromocytoma with total heterotaxia, and our case is the first one of this type, we report the case.

A previous study reported a relationship between the expression of heat-shock protein 60 (HSP60) by Helicobacter pylori and its adhesion to human gastric carcinoma (MKN45) cells. To examine whether the HSP60 homologue of H. pylori is associated with the adhesion of H. pylori to human gastric epithelial cells, an inhibition assay of adhesion of H. pylori to MKN45 cells was performed by flow cytometric analysis with monoclonal antibody (MAb) designated as H20 recognising HSP60 of H. pylori. The rate of adhesion of H. pylori pretreated with MAbH20 to MKN45 cells was lower than that of untreated H. pylori. Primary human gastric epithelial cells from a patient with gastric cancer were also prepared for comparison in the inhibition assay with MAbH20. H. pylori adhered to the primary human gastric epithelial cells, and this adhesion was significantly inhibited by MAbH20. These results suggest that the H. pylori HSP60 homologue recognised by MAbH20 might be associated with the adhesion of H. pylori to primary human gastric epithelial cells as well as to cultured gastric cancer cells.

症例は42歳の女性. 主訴は上腹部不快感. 1983年 (30歳時) S状結腸癌にてS状結腸切除術, 1989年 (36歳時) 上行結腸癌にて右半結腸切除術施行. 今回, 1995年9月28日に胃癌にて胃全摘術, 脾合併切除, Roux-en Yにて再建した. 切除胃は進行胃癌2病変と早期胃癌5病変を有する多発胃癌であった. 胃癌病巣の各種癌関連抗原の発現はp53, Ki-67は陽性, c-erbB-2, bcl-2は陰性であった. 背景胃粘膜は幽門部を中心とした腸上皮化生を伴う慢性胃炎であり, 胃内に広範囲にヘリコバクター・ピロリ感染が認められた.本症例は異時性多発大腸癌の根治術後に発症した同時性多発胃癌であり, 多発大腸癌と多発胃癌が重複した報告例は自験例のみであった. 多発癌フォローアップのためのhigh risk groupの設定が重要であると考えられた.

A pharmacokinetic analysis of cis-diamminedichloroplatinum (II) (DDP) was conducted comparing low-dose daily bolus infusions, and high-dose drip infusions. Eight patients with gastric cancer were treated with low-dose daily bolus infusions of DDP to a total daily dose of 75 mg/m2 bid for 5 days. Four patients with esophageal cancer and one patient with gastric cancer were treated with high-dose drip infusions of DDP to a total daily dose of 70-80 mg/m2. Side effects were assessed in all the patients, and the platinum concentration in plasma was determined by an atomic absorption method. The peak plasma concentration (Cmax) and area under the curve (AUC) were calculated in four cases of the low-dose therapy, and three cases of the high-dose therapy. The side effects of DDP were evaluated according to the World Health Organization (WHO) grading, paying particular attention to nausea/vomiting, appetite loss, renal toxicity, and bone marrow suppression. The incidence of nausea/vomiting and appetite loss was significantly reduced with low-dose daily bolus infusions when compared to the high-dose drip infusions. Bone marrow toxicity and renal toxicity were similar with both administration methods, although hydration was required for the high-dose drip infusions to prevent renal toxicity. The peak plasma concentration (Cmax) of total and free platinum, and the area under the curve (AUC) of total platinum, were similar with both administration methods, while the AUC of free platinum was higher with the low-dose daily bolus infusions compared to the high-dose drip infusions. The time when the concentration of total platinum was > 1 microgram per ml (holding time) was significantly longer with the high-dose drip infusions than with the low-dose daily bolus infusions. The present study suggests that low-dose daily bolus infusions of DDP would be useful in reducing gastrointestinal toxicity, without reducing the area under the curve which is important for antitumor activity.

Malignant fibrous histiocytoma (MFH) is on of the most common soft tissue sarcomas of adulthood, the only treatment for which involves surgical resection of the extremities and retroperitoneum, while no standard postoperative adjuvant chemotherapy has been established. We report herein on the establishment of a serially transplantable MFH strain in immunodeficient mice. An intraperitoneal tumor was resected from a patient with multiple recurrent MFH, inoculated into the subcutaneous tissue of mice with severe combined immunodeficiency (SCID), and established as a serially transplantable MFH strain, MH-1. The chemosensitivity of MH-1 was similar to that of the original fresh surgical specimen, as confirmed by the 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) test. We believe that this serially transplantable strain will be useful for further studies on chemotherapy effective against MFH.

A pharmacodynamic analysis of cis-diamminedichloroplatinum(II) (DDP) was conducted using two human gastric cancer xenografts, SC-1-NU and MKN-45, and one human breast cancer xenograft, MX-1, grown serially in BALB/c nu/nu mice. DDP was administered intraperitoneally (i.p.) at a total dose of 5, 10, or 20 mg/kg in a schedule of q7d x 3 or (qd x 5) x 3. DDP was also administered i.p. to BALB/c +/? mice, whose plasma was used for the assay of total and free platinum by the atomic absorption method. A total dose of 20 mg/kg DDP seemed to be the maximum tolerated dose that was effective on MX-1 and SC-1-NU. When the totally administered doses were equivalent, the antitumor effects of the q7d x 3 and (qd x 5) x 3 schedules were similar to each other. The antitumor activity of DDP against MKN-45 was dependent on the total administered dose as well as the area under the curve of free and total platinum in the plasma. Side effects were significantly reduced using a schedule of (qd x 5) x 3 in terms of body and spleen weight loss when a total of 10 or 20 mg of DDP per kg was administered. These results suggest that DDP would be useful when administered using a daily schedule for obtaining the same antitumor activity as that of bolus injection but with reduced adverse effects.

Helicobacter pylori (HP) may be involved in the pathogenesis of chronic gastritis, gastric ulcer and intestinal-type gastric cancer. In the present study, we detected HP infection serologically after gastric surgery by measuring the serum anti-HP IgG levels and determining their correlation with the serum gastrin levels. The HP-infection rate after distal gastrectomy was 81.5% (75/92), which was higher than that after total gastrectomy 17.2% (5/29). The serum gastrin levels after distal gastrectomy were within the normal range and there was no significant correlation between the serum gastrin level and serologically detected HP infection, nor between the number of days after distal gastrectomy and HP infection. The high HP infection incidence after distal gastrectomy was confirmed serologically and endoscopically, suggesting HP infection plays some role in the superficial gastritis of the residual stomach without correlating with the serum gastrin levels.

The attachment of 7 human colon cancer lines transplantable into nude mice, and primary tumors and liver metastases from 30 patients with colon cancer to 4 extracellular matrix proteins (EMPs)--Matrigel, laminin, fibronectin, and type IV collagen--was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H (MTT) assay. Cancer cells from the 4 established tumor lines which produced experimental liver metastases in vivo showed significantly greater attachment to each EMP than those from the other 3 tumor lines which did not. Although there were no significant differences between attachment to EMPs of cancer cells from 15 clinical primary tumors with liver metastases and those without, attachment to each EMP of cells derived from liver metastases was significantly greater than that of the cells from the corresponding primary tumors in 8 cases for which liver metastases and primary tumors were examined simultaneously. Attachment to EMPs, which could be determined simply and rapidly using the MTT assay, is thus considered a significant factor in experimental and clinical liver metastases of human colon cancers.

Few cases of gastric carcinoma with infiltrating multi-nucleated giant cells (MGCs) have been reported, and giant cells infiltrating the gastric carcinoma were previously described as osteoclast-like giant cells (OGCs). However, hepatoid adenocarcinomas have never been reported previously, and the present case is extremely rare. A 100-year-old Japanese man with gastralgia was found to have a mass in his gastric body. Histological examination showed a poorly differentiated adenocarcinoma with infiltration of MGCs. Vascular and lymphatic invasion were noted but there were no metastases. Almost all the tumor comprised cells with hepatoid-like features. The MGCs proliferated, with infiltration of lymphoid cells. A few MGCs contained mucous material in their cytoplasm, indicating these were foreign-body giant cells. Immunohistochemically, the hepatoid-like components were positive for AFP, and staining with polyclonal antibodies against carcinoembryonic antigen (CEA) showed the canalicular pattern. We concluded that this component was hepatoid adenocarcinoma. The MGCs were positive for CD68, and surrounding infiltrating lymphoid cells were diffusely positive for CD3. Infiltration of MGCs in gastric cancer may represent a cellular immune response against gastric cancer invasion. Further studies are required to elucidate the etiology of MGCs in gastric cancer.

We reported previously that a new Western-style diet (NWD) for 18 months, consisting of elevated lipids and decreased calcium, vitamin D and methyl-donor nutrients, induced colonic tumors in normal C57Bl/6 mice [Newmark, H.L. et al. (2001) A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871-1875], suggesting a new mouse model for human sporadic colon cancer. Here, we have extended this study during a longer feeding period of 2 years wherein tumor formation, tumor inhibition by addition of dietary calcium and vitamin D and their effects on gene expression were determined. We also similarly tested individual supplements of methyl donor (transfer) nutrients (folic acid, choline, methionine and dietary fiber), but these had no significant effect on colonic tumor incidence or multiplicity, whereas supplementation with combined calcium and vitamin D produced significant decrease in both colon tumor incidence and multiplicity, during 2 years of feeding. No visible colonic tumors were found at 6 months, very few at 12 months, more at 18 months and significantly at 24 months. In a related study of gene changes of the mouse colonic mucosa at 6 months of feeding taken from this study, long before any tumors were visibly detectable, indicated altered profiles of gene expression linked to later risk of dietary initiation of colon tumor formation. This type of early genetic altered profile, an indication of increased risk of later colonic tumor development, may become a useful tool for prediction of colon tumor risk while the colon grossly still appears histologically and physiologically normal.

We previously reported hyperproliferation and hyperplasia in C57Bl/6 mouse mammary gland after feeding a Western-style diet (WD); these findings decreased after supplementing WD with increased calcium and vitamin D(3). We now again fortified WD with increased calcium and vitamin D(3) from two sources: (1) a food source, calcium- and vitamin D(3)-enriched yogurt (WD(y) diet) or (2) adding calcium and vitamin D(3) directly to WD (WD(CaD) diet). After 6 months of feeding the number of mammary ducts was higher in mice consuming WD compared to WD(y) (216.0 vs. 202.7, P.05) and WD(CaD) (216.0 vs. 194.9, P.001). The percentage of small ducts increased in WD compared to AIN-76A controls (23.3% vs. 17.4%) but was lower in the WD(y) (17.1%) and WD(CaD) (14.8%) groups. WD mice had higher numbers of epithelial cells per duct than WD(y) (33.2 vs. 27.4, P.001) and WD(CaD) (33.2 vs. 27.8, P.001) mice, and AIN-76A-fed mice had higher numbers than WD(y) (31.1 vs. 27.4, P.005) or WD(CaD) (31.1 vs. 27.8, P.01) mice. Mitotic index was higher in WD than in WD(CaD) mice (0.0020 vs. 0.0009, P.001). Thus, small mammary gland ductules and mitosis increased after feeding WD and decreased after supplementing the diets with increased calcium and vitamin D(3), administered either in a dairy food (yogurt) or directly as calcium carbonate plus vitamin D(3) in WD, suggesting further study of these nutrients for their possible relationship to breast cancer prevention.

Orange peel is a rich source of flavonoids with polymethoxyflavones as major constituents, compounds associated with potential antioxidant, anti-inflammatory, and antitumor activities. We studied the effect of an orange peel extract (OPE) on intestinal tumor growth in Apc(Min/+) mice, a mouse model for human familial adenomatous polyposis (FAP). The OPE contained 30% polymethoxyflavones, a mixture that included tangeretin (19.0%), heptamethoxyflavone (15.24%), tetramethoxyflavone (13.6%), nobiletin (12.49%), hexamethoxyflavone (11.06%), and sinensitin (9.16%). Apc(Min/+) mice were fed one of four diets: (1) AIN-76A control diet; (2) a new Western-style diet (NWD), i.e., AIN-76A diet modified with decreased calcium, vitamin D, and methyl-donor nutrients and increased lipid content); (3) NWD with 0.25% OPE; and (4) NWD with 0.5% OPE, with all additives premixed in the diet. After 9 weeks of feeding NWD to the Apc(Min/+) mice, tumors increased mainly in the colon, with tumor multiplicity increasing 5.3-fold and tumor volume increasing 6.7-fold. After feeding 0.5% OPE in NWD, the development of tumors markedly decreased, with multiplicity decreasing 49% in the small intestine and 38% in the colon. NWD also led to increased apoptosis in intestinal tumors, and 0.5% OPE in NWD further increased apoptosis in tumors of the small and large intestine. Findings indicated that OPE inhibited tumorigenesis in this preclinical mouse model of FAP, and increased apoptosis may have contributed to this effect.

We report a rare case of intra-abdominal fibromatosis of the jejunal mesentery. A 71-year-old man, who was incidentally diagnosed with left hydronephrosis, was found to have a tumor near the duodeno-jejunal junction. The tumor appeared to invade the intestinal wall and was obstructing the left ureter. The tumor was indefinite in diagnosis preoperatively. The patient underwent an en-bloc excision of the tumor by a partial duodeno-jejunectomy combined with a left nephrectomy. Microscopic examination of the tumor showed that non-dysplastic fibroblasts proliferating in the jejunal mesentery had infiltrated into the adjacent small intestines and ureter, resulting in a diagnosis of intra-abdominal fibromatosis. This diagnosis was supported by findings of immunohistochemical analyses showing positive staining for vimentin and smooth muscle actin and negativity for keratin, CD34, C-kit and S-100. To our knowledge, this is the first documented case of intra-abdominal fibromatosis of the jejunal mesentery completely resected with the operative procedure described herein. In cases of a preoperatively undiagnosed retroperitoneal or mesenteric tumor that invades adjacent structures, it is important to consider intra-abdominal fibromatosis as a possible differential diagnosis. This may be helpful in planning the appropriate therapeutic strategies including extended multi-organ resection in selected patients.

The efficacy of intrahepatic arterial chemotherapy for liver metastasis from biliary tract or pancreatic cancer remains uncertain.Five patients with bilio-pancreatic liver metastasis underwent continuous hepatic arterial infusion chemotherapy. One treatment course basically consisted of a 14-day infusion period during which continuous infusions of 5-fluorouracil and intermittent bolus injections of cisplatin were given, and a subsequent 14-day intermission. After two consecutive courses, these drugs were administered bi-weekly.One complete and three partial responses were observed (response rate, 80%). In responders, the responses persisted until or even after the cessation of chemotherapy. The median survival was 15 months after the start of chemotherapy. The longest survivor has been disease-free for 46 months since a liver tumour remaining despite chemotherapy was eradicated by further treatment. Toxicity was acceptable.5-Fluorouracil and cisplatin-based continuous hepatic arterial infusion chemotherapy may serve as a promising treatment for bilio-pancreatic liver metastasis.

We report herein the case of 64-year-old man with gastrointestinal stromal tumor (GIST), who was treated by partial resection of the duodenum after preoperative transarterial embolization. He presented to our hospital with a history of tarry stools, dizziness, and severe anemia (hemoglobin, 7.5 g/dl). Gastroduodenal endoscopy revealed the presence of a submucosal tumor in the second portion of the duodenum. The presence of the tumor was subsequently confirmed by double-contrast gastrointestinal radiography and abdominal computed tomography. Super-selective angiography showed tumor staining fed from the anterior and posterior superior pancreaticoduodenal arteries, and the inferior pancreaticoduodenal artery. Two weeks after transarterial embolization through these vessels, the tumor size was found to have shrunk to 40% of its original size. Partial resection of the duodenum was performed and absence of tumor cells at the surgical margin was confirmed by intraoperative frozen-section examination. Histopathological examination revealed that the duodenal submucosal tumor consisted of spindle cells, and immunohistochemical analysis revealed positive tumor staining for c-kit protein, CD34 and alpha-smooth muscle actin (SMA), and negative staining for desmin and S-100; the positivity rate for MIB-1 staining was 2.2%. Based on these findings, the tumor was diagnosed as a GIST of low-grade malignancy, classified as the muscular type. It is considered that preoperative treatment of duodenal GISTs, such as transarterial embolization, may be useful for reducing the extent of resection, from pancreaticoduodenenctomy to a partial resection.