Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA.

Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1ß was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice.

Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment.

BACKGROUND: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. METHODS: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. RESULTS: Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. CONCLUSION: These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

Adiposity, adult weight change and breast cancer risk in postmenopausal Japanese women: the Miyagi Cohort Study.

BACKGROUND: The role of adult weight change in breast cancer (BC) risk is unclear in Japanese women. METHODS: A total of 10,106 postmenopausal women aged 40-64 years (the Miyagi Cohort) were followed from 1990 to 2003, and 108 BC cases were identified. Hazard ratios (HRs) were estimated according to body mass index (BMI) at the current age and at the of age 20 years, and weight change since age 20 years. RESULTS: Higher current BMI was associated with an increased risk of BC (P for trend=0.02), whereas higher BMI at the age 20 years was inversely associated with this risk (P for trend=0.002). There was a significant association between weight change since age 20 years and BC risk (P for trend=0.0086). Compared with stable weight, HR was 0.35 for weight loss of 5 kg or more (P for weight loss trend=0.04) and 1.55 for weight gain of 12 kg or more (P for weight gain trend=0.05). CONCLUSION: Adiposity at younger and current age has differential effects on BC risk among postmenopausal women; weight gain in adulthood being associated with an increased, and weight loss with a decreased risk.

Evaluation of 18F-2-deoxy-2-fluoro-glucose positron emission tomography for gastric cancer screening in asymptomatic individuals undergoing endoscopy.

(18)F-2-deoxy-2-fluoro-glucose Positron Emission Tomography (FDG-PET) has been recently proposed as a promising cancer-screening test. However, the validity of FDG-PET in cancer screening has not been evaluated. We investigated the sensitivity of FDG-PET compared with upper gastric endoscopy in gastric cancer screening for asymptomatic individuals. A total of 2861 consecutive subjects (1600 men and 1261 women) who were asymptomatic and who underwent both FDG-PET and upper gastrointestinal endoscopy between 1 February 2004 and 31 January 2005 were included in this study. Both endoscopists and a radiologist were unaware of the results of the other diagnostic tests. The FDG-PET images were examined using criteria determined by the pattern of FDG accumulation. Sensitivity and specificity of FDG-PET were calculated compared with endoscopic diagnosis as the gold standard. Among 2861 subjects enrolled in the study, there were 20 subjects with gastric cancer, of whom 18 were T1 in depth of cancer invasion. Positive FDG-PET results were obtained only in 2 of the 20 cancer subjects. The calculated sensitivity and specificity for overall gastric cancers were 10.0% (95% confidence interval (CI): 1.2-31.7%) and 99.2% (95% CI: 98.8-99.5%), respectively. (18)F-2-deoxy-2-fluoro-glucose Positron Emission Tomography was poorly sensitive for detection of gastric cancer in the early stages.

Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation.

Thrombotic microangiopathy (TMA) is a significant complication after hematopoietic stem-cell transplantation (HSCT); however, there is little information on it following reduced-intensity cord blood transplantation (RI-CBT). We reviewed the medical records of 123 adult patients who received RI-CBT at Toranomon Hospital between January 2002 and August 2004. TMA was diagnosed in seven patients based on intestinal biopsy (n = 6) or autopsy results (n = 1). While these patients showed some clinical symptoms such as diarrhea and/or abdominal pain, mental status alterations or neurological disorders were not observed in any of them. Laboratory results were mostly normal at the onset of TMA; >2% fragmented erythrocytes (n = 1), <10 mg/dl haptoglobin (n = 1), and >200 IU/dl lactic dehydrogenase (LD) (n = 4). On endoscopic examination, TMA lesions, consisting of ulcers, erosions, and diffuse exfoliation, were distributed spottily from terminal ileum to rectum. Intestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) colitis were confirmed in five and four patients, respectively. With therapeutic measures including supportive care (n = 4), fresh frozen plasma (n = 1), and a reduction of immunosuppressive agents (n = 1), TMA improved in four patients. The present study demonstrates that intestinal TMA is a significant complication after RI-CBT. Since conventional diagnostic criteria can overlook TMA, its diagnosis requires careful examination of the gastrointestinal tract using endoscopy with biopsy.

Endoscopically demonstrable esophageal changes after Helicobacter pylori eradication in patients with gastric disease.

BACKGROUND AND AIMS: An increased prevalence of reflux esophagitis has been reported following Helicobacter pylori (H. pylori) eradication in patients with duodenal ulcers in Western countries. However, it has remained unknown whether this might also appertain to individuals with other diseases. We therefore carried out this study to determine the effect of eradicating H. pylori infection in a series of Japanese patients. METHODS: Of a total of 203 H. pylori-positive patients successfully cured of infection, 82 cases (58 males, 24 females) with gastric disease, but not duodenal ulcers, were included in the present study; median age 56 years (range 18-80) and median follow up of 24 months (range 6-65). The patients were investigated clinically and endoscopically at regular intervals. RESULTS: Mild reflux esophagitis developed after eradication in three of 55 (5.5%) patients formerly without this condition, while it improved after eradication in five of 27 (18.5%) patients, with the disease endoscopically diagnosed prior to eradication. The estimated incidence of esophagitis within 3 years was 4.8% after cure of infection. Short segment Barrett's esophagus developed after eradication in six of 58 (10.3%) patients who did not have it prior to the therapy, while the condition did not improve in 24 patients affected before eradication. CONCLUSIONS: Endoscopic esophageal changes after H. pylori eradication in the present series of Japanese patients were relatively infrequent and mild. This therapeutic approach thus appears to be safe and unproblematic.

Hepatectomy using an ultrasonically activated scalpel for hepatocellular carcinoma.

BACKGROUND: The first retrospective studies were performed to compare the efficacy of the ultrasonic cavitational aspirator (aspirator group) and the ultrasonically activated scalpel (scalpel group) for hepatic resection in patients with hepatocellular carcinoma. PATIENTS AND METHODS: The aspirator group consisted of 8 patients (6 with liver cirrhosis and 2 with chronic hepatitis in the nontumorous liver), and the scalpel group of 7 patients (6 with liver cirrhosis and 1 with chronic hepatitis). All patients underwent limited hepatic resection, and the intermittent Pringle maneuver was applied during hepatic transection. RESULTS: There were no significant differences in preoperative hepatic function, type of hepatectomy, tumor size and maximum cross-sectional area of the resected specimen between the 2 groups. The amount of intraoperative blood loss was significantly less in the scalpel group than in the aspirator group (684 versus 1,859 ml, p < 0.05). The operation time was significanly shorter in the scalpel group than in the aspirator group (176 versus 262 min, p < 0.05). There were no significant differences in postoperative liver function and morbidity between the 2 groups. CONCLUSIONS: The ultrasonically activated scalpel is effective in reducing blood loss and in shortening the time of operation, and can be employed during limited resection of the liver with cirrhosis or chronic hepatitis.

Mitotic index is the best predictive factor for survival of patients with resected hepatocellular carcinoma.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), tumor recurrence is not infrequent after resection. It is presumed that characteristics of the tumor such as cellular malignancy might influence the prognosis of the patients in association with tumor stage and radicality of the procedure. METHODS: Univariate and multivariate analyses were used to retrospectively determine the clinicopathologic factors potentially related to survival in 40 patients who underwent hepatectomy for HCC. RESULTS: In univariate analysis, tumor stage I or II, mitotic index of 4 or less/10 random high-power fields, solitary tumor, and curative resection were significantly correlated with better survival. In multivariate analysis, the mitotic index and surgical curability were independently significant variables influencing survival of patients, and the mitotic index was the best predictive factor. A highly significant correlation was found between the mitotic index and Ki-67 labeling index. Compared to tumors with a mitotic index of 4 or less, those with a mitotic index of 5 or more had a higher association with multiple tumors and advanced tumor stage, which preclude curative resection. CONCLUSION: Analysis of the mitotic index is quite simple, and the mitotic index could be a useful factor for predicting the long-term survival of patients with HCC following hepatic resection.

Prediction of recurrence and extratumor spread of hepatocellular carcinoma following resection.

BACKGROUND AND OBJECTIVES: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy depends mostly on tumor recurrence. Portal vein invasion (Vp) and intrahepatic metastasis (IM) might strongly reflect the invasiveness of HCC, but the number of patients in the present series in whom either of these factors were detected was small. In this study, we defined Vp and IM as the extratumor spread, and we focused on the relationship between recurrence in patients after hepatectomy and the extratumor spread and the mitotic activities of cancer cells, in the hope that careful monitoring of recurrence might be possible by simply analyzing histology of the resected specimens. METHODS: Univariate and multivariate analyses were used to determine the factors potentially related to recurrence in 50 patients who underwent hepatectomy for HCC. RESULTS: The cumulative recurrence rate at 5 years was 81.0%. In univariate analysis, absence of the extratumor spread, mitotic index of four or less, and curative resection were significantly correlated with low incidence of recurrence. In multivariate analysis, the extratumor spread was the only significant variable influencing recurrence. The mitotic index in HCCs with the extratumor spread was significantly higher than the mitotic index in HCCs without the extratumor spread. CONCLUSIONS: As a predictive factor for recurrence after resection of HCC, the extratumor spread that reflects the malignant potential of cancer cells was found to be more accurate than is any single invasiveness parameter such as Vp or IM.

Diagnostic capability and rational resectional surgery for early gallbladder cancer.

Gallbladder carcinoma limited to the mucosa (pT1a) or muscularis proper (pT1b) with no lymph node metastasis (stage I) is defined as early carcinoma of the gallbladder. Eleven patients with early carcinoma of the gallbladder, treated by either simple or extended cholecystectomy (cholecystectomy plus wedge resection of the gallbladder bed of the liver and lymphadenectomy), were reviewed to determine the diagnostic capability and to clarify the rational resectional procedure for this stage of the disease. A definitive pre-operative diagnosis was made in only 2 patients with pT1b tumors. Most of the remaining 9 patients were diagnosed incidentally after cholecystectomy for polyps or stones. Among 7 patients with pT1a tumors, 5 underwent simple cholecystectomy and 2 underwent extended cholecystectomy. All 7 patients survived with a recurrence-free condition for 5 years or more following the operation. Two patients with pT1b tumors, however, died of a local recurrence or bile duct carcinoma following simple cholecystectomy. Two patients with pT1b tumors who were correctly diagnosed before the operation and underwent extended cholecystectomy survived without recurrence. It is concluded that patients with pT1a tumors can be successfully treated by simple cholecystectomy, while patients with pT1b tumors require extended cholecystectomy.

Therapeutic significance of palliative operations for gastric cancer for survival and quality of life.

BACKGROUND AND OBJECTIVES: There have been few reports on the objective assessment of quality of life (QOL) in patients with gastric cancer following palliative operations. The benefit of a palliative operation for survival and QOL of patients with gastric cancer is not clear. METHODS: Survival and hospital-free survival (HFS), which is considered to be one objective indicator of QOL, were studied in 95 patients undergoing palliative operations for gastric cancer. Univariate and multivariate analyses were used to determine the clinicopathologic factors potentially related to survival of patients. RESULTS: In univariate analysis, palliative gastrectomy and absence of peritoneal dissemination were significantly correlated with better survival. The significance of palliative gastrectomy for survival was, therefore, evaluated for various degrees of peritoneal dissemination: P0 no dissemination; P1, metastasis to the adjacent peritoneum; P2, a few scattered metastases to the distant peritoneum; and P3, numerous metastases. Survival and achievement of HFS for 3 months or longer were higher following palliative gastrectomy than gastrojejunostomy. Among gastrectomies, however, total gastrectomy performed in patients with P2 or P3 showed a poorer outcome for survival and HFS than total gastrectomy performed with P0 or P1 and distal gastrectomy. CONCLUSIONS: As a palliative measure, gastrojejunostomy and total gastrectomy performed with P2 or P3 peritoneal dissemination had no beneficial effect on the prolongation of survival or improvement of QOL of patients with gastric cancer.

Palliative operation for cancer of the head of the pancreas: significance of pancreaticoduodenectomy and intraoperative radiation therapy for survival and quality of life.

The benefits of a palliative operation and intraoperative radiation therapy (IORT) for survival and quality of life (QOL) of patients with cancer of the head of the pancreas are not clear. Survival and hospital-free survival (HFS), which are considered to be objective indicators of QOL, were studied in 13 patients who underwent palliative pancreaticoduodenectomy (PD) and 32 patients who underwent surgical bypass. Although there was no significant difference in the survival of patients who underwent PD or bypass (median survivals of 9 months and 7 months, respectively), HFS for 3 months or longer was achieved in 84.6% of the patients who underwent PD, which was significantly higher than that of the 53.1% in patients who underwent surgical bypass (p < 0.05). Among TNM stage III patients, a significant difference in survival was observed between surgical bypass associated with IORT and bypass alone (p < 0.05); the median survival time of the IORT group was 10 months, whereas that of the control group was 5 months. In addition, HFS of 3 months or longer was achieved in 83.3% of patients who underwent bypass with IORT but in only 25.0% of the patients who underwent surgery alone (p < 0.01). The addition of IORT to palliative PD neither prolonged survival nor improved HFS. These results show the beneficial effect of palliative PD on QOL, and the efficacy of IORT for survival and QOL was proved in cases with stage III pancreatic cancer who underwent surgical bypass. For patients subjected to palliative PD, however, IORT is not thought to be beneficial for either survival or QOL.

Histologic features and clinical significance of venous invasion in colorectal carcinoma with hepatic metastasis.

BACKGROUND: In colorectal carcinoma, venous invasion has been related to patient survival. Liver metastasis develops more frequently when venous invasion is present. However, the histologic features and clinical significance of venous invasion are not well understood. METHODS: A histologic study of venous invasion in colorectal carcinoma was performed on 19 patients with synchronous hepatic metastasis (Group A), 16 patients with metacaronous hepatic metastasis (Group B), and 26 patients with Dukes Stage C tumors who survived for 5 years without recurrence (Group C). The histologic features of venous invasion were classified into three types: tumor cells that were distant from the vein walls were categorized as floating type, those filling the lumen of a vein as filling type, and those surrounded by a vein obliterated with inflammatory reaction as occlusive type. RESULTS: Venous invasion was present in 89.5% of Group A patients and 75% of Group B patients, which was significantly higher than the 15.4% observed in Group C patients (P < 0.001). A slight to extensive degree of venous invasion was found in Groups A and B, but no extensive venous invasion was found in Group C. All patients in Groups A and B (except one patient) had floating, filling, or a combination of floating and filling types of venous invasion, whereas all patients in Group C had the occlusive type of venous invasion. A majority of the patients in all three groups showed invasion of extramural veins. CONCLUSIONS: There is a close relationship between venous invasion and the development of liver metastasis in patients with colorectal carcinoma. Patients with no sign of metastasis had a lower incidence and lower extent of venous invasion, and inflammatory damage to the vein walls around the intravenous tumor appeared to reduce the likelihood of distant metastasis.

Induction of islet cell differentiation and new islet formation in the hamster--further support for a ductular origin.

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocytochemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI;%) in control animals remained at a low level (0.25 +/- 0.01 and 0.26 +/- 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 +/- 0.7 and 0.80 +/- 0.1 (p < 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 +/- 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 +/- 0.8 (p < 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at approximately 8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of beta cell differentiation from cells in the ductular epithelium.

Alterations in pancreatic microcirculation and expression of endothelin-1 in a model of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by the presence of an inflammatory infiltrate with progressive destruction of acinar cells and fibrosis. The finding that endothelin-1 (ET-1), an endothelium-derived peptide having vasoconstrictive and mitogenic properties, reduces pancreatic blood flow (PBF) in normal rats suggested that the peptide may be associated with the reduced PBF seen in animal models of CP and with the morphological abnormalities of the disease. This study investigates changes in blood flow to the pancreas and other abdominal organs in a rat model of CP and compares ET-1 production in the pancreata of these rats and normal controls. CP was induced in male Wistar rats by the injection of oleic acid into the common bile/pancreatic duct. The radiolabeled microsphere technique was employed to measure blood flow to the pancreas, duodenum, liver, spleen, and kidneys. Immunohistochemistry was used to investigate the cellular production of ET-1. After 3 weeks, significant decreases were noted in body weight, pancreatic weight, and pancreatic DNA, amylase, and protein content in the animals with CP. PBF was reduced by 64% and duodenal blood flow by 80% relative to those in control animals. Hepatic and splenic blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flow was also seen in the experimental group after 3 weeks. Pancreata from animals with CP stained diffusely for ET-1 in the cytoplasm of vascular endothelial, acinar, and ductal cells. In the control pancreata, focal staining for ET-1 was observed only in acinar cells. This difference was significant in endothelial and ductal cells. There was weak staining of islet cells in both groups. The results suggest that elevation in local production of ET-1 may be associated with the morphological and hemodynamic changes of CP.

Continuous regional arterial infusion of protease inhibitor and antibiotics in acute necrotizing pancreatitis.

PURPOSE: This study was conducted to determine whether continuous regional arterial infusion (CRAI) of the protease inhibitor, nafamostat mesylate, in acute necrotizing pancreatitis, would reduce mortality. In addition, the effectiveness of CRAI of the antibiotic imipenem in combination with nafamostat was investigated for its effect in preventing secondary infection of the pancreatic necrotic tissue. PATIENTS AND METHODS: Fifty- three patients with acute necrotizing pancreatitis were divided into three groups: Group I, 16 patients who were referred >8 days after disease onset, received intravenous nafamostat and antibiotics; Group II, 22 patients referred within 7 days, received nafamostat via CRAI, and antibiotics intravenously; Group III, 15 patients referred within 7 days, received both nafamostat and imipenem via CRAI. RESULTS: The mortality rates in Group II (13.6%) and group III (6.7%) were significantly reduced, as compared with that in group I (43.8%). The incidence of infection of pancreatic necrosis in group III (0%) was significantly lower than those in group I (50%) and in group II (22.8%). CONCLUSION: CRAI of nafamostat and imipenem in acute necrotizing pancreatitis was effective in reducing mortality and preventing the development of pancreatic infection.

Expression of endothelin-1 in pancreatic tissue of patients with chronic pancreatitis.

Chronic pancreatitis is characterized by the presence of an inflammatory infiltrate, progressive destruction of acinar cells, and fibrosis. The finding that endothelin-1, an endothelium-derived peptide with vasoconstrictive and mitogenic properties, reduces pancreatic blood flow in normal rats suggested that the peptide may be associated with the reduced pancreatic flow seen in animal models of chronic pancreatitis and in the morphological abnormalities of the disease. The aim of this study was to investigate sites of endothelin-1 expression in the pancreas of normal subjects and patients with chronic pancreatitis. The techniques of immunohistochemistry, in situ hybridization, and Northern blotting were used. Endothelin-1-like immunoreactivity was localized predominantly to islet cells both in normal subjects and in patients with chronic pancreatitis. Semi-quantitative analyses of immunostaining showed that endothelin-1-like immunoreactivity in islet cells of patients with chronic pancreatitis was greater than in normal subjects. Co-localization studies with glucagon, insulin, somatostatin, and pancreatic polypeptide showed that endothelin-1-like immunoreactivity co-exists with glucagon and insulin. There was no apparent co-existence of endothelin-1-like immunoreactivity with somatostatin or pancreatic polypeptide. Endothelin-1 mRNA was expressed in sites similar to those of the immunostaining, as well as in vascular endothelial cells. Northern blot analysis showed an increase in the expression of endothelin-1 mRNA in the patient population. There was a significant correlation between intensity of endothelin-1 immunostaining and severity of fibrosis in the patients with chronic pancreatitis. These findings suggest that an elevation in local expression of endothelin-1 may be associated with the morphological and haemodynamic changes of chronic pancreatitis.