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Preoperative serum levels of sialyl Lewis(a) (CA 19-9), sialyl Lewis(x) (SLX), and sialyl Tn (STN) antigens in colorectal cancer patients were examined to establish predictive factors for serum levels of these antigens compared with carcinoembryonic antigen (CEA). A total of 308 patients who underwent resection for a colorectal cancer were divided into low and high antigen groups (higher or lower than a selected diagnostic-based cutoff value). The cutoff values were 37 U/ml for CA19-9, 38 U/ml for SLX, 45 U/ml for STN, and 2.5 ng/ml for CEA. The American Joint Committee on Cancer Classification and Stage grouping was used to classify the tumors. Statistical tests were conducted using univariate and multivariate logistic regression analyses. For CA19-9, 81 patients (26.3%) were assigned to the high antigen group: for SLX, 39 (12.7%); for STN, 33 (10.7%); and for CEA, 133 (43.2%). Multivariate logistic regression analysis revealed that predictive factors associated with high antigen levels were female sex (odds ratio [OR], 1.78 vs male sex), T4 (OR, 3.26 vs T1/T2), and M1 (OR, 3.35 vs M0) for CA19-9; M1 (OR, 6.40 vs M0) for SLX; mucinous carcinoma (OR, 8.45 vs well differentiated adenocarcinoma) and M1 (OR, 8.24 vs M0) for STN; and mucinous carcinoma (OR, 7.21 vs well differentiated adenocarcinoma), T3/T4 (OR, 3.84/4.18, respectively, vs T1/T2), and M1 (OR, 6.39 vs M0) for CEA. In conclusion, high serum levels of CA19-9, SLX, and STN are strongly associated with distant metastasis. In addition, high serum levels of CA19-9 may be an independent predictor for female gender and T4, and high serum levels of STN may be an independent predictor for mucinous carcinoma. [ABSTRACT FROM AUTHOR]

BACKGROUND: The relationship between patient prognosis and various tumor biological factors has been reported previously, and prognostic factors of tumor biology may improve predictions of prognosis after hepatectomy for hepatocellular carcinoma (HCC) and may contribute to a new staging classification. This study was designed to provide an immunohistochemical analysis of tumor biological factors in patients who underwent hepatectomy for HCC. METHODS: Factors analyzed included p53 overexpression, microvessel counts, proliferating cell nuclear antigen, and expression of nm23. We examined 81 HCCs from patients with chronic liver diseases. RESULTS: In patients who underwent chemoembolization before surgery, or those a who had confluent multinodular tumor, p53 expression tended to be higher than in patients without chemoembolization (33% vs 11%) or those with a simple nodular tumor (28% vs 10%), but the difference was not statistically significant ( P = 0.051 and P = 0.092, respectively). A lower tumor microvessel count and negative nm23 expression were significantly associated with poor disease-free survival by univariate analysis ( P < 0.01 and P < 0.05, respectively). A lower tumor microvessel count was found to be a significant prognostic factor for disease-free and overall survivals (risk ratios, 2.44 and 3.13, respectively; P << 0.05), in addition to tumor size, vascular invasion, and longterm ascites, by Cox's multivariate analysis. CONCLUSIONS: Tumor microvessel count appears to be a useful prognostic marker for predicting HCC recurrence and patient survival. [ABSTRACT FROM AUTHOR]

To clarify the relationship between multidrug resistance protein (MRP) and clinicopathologic features, the influence of adjuvant chemotherapy, and prognosis of patients who underwent resection of metastatic liver carcinomas originating from colorectal carcinomas, we examined the expression of MRP in tumor tissues by immunostaining. Specimens of 38 primary colorectal tumors and 44 metastatic liver tumors of colorectal origin were examined (metastatic group). We also examined 28 nonmetastatic colorectal carcinomas. The percentages of nonmetastatic tumors and of primary and metastatic tumors of the metastasis group that expressed MRP were similar. MRP expression in primary and metastatic tumors did not correlate with any clinicopathologic features. The use of adjuvant chemotherapy after operation for primary colorectal carcinomas was associated with increased MRP expression among metastatic liver tumors. Expression of MRP in the tumor did not influence the prognosis or survival rate after resection of primary or metastatic tumors. Our data suggest that MRP expression in metachronous liver metastases from colorectal carcinomas may be induced by administration of anticancer drugs but is not associated with clinicopathologic features of the tumor, liver metastasis, or prognosis. [ABSTRACT FROM AUTHOR]

The incidence of non-familial multiple primary cancer in colorectal cancer patients has increased in recent years in Japan. To clarify the characteristic genetic aberrations in such multiple cancers, we examined structural chromosomal aberrations by fluorescence in situ hybridization, using chromosome 17-specific and p53 cosmid DNA probes. We established short-term cultures of 78 surgical specimens and were able to obtain observable metaphase spreads in 23 single colorectal cancer specimens and in 6 colorectal cancer specimens from patients with double primary cancers. The frequency of chromosome 17 and/or p53 locus translocation was significantly greater in tumors with double cancer than in single colorectal cancers (P < 0.05 and P < 0.01, respectively). These aberrations in double cancers frequently appeared even at an early Dukes' stage (A and B) of colorectal carcinoma. Our results suggest that translocation of chromosome 17 and the p53 locus may be specific genetic events probably associated with carcinogenesis of multiple primary cancers in colorectal cancer. [ABSTRACT FROM AUTHOR]

Numerical aberrations of chromosome 17 and nuclear DNA content were compared in patients with hereditary non-polyposis colorectal cancer (HNPCC) and those with sporadic colorectal cancer (SCRC). During a period of 22 years, 30 cases (3.2%) from 28 families satisfied the Japanese clinical criteria of HNPCC. Using freshly frozen tissue samples, we investigated chromosomal aberration with fluorescence in situ hybridization with alpha satellite DNA probe for chromosome 17. Flow cytometric quantification of nuclear DNA content showed DNA aneuploidy in 9 of 15 patients (60.0%) with HNPCC and in 160 of 234 patients (68.4%) with SCRC, there was no significant difference between HNPCC and SCRC. The mean proportion of nuclei with aneusomy 17 (numerical chromosome aberration index: NCAI) in 14 patients with HNPCC was significantly higher than that in 42 patients with SCRC (46.8 +/- 5.0% vs 39.0 +/- 10.3%, P < 0.01). NCAI increased in proportion with the progression of the disease in SCRC (26.1% in stage I, 33.3% in stage II, 38.8% in stage IIIa, 42.7% in stage IIIb, and 46.2% in stage IV, P < 0.01), whereas NCAI in HNPCC was high in all stages (43.5%-49.2%). The proportion of patients with multiple numerical aberration of chromosome 17 was significantly higher in HNPCC (9/14) than among SCRC (11/42). Our data suggest that chromosome 17 is present in an unstable condition in HNPCC. [ABSTRACT FROM AUTHOR]

Background: This study assessed the mechanism of fistula formation in intraductal papillary mucinous neoplasm (IPMN) of the pancreas., Methods: A total of 274 patients with IPMN who had been diagnosed by endoscopic retrograde cholangiopancreatography and endoscopic ultrasonography (EUS) at our center were enrolled. The patients with IPMN which had fistula formation into other organs were investigated retrospectively as to (1) clinical prevalence and the organs penetrated by IPMN, (2) analysis of the mechanism of fistula formation by immunohistopathological study, (3) efficacy of EUS in progression assessment, and (4) prognosis., Results: Among the subjects, fistula formation into other organs was observed in 18 patients (6.6%) and into 28 organs. There were 7 patients (39%) in whom multiple organs were penetrated. Of 16 patients who had undergone investigation of the expression of mucin markers, 94% had an intestinal-type tumor. Of 9 patients who had undergone surgery or autopsy, 67% showed mechanical penetration without invasion around the fistula. Only papillary protrusions were seen by EUS in 4 of these patients with noninvasive papillary adenocarcinoma showing mechanical penetration. All 5 patients who had pancreatic parenchymal invasion showed a mass with a mixed-echo pattern in addition to papillary protrusions shown by EUS, corresponding to colloid carcinoma., Conclusions: There were 2 processes in the development of fistulas in IPMN. Of those patients showing fistula formation, 94% had intestinal-type IPMN, and 67% showed mechanical penetration. Delineation of a mass with the mixed-echo pattern suggested an invasive penetration due to colloid carcinoma.

Background: The diagnostic efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology may vary greatly depending on the treatment of the samples obtained and the level of proficiency of the cytopathologist or cytoscreener., Methods: We prospectively evaluated the diagnostic efficacy of the cell block (CB) method and that of smear cytology using tissue samples obtained in the same needle pass at EUS-FNA in 33 patients with pancreatic tumors, abdominal tumors or swollen lymph nodes. An average of 3.1 passes were applied during the procedure without affirmation by rapid cytology. About half of the material obtained by each single pass was subjected to smear cytology, while the other half was evaluated by the CB method. Four to 12 glass slides were prepared for both Papanicolaou stain and Giemsa stain. The CB sections were prepared using the sodium alginate method and subjected to HE, PAS-AB and immunohistochemical stains. Two pathologists independently made cytological and histological diagnoses. The final diagnosis was based on integration of cytohistological findings, diagnostic imaging, and clinical course., Results: The diagnostic accuracy of the CB method and that of smear cytology were 93.9 and 60.6%, respectively (p = 0.003), and their respective sensitivities were 92.0 and 60.0% (p = 0.02). It was easier to make a definite diagnosis of not only malignancies but also benign conditions by the CB method than by the smear method., Conclusion: The CB method with immunostaining showed a higher diagnostic yield than smear cytology in patients who had undergone EUS-FNA without rapid on-site cytology.

Background: Cystic duct cancer fulfilling Farrar's criteria is relatively rare, but tumors whose origin is estimated to be in the cystic duct exist. The clinical features of such "broadly defined" cystic duct cancer have not been clarified., Methods: The endoscopic retrograde cholangiography (ERC) findings, intraductal ultrasonography (IDUS) findings, histological findings, and prognoses of 11 cases of cystic duct cancers resected at our institution (group C) were retrospectively analyzed. As a control group, 55 cases of middle or lower bile duct cancer (group B) were used (in 20 of the 55 cases of group B, tumors extended to the cystic duct intraluminally (group B-C (+))., Results: (1) ERC findings of group C as compared with those of group B-C (+) were as follows: (a) unilateral bile duct narrowing (spoon-like appearance): 55% versus 5% (P<0.01); (b) bilateral bile duct narrowing (apple-core-like appearance): 27% versus 95% (P<0.001). (2) IDUS was unable to visualize the cysticocholedochal junction (negative "confluence sign") more often in group C (67%) than in group B-C (+) (13%) (P<0.01). (3) Histologically, tumors extended to the gallbladder and the bile duct in 36% and 91% of the cases in group C, respectively. (4) The median survival time of the two groups was 21 and 28 months, respectively., Conclusions: Cystic duct cancers frequently extended to the bile duct. The spoon-like appearance by ERC and the negative confluence sign by IDUS were characteristic findings.

Background: The aim of this study was to evaluate histopathologically the frequency, direction, and length of intraductal spread (IS) along the main pancreatic duct from the main tumor of small pancreatic cancer., Methods: Resected specimens from 20 cases of pTS1 (histologically 2 cm or less in diameter) pancreatic cancer (September 1983 to December 2005) were examined histopathologically. As controls, 40 resected specimens from cases of pTS2 (more than 2 cm and less than 4 cm in diameter) or larger sized pancreatic cancer (pTS2

Background: To elucidate the correlation of autoimmune pancreatitis (AIP) and mass-forming pancreatitis, in which a localized mass is formed in the pancreas., Methods: Nine cases of mass-forming pancreatitis were divided into two groups, one consisting of cases that met the histological diagnostic criteria for AIP by the Japan Pancreas Society (JPS) and the other consisting of cases which did not. Histological findings, immunohistological findings, and pancreatograms were compared between these groups., Results: Six cases met the histological criteria of JPS (group A) and the other three did not (group B). In the mass-forming portion in group A, the wall of the pancreatic duct showed marked thickening. However, the epithelium was well preserved, and dilatation of the branch ducts or protein plugs were rarely observed. All cases showed marked obliterative phlebitis. The IgG4 labeling index (LI) was 25% or more in all but one case. In the portion other than the mass, the lobular structure was well preserved and the IgG4 LI was less than 10%. The pancreatogram showed localized stenosis or obstruction at the site of the mass associated with a normal-appearing main pancreatic duct in the remaining portion. In group B, histological findings typical of chronic pancreatitis with dilated branch ducts and protein plugs were observed. Obliterative phlebitis was not confirmed. The IgG4 LI in the mass-forming portion was low (2.3%-11.1%)., Conclusions: There exists a subgroup of AIP showing localized mass formation and stenosis or obstruction of the main pancreatic duct with prominent obliterative phlebitis associated with a normal ductal segment.

Background: We histologically evaluated the epithelia of the gallbladder (GB) and bile duct (BD) in patients with anomalous arrangement of the pancreaticobiliary ductal system (AAPB), with regard to the shape of the common BD (CBD)., Methods: The GB and BD were studied histologically using surgical materials from 44 patients with AAPB: 27 with a dilated CBD (D-type) and 17 with a nondilated CBD (N-type)., Results: GB cancer and BD cancer were found in 11.1% and 3.7% of D-type and 17.6% and 0% of N-type respectively. Hyperplastic epithelium and atypical epithelium of the GB were frequently seen in both D-type (46%, 46%) and N-type (82%, 70%), while such epithelia of the BD were only seen in D-type (10%, 35%). The Ki67 labeling index of the nonneoplastic epithelium of the GB was high in both D-type (13.0%) and N-type (9.7%), though that of the BD was high in D-type (12.5%) but low in N-type (1.8%). The prevalences of pyloric gland metaplasia, intestinal metaplasia, and p53 protein overexpression of the nonneoplastic epithelium did not show any significant differences between D-type and N-type., Conclusions: It is suggested that the BD epithelium of N-type probably has a lower potential for developing malignancy than that of D-type, while the GB epithelia of both D-type and N-type have a high potential for developing malignancy. This might support the selection of simple cholecystectomy as the treatment of choice in AAPB patients of N-type, although further investigation of the BD epithelium is required in a larger number of such patients.

Intraductal papillary neoplasm of the bile duct (IPNB) or liver is a recently noted rare disease, and its pathogenesis remains unclear. Here we present a case of IPNB with an interesting morphology, which was treated by resection of the right hemiliver and extrahepatic bile duct. A 79-year-old woman was found to have a high alkaline phosphatase level and slight dilatation of the right intrahepatic bile duct on imaging studies. The right intrahepatic bile duct became dilated over a 2-year period; however, no solid mass could be detected, and tumor markers were not elevated. Hepatic resection was scheduled because a mucin-producing bile duct carcinoma of the liver was suspected. A right hemihepatectomy was conducted, and the extrahepatic bile duct was also resected after malignant cells were found in the surgical stump of the right bile duct and in the bile itself. Macroscopically, diffuse dilatation of the intrahepatic bile duct was noted, but no solid component or mucin within the duct was found. Histopathological findings revealed carcinoma in situ, IPNB, in the majority of intrahepatic bile ducts, with no lymph node metastasis, and it extended continuously to the epithelium of the common bile duct. No tumor recurrence or biliary dilatation was observed at follow-up 2 years after surgery. It is important to consider malignancy in the presence of a dilated bile duct and in the absence of any cause of occlusion. Complete resection of IPNB results in a good prognosis and no recurrence.

Background: We previously reported the effectiveness of the modified Cancer of the Liver Italian Program (CLIP) score in hepatocellular carcinoma (HCC) staging. To determine the best predictive staging system for HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 230 Japanese HCC patients following hepatic resection., Methods: We compared overall survival as predicted by different staging systems: the tumor node metastasis (TNM) system by the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), the modified JIS score using liver damage grade, the CLIP score, and our modified CLIP score using protein induced by vitamin K absence or the antagonist II (PIVKA-II)., Results: By a univariate analysis the PIVKA-II level (cut-off level, 400 mAU/ml) was significantly associated with patient survival (P = 0.031); however, alpha-fetoprotein level was not related to survival. Liver damage grade was significantly associated with patient survival (P = 0.039), although Child-Pugh classification was not related to survival. Univariate analysis showed that prediction of survival, according to disease stage, was better with the modified JIS score than with the TNM system, CLIP, modified CLIP, or JIS score. Multivariate analysis showed the modified JIS score showed the best ability to predict overall survival according to disease stage (Hazard ratio, 1.77; P = 0.002), and its Akaike information criteria statistic was the lowest (634.3)., Conclusions: The modified JIS score, a staging system that combines tumor factors and hepatic function, is a better predictor of prognosis than other systems in HCC patients who have undergone hepatic resection.

Background: Photodynamic therapy (PDT) is a new palliative option in patients with non-resectable bile duct carcinoma (BDC). Here, we assessed the efficacy of adjuvant photodynamic therapy in eight patients with BDC who underwent surgical resection., Methods: Five patients had extrahepatic BDC, two had intrahepatic cholangiocarcinoma, and one had ampullary carcinoma. Cancer cells were microscopically detected in the stump of the hepatic duct in six patients, and biliary stenosis caused by remnant tumor was observed in one patient. One patient had tumor recurrence with occlusion of the bile duct. At 48 h prior to PDT, porfimer sodium was injected intravenously. A pulse laser by an eximer dye laser (50-100 J/cm2) with a wavelength of 630 microm was applied through an endoscope to the hepatic stump or tumor lesion., Results: Marked destruction of the tumor and ductal epithelium was observed on day 1 after PDT. After PDT, four patients developed mild dermatitis, but no severe morbidity or mortality was noted. In patients who underwent PDT for the stump, one patient showed distant metastasis at 31 months, and four patients did not show tumor recurrence at 17, 12, 12, and 6 months, respectively. However, one of the eight patients died at 2 months, of an unrelated cause. In two patients with occlusion caused by tumor growth, resolution of bile duct stenosis was noted on day 7. These patients showed re-occlusion by tumor at 20 and 8 months., Conclusions: Adjuvant PDT is a safe and useful option for a better survival benefit in patients with BDC undergoing surgical resection.

Extraintestinal manifestations of ulcerative colitis (UC) are well known, but immunologically mediated hematological diseases are relatively rare. We describe two cases of immune thrombocytopenic purpura (ITP) associated with preexisting UC. Our patients had typical symptoms of UC, and endoscopy showed pancolitis. During treatment with 5-aminosalicylic acid and steroids, severe thrombocytopenia was noted. ITP was diagnosed based on a normal to high number of megakaryocytes in the bone marrow, positive autoantibody to platelet membrane antigen, and absence of splenomegaly. Medical treatment, including increased dosage of steroids, failed to control UC and ITP in both patients. In the first patient, the platelet count recovered after colectomy, while the second patient died of a cerebral hemorrhage. We stress that a diagnosis of ITP should be considered for thrombocytopenia in patients with UC, especially those showing extensive and significant colonic inflammation, and that colectomy of UC might resolve resistant ITP.

Genetic aberrations in radiation-associated colorectal cancer have not been studied in detail. We analyzed genetic aberrations in five rectal cancers that developed long after radiotherapy had been performed for cervical cancer. Microsatellite instability (MSI) in tumors was examined at five loci: D2S123, D3S966, TP53, DCC, and BAT26. Mutation of simple repeat sequences within the hMSH3, BAX, and transforming growth factor Beta type II receptor ( TGFBetaRII) genes was examined by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP). Mutation of p53 exons 5-8 was examined by PCR-SSP and direct sequencing. Mutations of the K- ras gene were analyzed by two-step PCR. No MSI was found in tumor specimens at any of the loci examined, and no mutations in the target genes were observed. K- ras mutation was detected in two carcinomas, but not in their irradiated normal mucosa, while p53 mutation was observed in another two carcinomas, but not in their irradiated normal mucosa. Our results suggest that the radiation-associated rectal carcinomas examined in this study did not develop through the mutator phenotype pathway; rather, tumorigenesis was probably mediated through the multistep carcinogenesis pathway.

Background: Macroscopic classification of metastatic liver tumors has been recommended to predict patient prognosis., Methods: We examined the morphological analysis of metastatic colorectal cancer in 64 patients who underwent hepatic resection and the relationship with clinicopathologic factors. To identify the irregularity of the tumor, we calculated three formulas: (1) actual area of representative cut surface of tumor/circular length of tumor margin, (2) actual area of representative cut surface of tumor/elliptic area, defined by the major and minor axes, and (3) deviation of radius of marginal curvature., Results: Following Yasui's macroscopic classification, the values of formulas (1) and (2) in confluent nodules were significantly lower than those in simple nodules ( P < 0.05), while the value of formula (3) in confluent nodules was significantly greater than that in simple nodules ( P< 0.05). Only a lower value of formula (1) (less than 0.19) was significantly associated with postoperative recurrence ( P< 0.05) and a lower value tended to be associated with a shorter disease-free survival after hepatectomy, but not significantly ( P= 0.09). However, most values were not associated with any clinicopathologic factors or postoperative survival., Conclusions: We conclude that differences in the morphological irregularity of liver tumors in metastatic colorectal cancer do not have clinical significance.

Specific loss of heterozygosity of chromosome 18 has been observed frequently in advanced colorectal carcinoma and is closely associated with its development. We investigated the prevalence of numerical aberrations of chromosome 18 in 44 specimens of colorectal carcinomas, using fluorescence in situ hybridization. We also examined the relationship between aneusomy of chromosome 18 and the clinicopathological features of these tumors. Aneusomy of the specimens (monosomy and polysomy) was determined when the same aneusomic population was detected in more than 15% of the nuclei. The frequency of monosomy and polysomy of chromosome 18 in colorectal carcinomas was 43% (19/44) and 29% (12/44), respectively. The prevalence of monosomy and polysomy 18 was significantly higher in cancers with invasion exceeding category T2 compared with T1 (P < 0.01), and with tumor size exceeding 20 mm in diameter compared with tumors less than 20 mm (P < 0.05). However, the prevalence of aneusomy 18 was not associated with other clinico-pathological features. The mean survival period and the 5-year survival rate after operation in patients with aneusomy 18 was not different from findings for those with disomy 18. Our results indicate that aneusomy of chromosome 18 is associated with the development of colorectal carcinoma; however, it is not a useful indicator of postoperative prognosis.