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A 39-year-old woman visited our hospital with complaints of nausea, vomiting, and lower abdominal pain for 2 weeks. Abdominal CT revealed thickening of the transverse colonic wall, dilated bowel, and a metastatic ischemic tumor in the liver (S7). We diagnosed her with obstructive colon cancer, clinical Stage Ⅳa(T, type 2, cT3, N0, M1a[liver]). At first, we placed a self-expanding metallic stent(SEMS)to decompress bowel obstructions. We planned a surgical resection of the primary tumor followed by partial resection of the liver. We performed a laparoscopic right hemicolectomy(D3)24 days after the stenting. Pathologically, we diagnosed her with BRAF-mutated colon cancer, pStage Ⅳa(pT4a, N1b[2/43], M1a[liver]). On completion of 4 courses of mFOLFOXIRI and bevacizumab, we confirmed a reduction of the S7 tumor but found a new tumor in S6. Since the tumors were potentially resectable, we performed partial liver resection(S6, S7)1 month later. A month following the hepatectomy, CT revealed a new tumor in S4. The patient has been receiving general chemotherapy (CapeOX and bevacizumab)without disease progression for 6 months. We experienced a challenging case of BRAF- mutated obstructive colon cancer with liver metastases.

We report a case of advanced gastric cancer with right gastroepiploic vein tumor thrombus treated using preoperative S-1 plus cisplatin(CDDP)in which pathological complete response was achieved. A 78-year-old man was diagnosed with type 2 gastric cancer located at the greater curvature of the antrum, accompanied by right gastroepiploic vein tumor thrombus. Four courses of S-1 plus CDDP were administered as neoadjuvant chemotherapy. After 2 courses, computed tomography(CT) revealed the disappearance of the tumor in the right gastroepiploic vein thrombus. Distal gastrectomy with D2 lymphadenec- tomy was performed, and the diagnosis was pathological complete response(CR). Eight courses of S-1(100mg/day on days 1-28, followed by 2 weeks of rest)were administered as adjuvant chemotherapy. During the 1-year postoperative follow up, the patient showed no recurrence. An S-1 plus CDDP regimen can be a useful preoperative chemotherapy option for advanced gastric cancer with tumor vein thrombus.

We experienced a successful case in which the patient was treated with a combination of operation and transcatheter arterial chemoembolization for a hypervascular tumor of unknown primary origin in the liver; we report this case with a literature review. A 76-year-old man noticed an upper abdominal tumor and he visited our department for detailed examination. Enhanced CT scan showed multiple hypervascular tumors scattered across both lobes of the liver, and the pattern of contrast effect implied that the tumors were primary neuroendocrine tumors or endocrine metastases. Gastroscopy and colonoscopy showed no tumor in the intestine. TACE was performed mainly for the tumors in the right lobe. One month later, we performed left lateral segmentectomy and partial hepatectomy for segment 6. Histopathological findings showed that the tumors in the left lateral segment had neuroendocrine properties, and the tumor in segment 6 was necrosed. One year has passed since the surgery without recurrence of neuroendocrine tumors in the liver or other organs.

A 62-year-old man presented with complaints of acute abdominal pain. Abdominal enhanced CT showed free air in the abdominal cavity, a thickened stomach wall accompanied by deep ulcer, and enlarged lymph nodes around the stomach. Emergent surgery was conducted, and a perforation in the upper part of the stomach was found. Total gastrectomy was performed. On pathological examination, a mucosa-associated lymphoid tissue lymphoma was diagnosed. Histologic examination revealed the absence of Helicobacter pylori in the gastric mucosa. After the operation, adjuvant chemotherapy was not administered. However, he has been well for 11 months without any recurrence. Gastric MALT lymphoma with spontaneous perforation is considered extremely rare. A brief review of the literature is presented.

We report 2 successful cases treated with trans-catheter arterial embolization(TAE)for hemorrhagic shock due to pseudoaneurysm rupture at the primary tumor site in advanced colorectal cancer. Case 1: A 73-year-old female underwent Hartmann surgery at another hospital for rectal perforation and peritonitis. Six months later, she had a massive bloody stool and was transferred to our hospital. She was diagnosed with bleeding from advanced rectal cancer that remained following the first surgery. Contrast computed tomography(CT)showed that a branch of the superior rectal artery(SRA)developed an aneurysm at the primary tumor site, and TAE was performed to stop bleeding on hospital day 3. Case 2: A 79-year-old male with type 2 sigmoid colon cancer and simultaneous multiple liver metastases developed copious blood in the stool before primary tumor resection and was transferred to our hospital. Contrast CT showed that a branch of the SRA developed an aneurysm at the primary tumor site, and TAE was immediately performed to stop bleeding.

We report a case of colon cancer with simultaneous liver metastases successfully treated with multidisciplinary therapy including two-stage hepatectomy. This is a case of a 72-year-old woman diagnosed with type 1 cecal cancer with 2 simulta- neous liver metastases(S4/8: 98mm, S3: 63mm). At first, laparoscopic resection of the primary site was performed to prevent colon ileus. Liver metastases rapidly grew and became unresectable; fortunately, 11 courses of mFOLFOX6 and bevacizu- mab were effective and liver metastases shrunk(S4/8: 85mm, S3: 67mm). At last, two-stage hepatectomy was performed as conversion surgery, and the patient survived without recurrence for more than 2 years.

A 60-year-old male undergoing pelvic evisceration with D3 lymph node dissection for pR0 in 2006f or carcinoma of the rectum was diagnosed pathologically with moderately differentiated adenocarcinoma, fStage ⅡA(UICC pT3, pN0, M0). Follow-up CT revealed hypovascular liver tumors with intrahepatic bile duct dilation in the right lobe 8 years after the pelvic evisceration. We conducted right lobe hepatectomy. The resected specimens showed that the tumor extended predominantly along the right intrahepatic bile duct. Histological findings and an immunohistochemical examination of CK7, CK20, and CDX2 revealed metastasis of the rectum cancer. We finally diagnosed him with intrahepatic bile duct metastasis from rectal adenocarcinoma.

Unlike the stomach, the esophageal mucosal layer has abundant vessels. To study the histopathologic character of cancer of the esophagus in comparison with that of stomach, the histologic findings (such as vascular or lymphatic permeation and lymph nodal involvement of cancer) were surveyed in 52 lesions of superficial esophageal carcinoma in which carcinoma invasion was limited to the submucosal layer, 448 cases of so-called early gastric carcinoma in which the carcinoma invasion was limited to the submucosal layer, and 109 cases of gastric carcinoma invading the proper muscle layer (PM-carcinoma). With respect to lymph node metastasis and lymphatic and vascular permeation, there was a particularly high incidence of carcinoma extending to the submucosal layer (SM-carcinoma) of the esophagus and a similar high incidence of PM-carcinoma of the stomach. Carcinoma limited to the mucosal epithelium and mucosal layer of the esophagus (MM-carcinoma) has an incidence similar to carcinoma in the mucous membrane and SM-carcinoma of the stomach, respectively. Thus, the cases in which carcinoma invasion was limited to the muscle layer of the mucosa of the esophagus were shown to have a prognosis similar to that of so-called early carcinoma of the stomach.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by the inhalation of organic substances and certain inorganic chemicals. The histopathologic features of chronic HP (CHP) have not been studied extensively. We examined the pathologic characteristics of 16 autopsy cases of clinically confirmed CHP and compared them with 11 cases of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). To clarify the exact intralobular location of the fibrotic lesions, we conducted 3-dimensional reconstruction of fibrosis of CHP and IPF/UIP. Granuloma was not detected in any CHP case. Similar to IPF/UIP, honeycombing lesions were found dominantly in the lower lobes in most CHP cases; upper lobe dominance and asymmetrical distribution of honeycomb lesions were more frequent in CHP than in IPF/UIP. In all lungs affected by CHP, centrilobular fibrosis was outstanding, often connecting to the perilobular areas in the appearance of “bridging fibrosis,” which was clearly demonstrated by 3-dimensional imaging. Centrilobular and bridging fibrosis were significantly more conspicuous in CHP than IPF/UIP; however, considerable overlap was found. It is important to thoroughly explore the possibility of antigen exposure in cases of lungs with UIP with centrilobular fibrosis to discriminate CHP from IPF/UIP.

Small cell carcinoma of the esophagus (SSCE) is regarded as a relatively uncommon neoplasm. Because of its aggressive characteristics with early systemic dissemination and widespread metastasis, SCCE is often associated with a poor prognosis. We report a case of carcinoembryonic antigen-positive SCCE coexistent with squamous cell carcinoma, which was successfully treated with cisplatin (CDDP) and irinotecan (CPT-11). The present case showed no evidence of distant metastasis at the time of preoperative examination. Therefore, the surgical resection was selected as a primary treatment followed by adjuvant therapy (CDDP and 5-flourouracil). However, multiple liver metastases appeared 8 months after the surgery. We changed the chemotherapy to CPT-11 and CDDP, because the regimen is effective for small cell carcinoma of the lung. After six courses of this regimen, the metastatic lesions had dramatically disappeared. These facts suggest that surgical intervention followed by a new regimen consisting of CDDP and CPT-11 is an effective treatment for SCCE.

Objective: Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. Method: Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1–/–), Mlh1 heterozygous (Mlh1+/–) and wild-type (Mlh1+/+) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, β-catenin and p53. Results: Male and female Mlh1–/– mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1+/– and Mlh1+/+ mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of β-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. Conclusion: Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.

Objective Recent studies have suggested that infectious organisms play a role in vascular diseases. In this study, to explore a possible link between oral infection and Buerger disease, we investigated whether oral (periodontal) bacteria were present in occluded arteries removed from patients with characteristic Buerger disease. Methods Fourteen male patients with a smoking history who had developed characteristics of Buerger disease before the age of 50 years were included in this study. Occluded arteries, including superficial femoral (n = 4), popliteal (n = 2), anterior tibial (n = 4), and posterior tibial (n = 4) arteries, were removed and studied. A periodontist performed a periodontal examination on each patient and collected dental plaque and saliva samples from them at the same time. The polymerase chain reaction method was applied to detect whether seven species of periodontal bacteria— Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Campylobacter rectus, Actinobacillus actinomycetemcomitans, Prevotella intermedia , and Prevotella nigrescens — were present in the occluded arteries and oral samples. In addition, arterial specimens from seven control patients were examined by polymerase chain reaction analysis. Results DNA of oral bacteria was detected in 13 of 14 arterial samples and all oral samples of patients with Buerger disease. Treponema denticola was found in 12 arterial and all oral samples. Campylobacter rectus, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis , and Prevotella nigrescens were found in 14% to 43% of the arterial samples and 71% to 100% of the oral samples. A pathologic examination revealed that arterial specimens showed the characteristics of an intermediate-chronic-stage or chronic-stage lesion of Buerger disease. All 14 patients with Buerger disease had moderate to severe periodontitis. None of the control arterial samples was positive for periodontal bacteria. Conclusions This is the first study to identify oral microorganisms in the lesions of Buerger disease. Our findings suggest a possible etiologic link between Buerger disease and chronic infections such as oral bacterial infections.

Healing is a phenomenon by which the intraductal component of breast cancer disappears and is replaced by fibrous tissue. Focally localized healing often prevents confirmation of the continuity of intraductal carcinoma. To clarify the clinicopathological characteristics of breast cancer with healing. At our hospital, 308 patients (311 breasts) underwent breast conservation therapy without neoadjuvant chemotherapy for breast cancer in 2000. These surgical specimens were histopathologically investigated with 5 mm serial sections. We assessed the proportion and the characteristics of breast cancer with healing. (1) The proportion of breast cancer with healing was 7% (21/311). (2) In the 21 patients, the mean age was 59.2 years, and the mean diameter was 2.8 cm. (3) The histological type of the breast cancer varied: noninvasive ductal carcinoma in 2 cases, papillotubular carcinoma in 5, solid-tubular carcinoma in 8, scirrhous carcinoma in 5, invasive lobular carcinoma in 1, and Paget’s disease in 1. However in all cases, the histologic type of the intraductal carcinoma foci was the comedo/solid type and the nuclear grade of cancer cells was high. (4) In cases with healing, areas of healing were seen in an average of 5 (1-26) blocks, compared with intraductal carcinoma foci in 13 blocks (2-40). Healing was located on the nipple side of the main lesion in 8 cases, the peripheral side in 9, and both sides in 4. In 3 cases, healing was seen at the surgical margin of the partial mastectomy specimen. The proportion of breast cancer cases with healing was 7% and these cases were intraductal carcinoma of the comedo/solid type, consisting of highly malignant cancer cells.

Objective: Proliferation of fibroblasts (desmoplastic reaction) in the lung adenocarcinomas is an important phenomenon that correlates with metastases and poor prognosis. Because basement membranes are often involved in the desmoplastic areas and many cytokines have binding capacity to basement membrane molecules, we hypothesized that basement membrane modify the paracrine effects between cancer cells and fibroblasts via the fibrogenic cytokines and this hypothesis was experimentally investigated. Methods: The effects of conditioned media derived from ten lung carcinoma cell lines and normal airway epithelial cells on DNA synthesis of fetal lung fibroblasts were determined. We focused on fibroblast growth factor 2 (FGF-2) as the candidate paracrine cytokines and examined their diffusion through an experimental basement membrane matrix model, Matrigel™. Results: All the conditioned media promoted DNA synthesis of fetal lung fibroblasts. Detection by ELISA methods and the neutralizing antibodies suggested that FGF-2 was one of the responsible factors for the growth promotion. Diffusion of FGF-2 across the polycarbonate membrane was suppressed by coating with Matrigel. When FGF-2-secreting A549 cells were covered with Matrigel, FGF-2 was stored in Matrigel and its diffusion into the culture media was significantly reduced. Binding of FGF-2 to Matrigel was completely blocked by a basic protein, protamine sulfate. In the presence of protamine sulfate in Matrigel overlaid on A549 cells, diffusion of FGF-2 increased 7-fold as much as that without overlaid Matrigel. Conclusion: These results suggest that the basement membrane acts as a barrier to the diffusion and a reservoir of cytokines secreted by cancer cells, and that the subsequent degradation of the basement membrane by cancer cells could release the stored cytokines and promote growth of fibroblasts.

Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including in the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important in affecting gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. The CDX2 homeobox transcription factor plays a key role in intestinal development, but CDX2 is also expressed in most of the intestinal metaplasia and part of the carcinomas of the stomach. We analyzed the methylation status of the CDX2 5' CpG island in gastric cancer cell lines by methylation-specific PCR (MSP), and then CDX2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. We further examined the methylation status of CDX2 in primary gastric carcinomas by MSP and compared it with the past lifestyle of the patients, including dietary habits. Methylation of CDX2 was found in 20 (34.5%) of the 58 male patients and one (6.7%) of the 15 female patients. Since the methylation frequency was low in the female patients, the analysis was performed only on the male cases. CDX2 methylation was correlated with the decreased intake of green tea and cruciferous vegetables, and also with full or overeating habits. These findings are consistent with epidemiological observations on gastric cancer. We also analyzed the methylation status of p16/INK4a and hMLH1, but their frequencies were not associated with dietary factors or other lifestyle factors. Thus, diet could be an important factor determining the methylation status of genes such as CDX2 and the resultant aberrant expression of genes involved in carcinogenesis.

Members of the inhibitor of apoptosis protein (IAP) family, including survivin, have been reported to be expressed in many tumors. However, their expression in esophageal cancer has not been clarified completely. We investigated the expression of mRNA for IAP family proteins in samples from esophageal cancers and their adjacent normal mucosa tissues by real-time quantitative RT-PCR. The survivin expression in esophageal cancer was significantly higher than that in normal mucosa (P < 0.05). Other IAP family proteins including cIAP1, cIAP2, NAIP and XIAP tended to show stronger expression in cancer tissue than normal mucosa, although the differences were not significant. As to the histological type of tumor, poorly differentiated squamous cell carcinomas exhibited significantly higher level of expression than well-differentiated carcinomas (P < 0.05). The proportion of apoptotic cells of cancer tissue inversely correlated with the intensity of survivin expression (P < 0.05). Immunohistochemical staining demonstrated cytoplasmic as well as nuclear expression of survivin in esophageal cancer, and further, in situ hybridization analysis demonstrated cytoplasmic expression of mRNA for survivin. The results suggest that the expression of IAP family proteins, especially survivin, may be associated with the biological character of esophageal cancer, such as apoptosis.

Background and aims: Although it has been reported that intestinal metaplasia implicated in gastric carcinogenesis is induced by the ParaHox gene CDX2 , it is unclear which genes are responsible for the formation of pseudopyloric glands and whether they play a role in gastric carcinogenesis. Pancreatic-duodenal homeobox 1 (PDX1) is also a ParaHox gene which contributes to the genesis and development of the pancreas, duodenum, and antrum. To clarify its significance for the formation of pseudopyloric glands and gastric carcinogenesis, we investigated expression of PDX1 and mucin in gastric carcinomas and surrounding mucosa. Methods: Gastric carcinoma tissues from 95 patients were used for immunohistochemical analyses of PDX1, and mucins MUC6 and MUC5AC. Results: PDX1 was found to be frequently expressed in pseudopyloric glands and intestinal metaplasia. MUC6 was more abundant than MUC5AC in pseudopyloric glands while higher levels of MUC5AC than MUC6 were evident in intestinal metaplasia. The frequency of PDX1 positive reactivity was higher in differentiated type carcinomas (39/43, 90.7%) and T1 carcinomas (42/43, 97.7%) than in undifferentiated type (33/52, 63.5%) and T2–4 (30/52, 57.7%) carcinomas. PDX1 and MUC6 double positive expression was observed in carcinomas, respectively, including the corpus, and also correlated with histological type and depth of invasion. In contrast, no link was apparent between PDX1 and MUC5AC double positive reactivity and histological type. Conclusion: Our study suggests that PDX1 plays an important role in the development of pseudopyloric glands, and that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis.

Hypoxia is a stress that causes alterations in signal transduction and gene instability. In the cancer microenvironment, hypoxia plays a significant role in forming a tumor phenotype and tumor progression. We aimed to identify the genes upregulated by hypoxia in human breast cancer cell lines, a hormone-dependent MCF-7 and a hormone-independent MDA-MB-231, using microarray analysis. These cells were exposed to two oxygen concentrations such as 21% and 1% in a time-course. Out of 12625 genes, 26 genes were identified as commonly upregulated in both MCF-7 and MDA-MB-231 cells. Some of these genes were already reported as hypoxia-related, but some of those were identified newly. These commonly upregulated genes between hormone-dependent and hormone-independent cells would be a clue to study hypoxia-related events and to explore the novel therapeutic targets in human breast cancer.

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast-like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast-like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate-resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease-9, in osteoclast-like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor-kappa B (RANK) in the giant cells and receptor activator of nuclear factor-kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte-derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast-like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.

The clinical and virological significance of low-level viremia by hepatitis B virus (HBV) in hepatitis C virus (HCV)-infected patients remains unclear. HBV-DNA and HCV-RNA were, therefore, quantitatively analyzed in livers and sera from co-infected patients. HBV-DNA and HCV-RNA were quantitated using real-time detection of polymerase chain reaction (RTD-PCR), based on Taq-Man chemistry, in 220 non-HCV-infected healthy volunteers and 93 HCV-infected patients without detectable HBsAg. Serum HBV-DNA was detected in 4 (1.8%) of 220 non-HCV-infected healthy volunteers and 32 (34.4%) of 93 HCV-infected patients without detectable HBsAg. HCV-infected patients displayed higher frequency of HBV infection than healthy volunteers (P < 0.0001). Hepatocellular carcinoma (HCC) was more frequent among co-infected patients than among HCV mono-infected patients (P < 0.001). However, quantities of HBV-DNA in sera from co-infected patients were very low (8-19,000 copies/ml). HBV-DNA was detected in liver tissue from co-infected patients at 2-20 copies per 100 hepatocytes, accounting for 1/1,000 to 1/10,000 of HBsAg positive patients. In livers of patients with HCC and HCV or HBV mono-infection, the viruses existed predominantly in non-cancerous tissue, with levels 10- to 1,000-fold and 1- to 100-fold higher than in cancerous tissue, respectively. In contrast, patients co-infected with HCV and HBV displayed decreased HBV levels in non-cancerous tissue, but no change in cancerous tissue. These results indicate that low-level HBV infection exists in HCV-infected patients. HCC was more common among HCV/HBV co-infected patients than among HCV mono-infected patients. HCV might initiate hepatocarcinogenesis, but does not necessarily determine progression to HCC.

Sarcoidosis, of unknown etiology, may result from exposure of a genetically susceptible subject to a specific environmental agent(s), possibly an infectious one, although none has been identified. Propionibacterium acnes is so far the only bacterium to be isolated from sarcoid lesions. Genomes of P. acnes have been detected in large numbers in sarcoid lymph nodes by the quantitative polymerase chain reaction. By in situ hybridization, P. acnes genomes were found in sarcoid lymph nodes in and around sarcoid granulomas. These results point to an etiological link between P. acnes and some cases of sarcoidosis. Host factors may be more critical than agent factors in the etiology of sarcoidosis, as already suggested from the phenomenon of the Kveim test, in which a suspension of sarcoid tissues injected intracutaneously causes sarcoid granulomas in patients with sarcoidosis but not in healthy people or patients with other diseases. A recombinant trigger-factor protein, RP35, from P. acnes causes a cellular immune response in some patients with sarcoidosis, but not in subjects without sarcoidosis. RP35 caused pulmonary granulomas in mice sensitized with the protein and adjuvant. Sarcoid granulomas may form during hypersensitivity to antigens of P. acnes indigenous to or proliferating in the affected organ.

Endoscopic mucosal resection (EMR) has been performed for intramucosal carcinomas with excellent results. To evaluate invasion depth of superficial esophageal squamous cell carcinomas (SESCCs) accurately, it is important to elucidate vertical and horizontal growth features. Using 179 specimens of SESCC taken by EMR, various factors associated with vertical and horizontal growth were examined pathologically to determine which were correlated with invasion depth, classified for this purpose into four levels, m1, m2, m3, and sm. Maximum tumor diameter, including high-grade intraepithelial neoplasia, differed between m1 and m2 cases and for invasive lesions between m2 and m3. Maximum tumor thickness varied between m1 and m2, m2 and m3, and m3 and sm. Multivariate analysis showed tumor thickness and diameter of invasion to be correlated with submucosal invasion. Tumor thickness and depth of the depressed lesions were correlated in depressed/flat type cases. In elevated type cases the thickness of the tumor did not differentiate between m3 and sm. Shape of the elevated lesion also influenced the invasion depth. Frequency of infiltrating type tumors, composed of irregular and small invading nests, was higher with sm than m3. To differentiate m3 and sm tumor the classification of gross type, thickness, depth of depressed lesions, shape of elevated lesions, and invasion patterns should all be evaluated.

The etiology of inflammatory bowel diseases is unknown. Mycobacteria spp., Bacteroides vulgatus, and Escherichia coli have been suspected to be involved. The aim of the present study was to examine the possible relationship between inflammatory bowel diseases and these microbes.We studied 45 patients; 16 with Crohn's disease, 11 with ulcerative colitis, and 18 with colon cancer as controls. We used a real-time quantitative polymerase chain reaction to detect and estimate numbers of bacterial genomes in formalin-fixed, paraffin-embedded tissue samples from the subjects. The bacteria studied were Mycobacterium tuberculosis, M. avium, M. paratuberculosis, B. vulgatus, and E. coli. Immunohistochemical staining was done to locate B. vulgatus and E. coli in tissue samples.The three Mycobacterium species were not detected. B. vulgatus and E. coli were detected more frequently and in greater numbers in samples from patients with inflammatory bowel diseases than in samples from control patients with colon cancer. The frequency and numbers were not related to the severity of the disease. Many bacteria of these species were found within the mucous layer, underneath erosions, in necrotic ulcer bed tissues, and in abscesses. E. coli cells were found in perivascular areas in the proper muscle layer and in germinal centers of lymph follicles.Our results suggest that Mycobacteria spp. are not involved in the etiology of Crohn's disease and that mucosa-associated B. vulgatus and E. coli are not a direct cause of inflammatory bowel diseases, although they may contribute to the diseases by preventing or delaying remission.

Background: Cigarette smoking has been shown to increase the risk of colorectal cancer. However, the relation between smoking and genetic alterations has not been clarified in this type of cancer. Methods: Mutations of p53, APC, -catenin and K-ras-2 genes were analyzed in colorectal carcinomas from 28 smokers and 33 non-smokers. Frequencies and types of mutations were compared between smokers and non-smokers. Results: The frequency of carcinomas with p53 mutation was higher in smokers (20/28, 71%) than in non-smokers (15/33, 45%) (P = 0.037). The common type of mutation was single-base substitution including G:C to A:T transition in both groups (68% in smokers and 67% in nonsmokers). With respect to G:C to A:T transitions, mutation at CpG sites was less frequent in smokers (9/15, 60%) than in non-smokers (10/10, 100%), whereas mutation at non-CpG sites was more frequent in smokers (6/16, 40%) than in non-smokers (0/10, 0%) (P = 0.028). The frequency of APC mutation was not significantly different between smokers (14/28, 50%) and non-smokers (15/33, 45%). No -catenin mutation was detected in carcinomas from smokers. K-ras-2 mutation occurred in smokers at a similar frequency (9/28, 32%) to that in non-smokers (13/33, 39%). Concerning pathological aspects, Dukes’ A carcinomas were less frequent in smokers (11%) than in non-smokers (33%), whereas Dukes’ D carcinomas were more frequent in smokers (25%) than in non-smokers (15%). Conclusion: The present results suggest that an increased frequency of p53 gene mutation, including G:C to A:T transitions at non-CpG sites, is associated with an increased risk of colorectal carcinogenesis in cigarette smokers.

The accuracy of the urea breath test (UBT) and histological grading for estimation of the density of Helicobacter pylori in gastric mucosa is not known. Real-time (TaqMan) PCR was used to estimate the total number of H. pylori genomes in biopsy samples. These values were compared with those obtained by the UBT and the histological grade obtained by the Sydney system. The UBT and endoscopy with antral and corporal biopsies were performed in 88 consecutive untreated patients with dyspepsia. Bacterial culture and the rapid urease test were done with fresh biopsy materials. TaqMan PCR and histological examination were done on serial paraffin sections of the biopsy samples. Of the five methods tested, TaqMan PCR had the highest sensitivity and specificity (both 100%) in the diagnosis of H. pylori infection. The mean density of H. pylori genomes for pairs of biopsy samples from individual patients was compared with the individual values obtained by the UBT; correlation between the results was significant. The density of H. pylori genomes was higher in histological grades 1, 2 and 3 than in grade 0, without significant differences between adjacent grades from 1 to 3. These results suggest that the severity of H. pylori infection of the stomach can be estimated by the UBT and that histopathologists might state whether the organism is present or absent, rather than making a quantitative statement as recommended in the Sydney system.

The cause(s) of sarcoidosis is unknown.Mycobacteriumspp. are suspected in Europe andPropionibacteriumspp. are suspected in Japan. The present international collaboration evaluated the possible etiological links between sarcoidosis and the suspected bacterial species. Formalin-fixed and paraffin-embedded sections of biopsy samples of lymph nodes, one from each of 108 patients with sarcoidosis and 65 patients with tuberculosis, together with 86 control samples, were collected from two institutes in Japan and three institutes in Italy, Germany, and England. Genomes ofPropionibacterium acnes,Propionibacterium granulosum,Mycobacterium tuberculosis,Mycobacterium aviumsubsp.paratuberculosis, andEscherichia coli(as the control) were counted by quantitative real-time PCR. EitherP. acnesorP. granulosumwas found in all but two of the sarcoid samples.M. aviumsubsp.paratuberculosiswas found in no sarcoid sample.M. tuberculosiswas found in 0 to 9% of the sarcoid samples but in 65 to 100% of the tuberculosis samples. In sarcoid lymph nodes, the total numbers of genomes ofP. acnesorP. granulosumwere far more than those ofM. tuberculosis. P. acnesorP. granulosumwas found in 0 to 60% of the tuberculosis and control samples, but the total numbers of genomes ofP. acnesorP. granulosumin such samples were less than those in sarcoid samples.Propionibacteriumspp. are more likely thanMycobacteriaspp. to be involved in the etiology of sarcoidosis, not only in Japanese but also in European patients with sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown aetiology. Many genomes of Propionibacterium acnes and P. granulosum have been detected in lymph nodes from patients with sarcoidosis. In situ localization of propionibacterial genomes in sarcoid lymph nodes may help to establish an aetiological link between sarcoidosis and these indigenous bacteria. Formalin-fixed and paraffin-embedded biopsy samples of lymph nodes from nine patients with sarcoidosis, nine patients with tuberculosis, and nine patients with non-specific lymphadenitis as controls were examined by quantitative real-time PCR (QPCR) for P. acnes and by in situ hybridization (ISH) that used catalysed reporter deposition (CARD) for signal amplification with digoxigenin-labelled oligonucleotide probes that complemented 16S rRNA of P. acnes. The signals per 250 micro m(2) of tissue sections were counted from inside and outside the granulomas of sarcoidosis and tuberculosis and from control lymph nodes. The number of genomes by QPCR was examined for correlation with the mean signal count by ISH with CARD. In sarcoid samples, one or several signals were detected in the cytoplasm of some epithelioid cells in granulomas and of many mononuclear cells around granulomas. The mean signal counts were higher (p < 0.001) in granulomatous areas than in other areas of sarcoid lymph nodes. Even in their non-granulomatous areas, counts were higher than in granulomatous areas (p = 0.0023) and non-granulomatous areas (p < 0.001) of tuberculous lymph nodes and control lymph nodes (p = 0.0071). Correlation between the results by QPCR and ISH with CARD was significant (r = 0.86, p < 0.001). The accumulation of P. acnes genomes in and around sarcoid granulomas suggests that this indigenous bacterium may be related to the cause of granulomatous inflammation in sarcoidosis.

Rare pancreatic endocrine tumors consisting of both exocrine and endocrine components have been reported sporadically. We investigated the ductal and acinar differentiation in pancreatic endocrine tumors. In immunohistochemical studies of 28 pancreatic endocrine tumors, staining with anti-carcinoembryonic antigen (CEA) or CA19-9 antibody indicated ductal differentiation, while staining with anti-amylase or anti-trypsin antibody indicated acinar differentiation. K-ras gene mutations and p53 gene alterations also were studied. Ten tumors were immunoreactive for CEA or CA19-9. Five tumors diffusely immunoreactive for CEA or CA19-9, in addition to endocrine markers, were diagnosed as duct-endocrine cell tumors of the pancreas. Two tumors diffusely immunoreactive for CEA or CA19-9 and also for pancreaticogut hormones as well as endocrine markers were diagnosed as duct-acinarendocrine cell tumors. These tumors showed uniform histologic features and synchronous ductal, acinar, and endocrine differentiation, distinct from the coexisting different cellular populations seen in collision tumors. All tumors were malignant. These duct-endocrine cell tumors or duct-acinar- endocrine cell tumors of the pancreas may be derived from a stem cell that retains the capability of expressing either an exocrine or endocrine phenotype. Only one K-ras gene mutation and no p53 gene alterations were detected in these tumors, which suggests that they constitute an entity with a different origin than ductal carcinomas.

(The order of authors on this article was changed on 09/01/2012.)Primary undifferentiated pleomorphic sarcoma of the spleen is a rare and highly aggressive neoplasm that usually presents with splenomegaly, constitutional symptoms and frequent distant metastases. We report a case of 77-year old male patient with a past history of dissecting aortic aneurysm that developed acute hemorrhagic shock. Aneurysmal rupture was clinically suspected, but the postmortem examination revealed a 25 mm-sized tumor in an atrophic spleen weighing 65 gram with massive retroperitoneal bleeding. Metastases were found in the right renal hilus, the right adrenal gland and femoral bone marrow. Histology of the tumor showed undifferentiated pleomorphic sarcoma. Tumor rupture with fatal bleeding and systemic metastases had occurred despite the small size of the tumor. Tumor size is not a reliable predictor of systemic metastasis or tumor rupture for splenic undifferentiated pleomorphic sarcoma. Keywords: Undifferentiated pleomorphic sarcoma; Malignant fibrous histiocytoma; Splenic neoplasms; Retroperitoneal hemorrhage DOI: http://dx.doi.org/10.3126/jpn.v1i2.5411 JPN 2011; 1(2): 151-153

More than 85% of patients with T1 colorectal cancer have no lymph node metastasis and can be cured by endoscopic resection. To avoid unnecessary surgery after complete endoscopic resection, accurate histologic methods for evaluating resected specimens are needed to discriminate those at high risk for lymph node metastasis. A retrospective multi-institutional, cross-sectional study of 806 T1 colorectal cancer patients was conducted. A budding/sprouting score was incorporated for predicting lymph node metastasis in addition to other parameters, including the depth of submucosal invasion, histologic grade, and lymphovascular invasion. Lymph node metastasis was detected in 97 patients. Independent predictors of lymph node metastasis by multivariate analysis were depth of submucosal invasion ≥1000 μm (odds ratio (95% confidence interval)=5.56 (2.14–19.10)) and high-grade budding/sprouting (3.14 (1.91–5.21)). Among lesions with a depth of submucosal invasion ≥1000 μm, lymph node metastasis was detected in 59 (29%) of 207 patients with high-grade budding/sprouting, and in 34 (9%) of 396 with low-grade budding/sprouting. Lymph node metastasis was detected in only 4 (2%) of 203 lesions with a depth of submucosal invasion

The patient was a 73-year-old woman with hematemesis, who was brought to our hospital by an ambulance. Emergency upper gastrointestinal endoscopy was performed, and a thickened wall and multiple ulcers were noted in the middle- lower region of the stomach body. The biopsy revealed gastric cancer (por), and the macroscopic depth of invasion was up to the subserosal layer. Multiple white granular protruding lesions were observed in the duodenal bulb and were diagnosed as follicular lymphoma by biopsy. As follicular lymphoma generally takes a long time to progress in many cases, the vital prognosis would be determined by the gastric cancer. Thus, total gastrectomy was performed for gastric cancer. For reconstruction, the double-tract method was used. Duodenal follicular lymphoma was continuously monitored by upper gastrointestinal endoscopy. Here, we describe the case of a patient with a complication of follicular lymphoma arising from duodenal and gastric cancer, which is very rare, and report this case along with a literature review.

The patient was a 43-year-old woman who visited our hospital with a primary complaint of intermittent abdominal pain. Upper gastrointestinal endoscopy revealed mild gastritis. The patient was treated with oral drugs, and the course was followed. Subsequently, the abdominal pain aggravated, and computed tomography (CT) was performed, in which right colic intussusception with a 4 cm cystic mass in the advanced portion was noted. Reduction by enema was attempted on the same day; however, a residual tumorous lesion was present in the ileocecal region. The patient was diagnosed with a cecal submucosal tumor with intussusception, and therefore, laparoscopic surgery was performed. Intussusception of the entire appendix in the ascending colon was noted, for which laparoscopic ileocecal resection was performed. In the excised specimen, a cystic lesion comprising the appendix filled with mucus was present. The postoperative recovery was favorable, and the patient was discharged on the seventh postoperative day. The lesion was histopathologically diagnosed as low-grade appendiceal mucinous neoplasm.

The basement membrane is considered to act as a barrier which hinders cancer cells from invading the surrounding stroma. In order to assess changes in essential components during neoplasia in the lung, we immunohistochemically studied distribution patterns of laminins alpha 3 and alpha 5 in 40 adenocarcinomas and 8 squamous cell carcinomas. The a 5 chain was generally preserved at the periphery, frequently disrupted in foci with alveolar collapse and absent in foci of fibroblastic proliferation within adenocarcinomas. Fragmentation and absence of laminin alpha 3 chain were more prominent than for alpha 5 chain. Laminin alpha 3 chain was partially fragmented or absent in peripheral areas of adenocarcinomas, being significantly different from alpha 5 chain. Non-small cell lung cancers with reduced alpha 5 chain showed a tendency for greater lymph node metastasis. In cultured normal air way epithelial cells, both laminin alpha 3 and alpha 5 chains were found to be expressed by northern analysis. Eleven of the twelve cultured lung cancer cell lines did not express alpha 3 chain and expression of alpha 5 chain was reduced in three. Quantitative RT-PCR analysis also demonstrated expression of laminin alpha 3 chain in adenocarcinoma tissues to be significantly lower than in normal lung tissues. These results suggest that expression of laminin alpha chains is often reduced in lung cancer cells and this might contribute to basement membrane fragmentation and subsequent proliferation of stromal elements, as well as play some role in the process of cancer cell invasion.

Heparan sulfate proteoglycans play important biological roles in cell‐cell and cell‐matrix adhesion, and are closely associated with growth factor actions. Loss of syndecan‐1, a cell surface‐bound heparan sulfate proteoglycan, has been reported for advanced head and neck carcinomas, and expression of endoglycosidic heparanase, which cleaves heparan sulfate glycosaminoglycans (HS‐GAGs), is associated with invasion and metastatic potential of malignant tumors. Paraffin sections of 103 primary esophageal squamous cell carcinomas were immunohistochemically examined for the expression of syndecan‐1 core protein, HS‐GAGs and heparanase protein, and the results were compared with various clinicopathological parameters, such as invasion depth. For 16 cases, fresh tumor samples were quantitatively analyzed for heparanase and syndecan‐1 mRNA expression by real‐time RT‐PCR in addition to the immunohistochemical studies. Syndecan‐1 core protein and HS‐GAGs expression was significantly decreased in pT2 and pT3 cases compared with their pTis and pTl counterparts. Decreased expression of core protein and HS‐GAGs was correlated with the incidence of lymphatic invasion, and venous involvement. Furthermore, decreased expression of HS‐GAGs was correlated positively with the incidence of nodal metastasis and distant organ metastasis, and negatively with the grade of tumor cell differentiation. The percentage of cytoplas‐mic heparanase protein‐positive cases increased significantly in pT2 and pT3 cases compared to that in pTis and pTl cases, and this was associated with lymphatic invasion, and venous and lymph nodal involvement. The level of heparanase mRNA was inversely correlated with the degree of HS‐GAGs expression rather than core protein. In conclusion, loss of syndecan‐1 and heparanase overexpression in esophageal squamous cell carcinomas are closely associated with malignant potential. Regarding the mechanism of loss of HS‐GAGs, heparanase upregulation appears to play an important role.

Department of Pathology, GraduateSchool of Medicine, The Tokyo University, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointes-tinal tract. Since c-kit mutation occurs only in one-third of GIST, there might be other molecularmechanisms. Loss of heterozygosity (LOH), microsatellite instability (MSI) and NF2 gene mutationwere investigated in 22 GISTs (9 low-risk and 13 high-risk tumors). LOH and MSI were evaluatedusing 41 markers on 21 chromosomal arms, and NF2 gene mutation was examined by PCR-SSCP.High frequency of LOH was observed on 14q (9/19, 47%), and 22q (17/22, 77%). The frequencieswere similar in low-risk and high-risk tumors, and were unrelated with gastric or intestinal origin.Two other abnormalities, additional LOH on other chromosomes and MSI at more than two loci,were characteristic of the high-risk tumors (P

Laparoscopic findings of nine patients with chronic schistosomiasis japonica were analyzed and compared to hepatic ultrasonograms, computed tomography (CT) scans and histological findings from the same patients. In all nine patients laparoscopy revealed yellowish, small speckles, approximately 50 microm in diameter, sparse or clustered over the liver surface, which were later found to represent subcapsular calcified ova of Schistosoma japonicum. While the liver surface was almost smooth in mild schistosomiasis, multiple whitish markings and irregular, relatively wide, groove-like septums were seen in more advanced cases. In severe schistosomiasis block-like formations of variable size, separated by groove-like depressions, made the liver surface appear like a tortoise shell. In moderate or severe schistosomiasis ultrasonography revealed spotted high echoes and CT scans demonstrated network patterns and lineal calcified spots. The liver surface of chronic schistosomiasis japonica without re-infection appeared stable without change over time but with a tendency to improve. Hepatocellular carcinoma was initially recorded in two of the nine patients and follow-up revealed a further two with the same diagnosis. However, all these four cases also had chronic hepatitis C (HCV). Hepatocellular carcinoma was not detected in patients without viral hepatitis, indicating that hepatic viral infection is more important than schistosomiasis in promoting the development of hepatocellular carcinoma.

Tissue factor (TF), an initiator of the extrinsic coagulation cascade, is expressed in a wide range of cancer cells and plays important roles in cancer progression and metastasis. Recently, the intracellular function of TF has been revealed to be involved in cancer invasion, independent of the blood coagulation pathway. To evaluate the clinical significance of TF expression, we performed an enzyme-linked immunosorbent assay (ELISA) in the plasma of 67 breast cancer patients and immunohistochemistry in 213 breast cancer tissues. In the ELISA study, we showed an up-regulation of plasma TF concentration in breast cancer patients compared with normal controls. Immunohistochemistry demonstrated that TF was expressed in tumour cells and stromal cells and tumour TF expression closely correlated with stromal TF expression (P = 0.0005). The concentration of plasma TF was associated with tissue TF expression in both tumour and stroma. The multivariate analysis demonstrated that tumour TF expression was an independent prognostic indicator for overall survival (P = 0.0452). Our data show that plasma TF concentration reflects tissue TF expression and tumour TF expression can provide some predictive value for prognosis and distant metastasis, which indicates the importance of TF function in tumour progression. © 2000 Cancer Research Campaign

A line of hepatitis C virus (HCV) transgenic mice was established previously that was mediated by Cre/loxP system using HCV cDNA, including core, E1, E2 and NS2 genes. Intravenous infection of a recombinant adenovirus that expresses Cre DNA recombinase (AxCANCre) induced HCV structural protein expression in the liver of transgenic mice. HCV core protein production and transgene recombination in the mouse liver were serially evaluated after AxCANCre infusion. Core proteins were expressed efficiently and transgene was almost completely recombined in the liver of mice after 3 days and then the levels of both core protein production and transgene recombination decreased continuously for 28 days. However, 30.6% of the transgene recombination remained at 28 days and only 2.7% of core production remained at 28 days after infection. Compared with non-transgenic controls, the serum alanine aminotransferase levels in transgenic mice were significantly higher 10, 14, and 21 days after adenovirus infection. Histological scoring also indicated severe pathological changes in the liver of transgenic mice after adenovirus infection. AxCANCre infusion increased CD8+ lymphocyte infiltration into the liver of transgenic mice compared with that of non-transgenic controls. Furthermore, cytotoxic T lymphocytes (CTLs) isolated from transgenic mice during liver injury were specific for the HCV proteins. These results suggest that HCV structural proteins expressed in the liver of transgenic mice enhanced liver injury. HCV-specific CTLs may be to enhance hepatitis. Thus, the present HCV transgenic mouse model provides a useful model of liver injury due to HCV, and the host immune response may play a pivotal role(s) in the pathogenesis of HCV. J. Med. Virol. 62:308–317, 2000. © 2000 Wiley-Liss, Inc.

Human herpesvirus 8 (HHV-8, Kaposi's sarcoma-associated herpesvirus, KSHV) is a new herpes virus isolated from patients with AIDS-associated Kaposi's sarcoma (AIDS-KS). The ORF59 protein of HHV-8 has recently been shown to encode a processivity factor (PF-8) for HHV-8-encoded DNA polymerase. By immunoscreening a cDNA library derived from the HHV-8-infected cell line TY-1, ORF59 antigen was identified in AIDS-KS patients. Immunoblotting revealed that recombinant ORF59 protein reacted with sera from patients with AIDS-KS. Enzyme-linked immunosorbent assay (ELISA) using ORF59-recombinant protein as the antigen revealed that 7 of 22 (31.8%) AIDS-KS patients and 6 of 263 (2.2%) Japanese HIV-negative patients or healthy blood donors were positive for anti-ORF59 antibodies. Immunohistochemistry using anti-ORF59 rabbit antibodies revealed that this protein was expressed in some of the tumor cells found in KS tissues and that ORF59 protein was detected in 11 of 22 (50%) AIDS-KS tissues. In situ hybridization indicated that some of KS tumor cells were positive for HHV-8 T1.1 mRNA in the same specimen. These data suggest that ORF59 is one of the HHV-8 encoded antigens in patients with AIDS-KS and also indicated that viral replication occurred in some of KS tumor cells. J. Med. Virol. 59:346–355, 1999. © 1999 Wiley-Liss, Inc.

We report a case of granulocytic sarcoma arising from the thymus in a 17-year-old nonleukaemic patient. The patient presented with an anterior mediastinal tumour and underwent surgical resection. Histological examination showed a diffuse infiltrate of immature round cells in the thymus. Tumour cells were diffusely peroxidase positive, but naphthol AS-D chloroacetate esterase negative. Immunohistochemical staining revealed expression of CD34 and terminal deoxynucleotidyl transferase (TdT), but not of CD13 and CD33. Ultrastructurally, electron-dense or medium-density granules were present in the cytoplasm. Four months after successful autogenic bone marrow transplantation, pleural and pericardial fluid contained tumour cells with azurophilic granules, which expressed CD13 and CD33, but not CD34 and TdT. The patient died of the disease 18 months after clinical manifestation, but still without developing leukaemia. The granulocytic sarcoma in the present case may have originated from myeloid precursors in the thymus and remained within the extramedullary site despite the differentiation into a more committed myeloid lineage at the relapse.

We have previously detected an increased frequency of loss of heterozygosity (LOH) on chromosome 18q during progression of colorectal carcinomas. To clarify the target of 18qLOH, mutation of Smad4 and Smad2 genes was analysed in 176 colorectal tumors with different stages, including liver metastasis, from 111 sporadic, 52 familial adenomatous polyposis (FAP) and nine hereditary nonpolyposis colorectal cancer (HNPCC) patients. Mutation of other Smad gene families in the TGF-beta signaling pathway was also examined. Twenty-one Smad4 mutations and one Smad2 mutation were detected, whereas mutation of Smad3, 6 and 7 genes was not detected. Smad4 mutations included seven frameshift, one inframe deletion, four nonsense and nine missense mutations, 95% of which resulted in alteration of Smad4 protein regions included in homo-oligomer and hetero-oligomer formation. Frequencies of tumors with Smad4 mutation were 0/40 (0%) in adenoma, 4/39 (10%) in intramucosal carcinoma, 3/44 (7%) in primary invasive carcinoma without distant metastasis, 6/17 (35%) in primary invasive carcinoma with distant metastasis, and 11/36 (31%) in distant metastasis (metastatic/non-metastatic: P=0.006 approximately 0.01). Loss of the other allele was observed in 19 of 20 (95%) invasive and metastasized carcinomas with Smad4 mutations. In four cases both primary and metastasized carcinomas in the same patients showed the same mutations. The present results suggest that Smad4 gene is one of true targets of 18qLOH, and that its inactivation is involved in advanced stages, such as distant metastasis, in human colorectal carcinogenesis.

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 210-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.

To clarify the endoscopic findings of intestinal graft-versus-host disease (GVHD), we reviewed the endoscopic findings of 19 patients who underwent colonoscopy because of abdominal pain, watery diarrhea or bloody stool among 196 bone marrow transplant (BMT) recipients between 1986 and 1997. BMT had been performed for treatment of various hematopoietic disorders. Eleven patients were diagnosed as having intestinal GVHD, based on the pathological findings of biopsy specimens. Although the grade of inflammation differed among cases, the terminal ileum was most vulnerable to GVHD, based on our observations. Compared to the ileum, findings in the colon tended to be mild. Therefore, evaluation of intestinal GVHD requires observation of the terminal ileum when the colorectal findings are mild. The findings consisted of shallow ulcerations, erythema and easy bleeding. However, there were very few specific endoscopic findings of intestinal GVHD. Since intestinal GVHD and cytomegalovirus (CMV) enterocolitis share several clinical characteristics, including preferential involvement of the ileum, biopsy is indispensable for the final diagnosis.

To determine the neuroendocrine (NE) features of thymic epithelial tumor, immunohistochemistry and electron microscopy studies were performed on eight NE tumors (thymic carcinoids) and 26 non-NE tumors (nine thymic carcinomas, five atypical thymomas, and 12 thymomas other than lymphocytic thymoma). Immunohistochemical studies were performed with antibodies against general markers for NE cells (synaptophysin, alpha subunit of a guanine nucleotide-binding protein, Go, and small-cell lung carcinoma cluster 1 antigen), and a broad panel of antibodies for hormonal substances. Thymic carcinoid showed synchronous diffuse immunoreactivity for the three NE markers and contained cells that were positive for a variety of hormonal products: human chorionic gonadotropin (hCG) alpha-subunit (eight of eight), hCG beta-subunit (three of eight), adrenocorticotropic hormone (ACTH) (three of eight), calcitonin (two of eight), calcitonin gene-related peptide (two of eight), and serotonin (one of eight). Conversely, although positivity for NE markers was neither synchronous nor diffuse in non-NE tumors, seven of nine thymic carcinomas, three of five atypical thymomas (focal or dispersed distribution), and none of the five thymomas were positive for at least two of these NE markers. A small number of neoplastic cells were positive for hCGalpha-subunit or ACTH in three thymic carcinomas and one atypical thymoma. Ultrastructurally, dense core granules (DCG) were much more frequent in thymic carcinoid, but several DCG-like granules were identified in 12 of 13 non-NE tumors with or without immunoexpression of NE markers. The presence of focal or dispersed NE cells in thymic carcinoma and atypical thymoma may reflect multidirectional differentiation within the tumor, which, like cytological atypia, epithelial CD5 expression, and lack of immature T cell infiltration, may be another feature of this group at thymic tumors.

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.