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大腸腺腫,腺腫内癌,sm癌,進行癌,平坦陥凹型癌,計51例における癌遣伝子産物(ras, c-myc, erbB-2),および増殖因子(EGF, TGF-β)の発現をパラフィン包埋材料の連続切片を用いて免疫組織化学染色により検討した,rasを除く遺伝子産物は腺腫群では低値を示し,浸潤傾向とともに高値を示した.進行癌周囲正常粘膜ではras, erbB-2が高値を示した.癌周囲異型粘膜の染色濃度には癌の病理学的形態による特異的な所見はなかった.sm浸潤部では進行癌が他群に比較して高値を示した.腫瘍性病変の各群とも癌遺伝子産物は重複して陽性を示した.またいずれの群においても浸潤を伴うものではこの部で非浸潤部と比較して重複陽性例が多かった.以上より大腸癌における発癌には複数の癌遺伝子の活性化が関与していることが示唆された.

Specific types of early gastric cancer were investigated in accordance with the cancer surface area and the degree of penetration by means of quantitative measurements of the surface area of early gastric cancer using the interactive image analysis system. The results indicated a significant correlation between the surface area and the penetration depth in ordinary early gastric cancer. However these correlations were not observed in both well and poorly differentiated adenocarcinoma cases of the so-called PEN and SUPER types, which showed a significant specificity when compared with ordinary early gastric cancer. The PEN and SUPER types of early gastric cancer also exhibited various clinicopathological characteristics, and it was suggested that the poorly differentiated PEN type might be the initial lesion of a linitis plastica type gastric cancer. Examination of the conditions of the mucosa surrounding the cancer revealed a difference between the PEN and the SUPER types, and this suggested that the environment at the site of a cancer growth influences the type of growth and the spread of early gastric cancer.

During colonoscopy, estimation of the depth of invasion in early colorectal lesions is crucial for an adequate therapeutic management and for such task, magnifying chromoendoscopy (MCE) has been proposed as the best in vivo method. However, validation in large-scale studies is lacking. The aim of this prospective study was to clarify the effectiveness of MCE in the diagnosis of the depth of invasion of early colorectal neoplasms in a large series.A total of 4,215 neoplastic lesions were evaluated using MCE from October 1998 to September 2005 at the National Cancer Center Hospital, Tokyo, Japan. Lesions were prospectively classified according to the clinical classification of the pit pattern: invasive pattern or non-invasive pattern. All lesions were histopathologically evaluated.There were 3,371 adenomas, 612 intramucosal cancers (m-ca), 232 submucosal cancers (sm-ca): 52 sm superficial (sm1) and 180 sm deep cancers (sm 2-3). Among lesions diagnosed as invasive pattern, 154 out of 178 (86.5%) were sm2-3, while among lesions diagnosed as non-invasive pattern, 4,011 out of 4,037 (99.4%) were adenomas, m-ca, or sm1. Sensitivity, specificity and diagnostic accuracy of the invasive pattern to differentiate m-ca or sm1 (1000 microm) from sm2-3 (or = 1000 microm) were 85.6%, 99.4%, and 98.8%, respectively.The determination of invasive or non-invasive pattern by MCE is a highly effective in vivo method to predict the depth of invasion of colorectal neoplasms.

Background Tumor thrombus in the portal vein is a common complication of hepatocellular carcinoma, but an extremely rare complication of common bile duct cancer. Case presentation A 78-year-old woman was referred to our department because of jaundice. Laboratory data showed severe liver dysfunction with high serum levels of total bilirubin and CA19-9. Computed tomography showed lesions in the middle bile duct and main portal vein. FDG PET scan and 3D imaging showed hot spots in the same location as those revealed by CT. Under a diagnosis of middle bile duct cancer with portal vein tumor thrombus, the patient underwent surgery. At laparotomy, the main tumor was found to be located in the middle bile duct with a tumor thrombus, 2 cm in diameter, in the main portal vein. The patient underwent pancreatoduodenectomy with thrombectomy. Histological examination showed that this thrombus had the same histological features as those of the main bile duct cancer (poorly differentiated adenocarcinoma). The postoperative course was uneventful and the patient is doing well without any signs of recurrence 18 months after surgery. Conclusion To our knowledge, this is the first report of successful resection of middle bile duct cancer with portal vein tumor thrombus.

Presented herein are two unusual epithelioid angiomyolipomas (AML) displaying prominent stromal sclerosis. Both patients were middle-aged women without a clinical history of tuberous sclerosis. One patient (case 1) had a 2 cm lesion arising in the renal cortex, and another (case 2) had a pararenal retroperitoneal tumor measuring 13 cm. Both tumors were composed of sheets or nests of polygonal epithelioid or short spindle cells having uniform round to oval nuclei and eosinophilic cytoplasm with cords of hyalinized sclerotic stroma between them. The tumor in case 2 had small areas of mature-looking fat cells. Immunohistochemically, epithelioid tumor cells were diffusely positive for actins and desmin in both cases, and melanoma antigen recognized by T cells (MART)-1 was positive in patient 2. Scattered HMB-45-immunoreactive cells were identified in the sclerotic cords of both tumors, but epithelioid tumor cells were essentially negative for HMB-45. The characteristic clinicopathological and immunohistochemical features of the present cases are analogous to a subset of epithelioid AML or sclerosing perivascular epithelioid cell tumors previously reported.

The incidence of colorectal neoplasia is increased in patients with long-standing and extensive ulcerative colitis (UC), and death from colorectal neoplasia is the most important factor for long-term mortality in patients with UC. To improve the prognosis of patients with UC-associated neoplasia, it is very important to diagnose it at an early or precancerous state in patients with long-standing UC. However, UC-associated neoplasia is often difficult to detect endoscopically and difficult to discriminate from inflammatory regenerative epithelium pathologically. There are three important problems in diagnosing UC-associated neoplasia: the first is how to detect UC-associated dysplasia and early cancer endoscopically; the second is how to discriminate UC-associated dysplasia from inflammatory regenerative epithelium pathologically; and the third is how to identify individuals at increased risk of neoplasia, especially dysplasia, in patients with long-standing and extensive UC. We reviewed the clinicopathological and genetic characteristics of UC-associated neoplasia focusing on these three problems.

TGF-beta-stimulated clone-22 (TSC-22) was reported to be a differentiation-inducing factor which negatively regulates the growth of salivary gland cancer cells. In the present study, we examined the expression of TSC-22 in salivary gland tumors by immunohistochemistry. In pleomorphic adenoma (PA), most of the sparse myoepithelial-like tumor cells, which are considered as the differentiated cells because they produce extracellular matrix, expressed TSC-22. However, only a limited number of cases of the solid myoepithelial-like tumor cells in PA, which are considered as the growing cells, expressed TSC-22. In adenoid cystic carcinoma (ACC), inner ductal cells in the tubular structure, strongly expressed TSC-22, though the outer myoepithelial-like tumor cells did not express TSC-22. In the cribriform structure, myoepithelial-like tumor cells did not express TSC-22. However, a small ductal structure in the micro-cyst wall strongly expressed TSC-22. Sparse type myoepithelial-like tumor cells in ACC also expressed TSC-22. In mucoepidermoid carcinoma, epidermoid tumor cells and mucous-producing tumor cells in mucoepidermoid carcinoma frequently expressed TSC-22. Thus, the expression of TSC-22 was frequently observed in the cells with differentiated-phenotypes, although rarely in the cells with growing potentials. These results suggest that TSC-22 may play an important role in maintaining the differentiated phenotype in salivary gland tumors.

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are representative agents for the chemoprevention of sporadic colorectal neoplasia. However, few reports have described the chemopreventive effects of such agents on colitis-associated tumorigenesis. To clarify whether treatment with the COX-2 inhibitor may reduce the risk of colitis-associated neoplasia, we investigated the effect of one such agent, etodolac, on tumorigenesis in the colitis-associated neoplasia model using p53-deficient mice treated with dextran sulfate sodium (DSS). The p53-/- mice were divided into four groups: i) treatment with DSS + etodolac, then after two cycles of DSS, the mice were given distilled water for 84 days. In addition, etodolac was administered three times a week at a dose of 10 mg/kg body weight throughout the experiment. ii) Treatment with two cycles of DSS only, followed by distilled water for 84 days. iii) Treatment with etodolac alone. iv) Distilled water alone was administered to the control group. The incidence of mice with neoplasia was 82.4% in the DSS + etodolac group and 100% in the DSS-alone group. No neoplasia was observed in the etodolac-alone and control groups. The mean (+/- SEM) number of total neoplasias per mouse was 1.29+/-0.2 in the DSS + etodolac group and 3.0+/-0.52 in the DSS-alone group, the inter-group difference being significant (p

Endoscopic photodynamic therapy (PDT) using a pulsed gold vapor laser (wavelength 628 nm, LaserSonics Inc.) was performed on eight cases of early gastric cancer. Three patients refused to have surgery, and the others were in a high-risk group due to old age or complications with other diseases. Hematoporphyrin derivative (HpD I, 2.5-3 mg/kg, Photofrin Inc.) was injected intravenously, and 48-72 hours later, the entire cancer lesion and 5 mm width mucosa encircling it were irradiated with a gold vapor laser through a single quartz fiber. The irradiation was delivered at 300-330 mW for 5-20 minutes, which gave about 90 J/cm 2 dosage. In seven of eight cases, local cure was achieved. Recurrence was noted only in one patient. In one of eight patients, operation was carried out 1 month after PDT. Pathological examination of the resected stomach revealed that the effect of PDT extended into the tunica muscularis propria. Side effects of HpD, such as skin rash, were noted in two patients, but no serious complications of PDT were encountered. This suggests that PDT with a pulsed gold vapor laser is clinically useful in the treatment of early gastric cancer.

近年, 診断技術の進歩とともに食道炎および食道潰瘍に遭遇し治療する機会が多くなってきた.しかし, 中部食道潰瘍の報告はまれである. われわれは, この原因不明の中部食道潰瘍の1例を経験したので報告する. 症例は56歳の男性で, 発熱と胸骨後部痛にて来院した.特別な化学物質や薬物の服用の既往はなかった. 食道造影X線検査および食道内視鏡にて, 切歯列より26cmからの中部食道に大きな全周性の潰瘍を認めたが, 内視鏡による鉗子生検では悪性所見を認めなかった. 制酸剤および中心静脈栄養などにて保存的治療を施行していたが, 突然大量吐血し, 緊急手術として胸部食道全摘術が行われた. 摘出標本では, 潰瘍は食道上部2/3に存在し凝血塊の付着を認めた. 口側および肛門側の潰瘍辺縁は明瞭であった. 食道下部および胃には, 潰瘍および腫瘤を認めなかった. 病理組織学的には活動性の慢性潰瘍の所見であった.

Colorectal adenocarcinoma with rhabdoid phenotype is extremely rare, and only 1 case of adenocarcinoma showing rhabdoid dedifferentiation has been reported. The authors present another case of cecal adenocarcinoma with prominent rhabdoid feature in a 66-year-old man. The 13-cm sized tumor consisted mainly of rhabdoid cells and partly of adenocarcinoma, and transition from adenocarcinoma to rhabdoid areas was noted. Ultrastructural analysis revealed intracytoplasmic aggregates of intermediate filaments in the rhabdoid cells. Adenocarcinoma cells were diffusely immunoreactive to cytokeratin 7 and AE1/3, but occasionally positive for vimentin. The rhabdoid cells were negative for cytokeratin 7, weakly/focally immunoreactive to AE1/3, and diffusely positive for vimentin. These results suggested that the rhabdoid cells were dedifferentiated adenocarcinoma. Analysis of the rhabdoid cells with molecular techniques is also presented.

Stimulation of the CD155/poliovirus receptor, which localizes in the cell-matrix and at cell-cell junctions, inhibits cell adhesion and enhances cell migration. Necl-5, a mouse homolog of CD155, is implicated in the formation of adherence junctions. Recently, Necl-5 has also been found to enhance cell proliferation via the stimulation of serum and platelet-derived growth factor through the Ras-Raf-MEK-ERK signaling pathway. In our present study, we find that CD155 significantly enhances the serum-induced cell proliferation of NIH3T3 cells which have been transformed by an oncogenic Ras (V12Ras-NIH3T3), but not the parental cells. CD155 expression in V12Ras-NIH3T3 cells is also found to upregulate cyclin D2, downregulate p27(Kip1) and shorten the G0/G1 phase of the cell cycle. An inhibitor of focal adhesion kinase does not reduce this CD155-mediated enhancement of V12Ras-NIH3T3 cell proliferation. The expression of CD155DeltaCP, which lacks the cytoplasmic region including the immunoreceptor tyrosine-based inhibitory motif (ITIM), has a reduced ability to enhance the serum responsiveness of V12Ras-NIH3T3 cells, suggesting that the ITIM might be required for this effect of CD155. In addition, the overexpression of exogenous CD155 enhances the serum responsiveness of HT1080 cells, which harbor a mutant N-ras gene. On the other hand, siRNA-induced knockdown of endogenous CD155 and/or CD155DeltaCP expression significantly repress the serum responsiveness of DLD-1 cells, which express endogenous CD155 and harbor a mutant K-ras gene, suggesting that this mutant may function in a dominant negative manner. Taken together, our present data suggest that CD155, at least in part, enhances the proliferation of ras-mutated cells.

A 56-year-old man was found to have a pancreatic tail tumor. His blood chemistry showed no infection with hepatitis B or C virus and no elevations of tumor markers or pancreatic hormones. Abdominal ultrasound showed an encapsulated, rather heterogeneous, hypoechoic tumor, 6.5 cm in maximum diameter, with a beak sign. Helical dynamic CT revealed an irregularly enhanced tumor with pooling of contrast medium in the delayed phase. Abdominal angiography showed a hypervascular tumor. With a tentative diagnosis of non-functional islet-cell tumor, the patient underwent resection of the pancreatic body and tail with splenectomy. The contour of the liver and its surface were normal. In microscopic examination, tumor cells arranged in a trabecular pattern with focal bile pigment resembling hepatocellular carcinoma (HCC). Immunohistochemically, these tumor cells were positivefor HEPPAR-1, CAM5.2, cytokeratin 18 and COX-2, but negative for MUC-1, and cytokeratins 7, 20 and 8. These results supported a diagnosis of HCC without any adenocarcinoma component. The patient is currently doing well without any signs of recurrence in either the remaining pancreas or liver three years after surgery. We report the rare case with ectopic HCC in the pancreas with a review of the literature.

A p53 functional analysis system, which can identify the types of abnormality of p53, such as loss of function, dominant negative function, or gain of oncogenic function, is now required. In this study, we examined the functional diversity of several mutations of p53 derived from human head and neck cancer cells. The entire open reading frame of p53 cDNA was subcloned into a mammalian expression vector, pEGFP-C3, and genetic mutations were determined. Then, intracellular localization and transcriptional activity of the tumor-derived p53 proteins were examined in Saos-2 cells. A mutant-p53 (Glu17Lys, His193Leu) or a truncated p53 (Delta121) did not activate the reporters containing p53 responsive elements from p21waf1, BAX, MDM2, p53AIP1, and PUMA genes at all. However, a mutant-p53 (Asn30Ser) showed the transcriptional activity on all of the reporters as wild-type p53 did. On the other hand, a mutant-p53 (Asp281His) activated the p21waf1 promoter strongly and the MDM2 promoter faintly, but did not activate the BAX promoter. Interestingly, this mutant-p53 prevented Saos-2 cells from undergoing apoptosis after treatment with a DNA damaging agent, adriamycin. This mutant-p53 induced cell cycle arrest but not apoptosis. Furthermore, another mutant-p53 (Glu17Lys, His193Leu) also prevented the cells from undergoing apoptosis after DNA damage probably in a transcription-independent manner. These results suggest that some cancer cells may contain the oncogenic mutation of the p53 gene, and the oncogenic p53 protein prevents cancer cells from undergoing apoptosis after DNA damage. Detailed information for mutated p53 gene in cancer cells might provide useful suggestions for the therapeutic strategy.

A screening colonoscopy was performed on an asymptomatic 68-year-old woman. A diminutive 1 mm diameter Paris-type 0-IIc neoplastic lesion was diagnosed in the ascending colon (fig 1A). Further characterisation using high-magnification chromoscopic colonoscopy and 0.05% crystal violet intravital staining revealed a Kudo-type IIIs crypt architecture in the depressed component, which suggested that this lesion was limited to the mucosal layer. Endoscopic mucosal resection (EMR) was considered to be the most appropriate firstline endoluminal treatment in this case to confirm histologically the absence of neoplastic disease beyond 1000 μm in the vertical margin, where data from both Japan and Europe have shown that despite diminutive endoluminal appearances, such …

Genetic alterations and their association with clinicopathological features in colorectal mucinous carcinoma (MC) remain unknown. In particular, little is known about the mutational status of the BRAF gene, which is activated by oncogenic Ras. This study aimed to evaluate the status of BRAF together with K-ras, p53 and mismatch-repair deficiency to clarify their association with tumorigenesis of colorectal MC. BRAF and K-ras mutations were determined in 43 colorectal MCs by direct sequencing. p53 alteration was investigated immunohistochemically. The status of mismatch-repair deficiency was assessed by microsatellite analyses and immunohistochemistry for hMLH1. We also examined the association between these molecular alterations and clinicopathological features including histological configuration. BRAF mutation was detected in 4 (9.3%) tumors and was located at codon 599 of exon 15 in all cases. K-ras mutation was detected in 13 tumors (30.2%). No BRAF and K-ras mutations were identified simultaneously in the same tumor. The incidence of mismatch-repair deficiency tended to be higher in MC with BRAF mutation than without. In terms of histological configuration, we classified the cases according to growth type by tumor edge morphology. All MCs with BRAF mutation and 9 of 13 MCs (69.2%) with K-ras mutation were classified as polypoid type. BRAF and K-ras mutation did not affect patient prognosis, but non polypoid type was significantly more aggressive than polypoid type. Our findings indicate that BRAF mutation plays an important role in the tumorigenesis of colorectal MC and in tumor edge morphology, similar to K-ras mutation.

Objectives: Although it has been reported that epidermal growth factor receptor (EGFR) is able to translocate from the plasma membrane to the nucleus, the pathophysiological role of this translocation in tumorigenicity is still unclear. In the present study, to elucidate the pathophysiological significance of EGFR translocation, we investigated the expression not only of conventional EGFR but also its phosphorylated form (pEGFR), focusing on its cellular localization in esophageal cancer tissues. Methods: Fifty-two specimens of esophageal squamous cell carcinoma (SCC) obtained by surgery were examined immunohistochemically for their EGFR and pEGFR immunostaining patterns. The relationships between clinicopathological parameters and EGFR or pEGFR immunostaining patterns were then analyzed. Results: In 37 (71.2%) of the 52 esophageal SCCs, EGFR immunoreactivity was clearly localized at the plasma membrane of the cancer cells, whereas pEGFR immunoreactivity was clearly localized in the nucleus in 19 (36.5%) cases. Nuclear expression of pEGFR significantly correlated with TNM stage and lymph node metastasis, and moreover was associated with a poor outcome of esophageal SCC. Conclusions: Nuclear translocalization of pEGFR is associated with an increase in the malignant potential of esophageal SCC and may affect prognosis in patients with esophageal SCC.

The differential diagnosis between autoimmune pancreatitis and pancreatic cancer is sometimes difficult, especially for those patients in whom laboratory and radiological criteria are lacking.A 72-year-old woman was found to have a tumor in the head of the pancreas. Laboratory data showed no abnormal values, including gammaglobulins or autoantibodies. Endoscopic retrograde cholangiopancreatography showed extrinsic stenosis of the main pancreatic and lower common bile ducts. Computed tomography showed a lesion in the head of the pancreas. With a tentative diagnosis of head of the pancreas cancer, the patient underwent pancreaticoduodenectomy. Macroscopically, a tumor 2 cm in diameter not having clear margins was evident in the head of the pancreas. Histological examination showed the infiltration of lymphocytes, plasma cells, and eosinophils with lymphoid follicles around the main pancreatic duct. Immunohistological examination demonstrated that the main pancreatic duct was surrounded by abundant IgG4-positive plasma cells.The patient was diagnosed as having autoimmune pancreatitis on the basis of the immunohistological findings alone, without any well-defined criteria such as high serum level of IgG4 and presence of autoantibodies before or after surgery.

Background Simultaneous double cancers of the biliary tract are rare. Most of them are thought to be associated with pancreaticobiliary maljunction (PBM); however, the characteristics of tumours without PBM are still unclear. Methods Histology, immunoreactivity with carcinoembryonic antigen, carbohydrate antigen 19-9 and p53 and mutations in the K-ras gene were examined in tumours resected from cases of simultaneous double cancers of the biliary tract. Results Four cases of simultaneous double cancers of the biliary tract were identified among 108 patients with biliary tract cancer (3.7%). None of the four cases associated with PBM, and the results of histological, immunohistochemical and genetic examinations differed between the bile duct and gall bladder cancers in each case. Conclusion Even when they do not associate with PBM, double cancers in the biliary tract are more likely to be the result of multicentric development.

The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.

A 67-year-old man, who had undergone surgery to resect multiple gastric cancers 4 years ago, visited our hospital for surveillance colonoscopy. Colonoscopy revealed a discolored, 7-mm in diameter, flat-elevated lesion with central depression in the transverse colon near the splenic flexure. Although the findings of endoscopy and barium enema were suggestive of submucosal invasion, the patient chose to undergo endoscopic mucosal resection. Pathological examination of the resected specimen revealed signet-ring cell carcinoma and a positive surgical margin. A second operation was performed, and no residual tumor or metastasis to lymph nodes was found in the resected specimens. Primary colorectal cancers composed of signet-ring cell carcinoma detected and treated at an early stage are extremely rare. We present a case and review the literature.

AIM: To clarify whether mucosal crypt patterns observed with magnifying colonoscopy are feasible to distinguish non-neoplastic polyps from neoplastic polyps. METHODS: From June 1999 through March 2000, 180 consecutive patients with 210 lesions diagnosed with a magnifying colonoscope (CF-200Z, Olympus Optical Co., Ltd., Tokyo, Japan) were enrolled. Magnification and chromoendoscopy with 0.2% indigo-carmine dye was applied to each lesion for mucosal crypt observation. Lesions showing types I and II crypt patterns were considered non-neoplastic and examined histologically by biopsy, whereas lesions showing types III to V crypt patterns were removed endoscopically or surgically. The correlation of endoscopic diagnosis and histologic diagnosis was then investigated. RESULTS: At endoscopy, 24 lesions showed a type I or II pit pattern, and 186 lesions showed type III to V pit patterns. With histologic examination, 26 lesions were diagnosed as non-neoplastic polyps, and 184 lesions were diagnosed as neoplastic polyps. The overall diagnostic accuracy was 99.1% (208/210). The sensitivity and specificity were 92.3% (24/26) and 99.8% (184/186), respectively. CONCLUSION: Magnifying colonoscopy could be used as a non-biopsy technique for differentiating neoplastic and non-neoplastic polyps.

Treating malignant tumor through the induction of cell differentiation has been an attractive concept, but clinical development of differentiation-inducing agents to treat malignant tumor, especially for solid tumors has been limited to date. Nerve growth factor, all trans retinoic acid, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-0-tetradecanoylphorbol 13-acetate, hexamethylene-bis-acetamide, transforming growth factor-beta, butyric acid, cAMP, and vesnarinone are known to have a differentiation-inducing capability on solid tumors in vitro and/or in vivo. Moreover some of the differentiation-inducing agents have been used for treating patients with solid tumor, but the therapeutic effect of the differentiation-inducing agents on solid tumor is not strong when compared with that of conventional chemotherapeutic agents. However, because most of the differentiation-inducing agents can potentiate the effect of conventional chemotherapy or radiation therapy, combination of differentiation-inducing therapy with conventional chemotherapy or radiation therapy might be used as a second- or third-line therapy in patients with advanced cancer. Furthermore, analysis of the molecular mechanisms of the tumor differentiation therapy might provide selective and targeted molecules for novel cancer therapy.

Recently, according to increasing gastroesophageal reflux disease (GERD), the patients with Barrett's esophagus (BE) are increasing. Since Barrett have reported cases of esophageal ulcers surrounding by columnar epithelium, the various criteria of the BE have been proposed. In 1998, practice guidelines for BE were developed under the auspices of the American College of Gastroenterology. They proposed that BE was a chance in the esophageal epithelium of any length that can be recognized at endoscopy, and confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia. Endoscopically, BE is determined, when 'gastric-appearing mucosa' or apparent 'columnar lined esophagus' is evident proximal to the esophagogastric junction. Histologically, BE has double muscularis mucosae, and contains a mixture cell types; gastric-fundic type epithelium, junctional type epithelium, and specialized columnar epithelium (SCE). Especially SCE is distinctive features of BE, available for diagnosis. On the other hand, BE is premalignant condition for the adenocarcinoma of the esophagus, therefore the features of the BE are researched to prevent and find out earlier development of adenocarcinoma. In this review, we referred to the definition of BE with some topics.

Dendritic cells (DCs) are very potent antigen-presenting cells that play an essential role in the primary immune response to carcinoma. Tumor-infiltrating DCs have been found to be clinically significant in many human malignancies such as colon, stomach, lung, breast and hepatic carcinoma. However, clinical significance of activated and/or immature DCs in gallbladder carcinoma has not been reported yet. Thus, we immunohistochemically evaluated CD83+ DCs and CD1a+ DCs of cancerous and peritumoral area in 29 cases of resected gallbladder. In the results, CD83(+) DCs were significantly fewer in cancerous area than that in peritumoral area (1.55/hpf vs. 4.26/hpf, p=0.0047), but the numbers of CD1a(+) DCs did not differ (p=0.075). In addition, we defined a CD83 index as CD83(+) DCs/(CD83(+) DCs plus CD1a(+) DCs), and analyzed the relationship between CD83 index and clinicopathological factors. The group with a higher CD83 index (index >0.316) showed significantly better prognosis than the group with a lower CD83 index (index < or =0.316) in cancerous and peritumoral areas. In conclusion, we suggest the importance of tumor-infiltrating CD83(+) DCs as a useful prognostic factor for patients with gallbladder carcinoma.

Background and aims: Although regenerating gene (REG) Iα protein may be involved in the inflammation and carcinogenesis in the gastrointestinal tract, its pathophysiological role in ulcerative colitis (UC) and the resulting colitic cancer remains unclear. We investigated expression of the REG Iα gene and its protein in UC and colitic cancer tissues. We examined whether cytokines are responsible for REG Iα gene expression and whether REG Iα protein has a trophic and/or an antiapoptotic effect on colon cancer cells. Methods: Expression of REG Iα mRNA and its gene product in UC tissues was analysed by real time reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. The effects of cytokines on REG Iα promoter activity were examined in LoVo cells by luciferase reporter assay. The effects of REG Iα protein on growth and H2O2 induced apoptosis were examined in LoVo cells by MTT and TUNEL assays, respectively. Results: REG Iα protein was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG Iα mRNA expression in UC tissues correlated significantly with severity of inflammation and disease duration. REG Iα promoter activity was enhanced by stimulation with interferon γ or interleukin 6. REG Iα protein promoted cell growth and conferred resistance to H2O2 induced apoptosis in LoVo cells. REG Iα protein promoted Akt phosphorylation and enhanced Bcl-xL and Bcl-2 expression in LoVo cells. Conclusions: The REG Iα gene is inducible by cytokines and its gene product may function as a mitogenic and/or an antiapoptotic factor in the UC-colitic cancer sequence.

Background: Surveillance colonoscopy is widely recommended in patients with longstanding and extensive ulcerative colitis (UC) in order to detect colorectal neoplasia at an early stage. However, it still remains questionable whether surveillance colonoscopy effectively enables early detection of UC associated neoplasia. There is a great need for sensitive markers to identify individuals at increased risk of neoplasia. The oestrogen receptor (OR) gene shows age related methylation in the colorectal epithelium and is methylated frequently in sporadic colorectal neoplasia, suggesting that OR methylation may predispose to colorectal neoplasia. Aim: To clarify whether analysis of methylation of the OR gene in non-neoplastic epithelium can contribute to prediction of increased neoplasia risk in UC patients. Materials and methods: A total of 165 non-neoplastic colorectal epithelia from 30 patients with longstanding and extensive UC, including 13 UC patients with neoplasia and 17 patients without, were evaluated. Methylation specific polymerase chain reaction was performed to determine the methylation status of the OR gene. Results: Methylation of the OR gene was detected in 54 of 70 (77.1%) non-neoplastic colorectal epithelia in UC with neoplasia but in only 23 of 95 (24.2%) without neoplasia. Methylation of the OR gene was significantly more frequent in non-neoplastic epithelium from UC with neoplasia than in chronic colitic epithelium from UC without neoplasia. Furthermore, in UC with neoplasia, the OR gene was extensively methylated in non-neoplastic epithelia throughout the colorectum compared with those in UC without neoplasia. Conclusion: These results suggest that analysis of OR gene methylation may have potential as a useful marker for identifying individuals at increased risk of neoplasia among those with longstanding and extensive UC.

A 59-year-old woman underwent surgery for uterine corpus cancer in March 1998. She also underwent pylorus-preserving pancreaticoduodenectomy with pancreaticogastrostomy for common bile duct cancer in November 1998. She was followed up at our outpatient clinic after pylorus-preserving pancreaticoduodenectomy. In November 2002, her carcinoembryonic antigen level became elevated and abdominal ultrasound revealed a huge tumor. Gastroscopy showed a Borrmann type 3 tumor at the anastomosis of the pancreaticogastrostomy, and a biopsy revealed adenocarcinoma. With a diagnosis of advanced gastric cancer, she underwent total gastrectomy, splenectomy, and residual pancreatectomy in January 2003. The pathologic findings revealed that the gastric cancer was separated from the pancreas, suggesting that the cancer had developed from the stomach. The present report describes a rare case of gastric cancer that had developed at the anastomosis of a pancreaticogastrostomy.

The deletion of tumor suppressor genes and amplification of activating oncogenes appear to be critical events in tumorigenesis. We carried out fluorescence in situ hybridization (FISH) analysis of the breast cancer cell line MCF7 and clinically obtained cancer tissue sections on the basis of which we suggest a breast cancer development model. We selected 28 genes for FISH probes from breast cancer patients. Of the 28 genes studied, 14 were shown to be consistently amplified in the breast cancer cell line MCF7. We selected three genes from clinical tumor samples on the basis of results from MCF7 analysis. The amplification of Her2/neu or ZNF217 is closely associated with the stages of breast cancer. The frequency of amplification of Her2/neu increased notably in patients at stages later than IIB based on TNM staging, whereas the amplification of ZNF217 correlated with T2N1M0 at stage IIB and later stages. c-MYC amplification was not related to the stage. Her2/neu, ZNF217 and c-MYC were found to have a significantly increased copy number in breast cancer cells. In breast cancer progression, c-MYC amplification is an early event, while ZNF217 and Her2/neu amplification may play a role in the later stage of tumor development.

Primary extraskeletal epithelial neoplasms containing osteoclast-like giant cells (OGCs) are rare. We herein describe a case of adenosquamous carcinoma that developed in the endometrium together with non-neoplastic OGCs. The patient was a 72-year-old woman who underwent radical hysterectomy with salpingo-oophorectomy and lymph node dissection after being diagnosed with uterine cancer. Histologically, the tumor was found to be an adenosquamous carcinoma containing a large number of OGCs and mononuclear cells (MNCs) that had infiltrated into the stroma. Immunohistochemically, the OGCs and MNCs stained strongly positive for KP-1 and alpha-1-antichymotrypsin, and negative for the epithelial markers epithelial membrane antigen (EMA) and cytokeratins. These findings suggest that the OGCs and MNCs in this patient's tumor originated from monocytes/histiocytes, and most likely developed as part of the stromal reaction to the neoplasm.

A rare case of ovarian small cell carcinoma is reported. Laboratory examination of a 46-year-old woman with a lower abdominal tumor showed marked hypercalcemia. Her condition deteriorated progressively, and she died one month after admission. A right ovarian tumor, 8 cm in diameter, metastases to multiple organs, and intraperitoneal bleeding were confirmed by autopsy. Microscopically, the small tumor cell had rounded nuclei with small distinct nucleoli and a scanty cytoplasm. Small cell carcinoma was diagnosed from these histological features and the clinical course associated with hypercalcemia. Immunohistochemical studies showed positive staining of neuron specific enolase (NSE) and keratin. Genetic analysis using DNA extracted from paraffin sections of metastatic lesions revealed mutation of K-ras codon 12. Loss of heterozygosity of the p53 and adenomatous polyposis coli (APC) genes was not informative. Previous reports have shown that ras gene mutations occur in 30% of epithelial ovarian tumors and significantly more frequently in mucinous than in other types of ovarian tumors. These results suggest that small cell carcinoma is of epithelial origin and may have a genetic alteration similar to that of mucinous tumors.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) and p53 alterations were expected to be diversely involved in endometrial carcinogenesis. Patients (n=92) with endometrial carcinoma (EC) were analyzed, and PTEN and p53 were immunostained in the tissue sections. Tumor histology, grade of differentiation, presence of endometrial hyperplasia, staining status of PTEN and p53 and clinical information were examined. There were 37 cases (40%) negative for PTEN staining, which suggests lost or reduced PTEN function. Loss of PTEN staining was significantly related to the advanced staging in the grade 1 (G1) and grade 2 (G2) endometrioid adenocarcinoma group (p=0.026). Also, 18 cases (20%) showed positive staining for p53. p53 staining was largely found in grade 3 (G3) endometrioid adenocarcinoma and other phenotypes of EC. In the G1 and G2 group, all 29 cases with reduced PTEN staining showed p53-negative staining (p=0.025). In the G3 and others group, 6 of 8 cases with reduced PTEN staining showed p53-positive staining. p53-positive staining was associated with a high probability of tumor recurrence in the G1 and G2 group (p=0.0234). In contrast, in the G3 and others group, p53-positive cases had a low probability of tumor recurrence (p=0.0473). Both PTEN and p53 staining may be good indicators of clinical stage and probability of tumor recurrence in EC. Reciprocal abnormality of p53 or PTEN occurred at an early phase of carcinogenesis, however simultaneous abnormality of p53 and PTEN often occurred at the a late phase of carcinogenesis. Thus, immunohistochemistry for PTEN and p53 in biopsy specimens of EC can provide supportive information for determining a treatment plan.

A firm, ulcerated tumor formed on the left side of the tongue of an elderly woman. Histopathological analysis showed that this unusual neoplasm was composed of monomorphic polygonal cells that exhibited a clear cytoplasm containing large amounts of periodic acid Schiff (PAS)-positive, diastase-digestive material. Most of the tumor cells stained immunohistochemically for Cytokeratin, high-molecular, CAM5.2, and epithelial membrane antigen (EMA), but were negative for alpha-smooth muscle actin, vimentin, glial fibrillary acid protein (GFAP), and S-100 protein. These findings supported a diagnosis of clear cell adenocarcinoma. Although patients with this type of tumor generally have a favorable prognosis, the tumor in our patient was fast-growing and contained a large number of Ki-67 positive cells, which are known to be highly proliferative. Thus, this case highlights the fact that even clear cell adenocarcinomas that are usually slow-growing should be investigated by conventional morphological techniques and their proliferative activity quantified in order to select the most appropriate treatment strategy.

We report three cases of focal glomerular sclerosis (FGS) with proteinuria that improved with the administration of angiotensin type 1 receptor blocker (ARB, losartan or valsartan). These three patients were a 41-year-old male (case 1), a 22-year-old male (case 2) and a 47-year-old male (case 3), who showed proteinuria, renal dysfunction, and hyperlipidemia. In case 1, proteinuria and renal dysfunction were improved by losartan administration and low protein diet therapy. In case 2, losartan with steroid and immunosuppressant led to the complete remission of proteinuria, improvement of renal dysfunction and reduction of the glomerular injury score from repeat biopsy specimen by approximately 20%. In case 3, proteinuria was reduced by valsartan administration with steroid and immunosuppressant therapy. ARB treatment with steroid and immunosuppressant might be more effective on the reduction of proteinuria in FGS patients.

Mutations of p53 tumor suppressor gene increase with tumor progression in colorectal cancers. In this study, we examined the expressions of p33ING1, p14ARF, MDM2 and p21WAF1 mRNA in 25 advanced colorectal cancers by quantitative RT-PCR method, and compared the expression levels of p33ING1, p14ARF, p21WAF1 and MDM2 in relation to p53 status in the tumors. Fifteen of 25 colorectal cancers (60%) showed abnormal accumulation of p53 protein in the nucleus, and the remaining 10 colorectal cancers (40%) were negative for p53 immunostaining. We found a G --T transition (nonsense mutation) at the first nucleotide of codon 298 (exon 8) in one p53-negative case, and a frame shift mutation on exon 7 in another p53-negative case. In remaining eight p53-negative cases, there was no mutation in the entire open reading frame of p53 cDNA. Interestingly, in eight cases with p53 wild-type gene, 6 cases (75%) showed a marked down-regulation of p14ARF mRNA, and three cases (37.5%) over-expressed MDM2 mRNA. Only one case with wild-type p53 gene showed normal level expression of p53 regulatory-factors (p33ING1, p14ARF, and MDM2). Thus, p53 tumor suppressor pathway was disrupted in 24 of 25 colorectal cancers (96%).

Multilocular cystic renal cell carcinoma (MCRCC) is an uncommon variant of renal neoplasm and its histogenesis is unclear. The aim of this study was to use immuno- and lectin histochemistry to delineate histochemical patterns which might indicate the histogenetic origin of MCRCC from a particular part or parts of the nephron. We present our experience with nine cases of MCRCC. Fifteen cases of renal cell carcinoma with cystic degeneration (RCC-CD) were selected for comparison with MCRCC. We carried out clinicopathological and immunohistochemical examinations of the MCRCC cases. Clinically, the prognosis of the patients was quite good, in that all nine patients are alive and without recurrence at the time of this report. The MCRCCs reacted strongly in a higher proportion of cases with the distal nephron markers, such as peanut agglutinin (PNA, 88.9%) and MUC1l-core antibody (MUC1, 100%), but none reacted preferentially with proximal nephron markers such as vimentin, Leu Ml and Lotus tetragonolobus (LTA). The RCC-CD tumours reacted with vimentin (40%), Leu Ml (66.7%) and LTA (86.7%). Except for two cases, the RCC-CD tumours did not react with PNA or MUC1 core antibody. These results illustrate the different patterns of expression of MCRCC and RCC-CD and suggest that MCRCC originates from the distal nephron. Therefore, MCRCC should be differentiated from other types of renal cell carcinoma on the basis of the histogenesis of the tumour and the clinicopathological findings.

Ulcerative colitis (UC)-associated neoplasia is one of the complications seen in patients with long-standing UC. Based on many epidemiological studies, colitis is assumed to promote colon tumorigenesis. Tumorigenesis is known to be suppressed in rodents and humans by selective cyclooxygenase-2 inhibitors. However, whether these drugs would serve as protective agents against UC-associated neoplasia remains unclear. Therefore, using a colitis-induced tumorigenesis rat model, we investigated the effects of etodolac, a selective cyclooxygenase-2 inhibitor, on tumorigenesis. The following 4 groups were examined: group A, administered trinitrobenzene sulfonic acid and 1,2-dimethylhydrazine; group B, in addition to the treatment in group A, also received etodolac; group C, administered etodolac alone; and group D, did not receive any agent throughout the study and served as an untreated control. The rats were sacrificed 163 days after the start of experiment, and the number of aberrant crypt foci and tumors in the intestine were counted using a stereoscopic microscope following methylene blue staining. The mean number of aberrant crypt foci was 52.4 in group A, 18.9 in group B, 0 in group C and 0.5 in group D. A total of 9 tumors were observed in group A alone, with none in the remaining groups. The numbers of aberrant crypt foci and tumors in group B were significantly lower than in group A. Etodolac, a selective cyclooxygenase-2 inhibitor, suppresses the occurrence of aberrant crypt foci and tumors in colitis-induced tumorigenesis in rats.

Depth of submucosal invasion (SM depth) in submucosal invasive colorectal carcinoma (SICC) is considered an important predictive factor for lymph node metastasis. However, no nationwide reports have clarified the relationship between SM depth and rate of lymph node metastasis. Our aim was to investigate the correlations between lymph node metastasis and SM depth in SICC.SM depth was measured for 865 SICCs that were surgically resected at six institutions throughout Japan. For pedunculated SICC, the level 2 line according to Haggitt's classification was used as baseline and the SM depth was measured from this baseline to the deepest portion in the submucosa. When the deepest portion of invasion was limited to above the baseline, the case was defined as a head invasion. For nonpedunculated SICC, when the muscularis mucosae could be identified, the muscularis mucosae was used as baseline and the vertical distance from this line to the deepest portion of invasion represented SM depth. When the muscularis mucosae could not be identified due to carcinomatous invasion, the superficial aspect of the SICC was used as baseline, and the vertical distance from this line to the deepest portion was determined.For pedunculated SICC, rate of lymph node metastasis was 0% in head invasion cases and stalk invasion cases with SM depth3000 micro m if lymphatic invasion was negative. For nonpedunculated SICC, rate of lymph node metastasis was also 0% if SM depth was1000 micro m.These results clarified rates of lymph node metastasis in SICC according to SM depth, and may contribute to defining therapeutic strategies for SICC.

Alpha-fetoprotein producing gastric cancer (AFP-GC) rarely occurs, but it is classified as a special subtype of gastric cancer (GC). This tumor, as represented by the production of AFP, exhibits not only specific function but also different histology compared with ordinary-GC (O-GC). Clinically, it is likely to metastasize to the liver and, as a consequence, poor prognosis is recognized as one of the features. Recently, AT motif binding factor-1 (ATBF1) was identified as a modulator of AFP production by hepatocellular carcinoma, and the decreased expression of the protein was also reported in AFP-GC. However, little is known about the biological significance of the decreased expression. In this study, to clarify the biological characteristics of AFP-GC, antibody was raised against ATBF1 and immunohistochemistry was carried out. The antibody specifically recognized ATBF1, and the degree of expression could be characterized by immunohistochemistry. ATBF1 was expressed in O-GC and the area of tubular adenocarcinoma components of AFP-GC. On the other hand, the expression pattern varied in the hepatoid carcinoma components of AFP-GC, and AFP was expressed in the area without ATBF1 expression. Taken together, these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription. Furthermore, in terms of differentiation induction, ATBF1 expression was decreased in the areas with little glandular formation. This may suggest that aberrant expression of ATBF1 induces the expression of various factors that are otherwise suppressed, and that this somehow determines the biological features of AFP-GC.

Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.

Alpha-fetoprotein producing gastric cancer (AFP-GC) rarely occurs, but it is classified as a special subtype of gastric cancer (GC). This tumor, as represented by the production of AFP, exhibits not only specific function but also different histology compared with ordinary-GC (O-GC). Clinically, it is likely to metastasize to the liver and, as a consequence, poor prognosis is recognized as one of the features. Recently, AT motif binding factor-1 (ATBF1) was identified as a modulator of AFP production by hepatocellular carcinoma, and the decreased expression of the protein was also reported in AFP-GC. However, little is known about the biological significance of the decreased expression. In this study, to clarify the biological characteristics of AFP-GC, antibody was raised against ATBF1 and immunohistochemistry was carried out. The antibody specifically recognized ATBF1, and the degree of expression could be characterized by immunohistochemistry. ATBF1 was expressed in O-GC and the area of tubular adenocarcinoma components of AFP-GC. On the other hand, the expression pattern varied in the hepatoid carcinoma components of AFP-GC, and AFP was expressed in the area without ATBF1 expression. Taken together, these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription. Furthermore, in terms of differentiation induction, ATBF1 expression was decreased in the areas with little glandular formation. This may suggest that aberrant expression of ATBF1 induces the expression of various factors that are otherwise suppressed, and that this somehow determines the biological features of AFP-GC.