Hirokazu Noshiro

We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB) and the biological function of activated NF-kappaB in gastric carcinoma cells. Human gastric carcinoma cell line GCTM-1 was used to examine NF-kappaB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1beta and MMP-9 and activation of NF-kappaB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically. IL-1beta enhanced NF-kappaB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-kappaB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1beta-treated GCTM-1 cells. IL-1beta did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1beta and nuclear NF-kappaB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1beta were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen. One of the molecules that may play a role in NF-kappaB activation in some gastric carcinomas is IL-1beta. The present results suggest that IL-1beta increases the invasive ability of carcinoma cells through activation of NF-kappaB and the resulting MMP-9 expression.

To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraductal papillary-mucinous tumours. Retrospective study. University department of surgery, Japan. 21 patients with mucinous cystic neoplasms (group 1) and 48 with intraductal papillary-mucinous tumours (group 2). The mean age was younger in group 1 (53(3.4) years) than in group 2 (65(1) years, p < 0.0001). The male:female ratio was smaller in group 1 than in group 2, being 0.17 (3/18) and 1.4 (28/20), respectively, (p = 0.0007). The main sites of the lesions were also significantly different: in group 1 four (19%) were located in the head and 17 in the body or tail, while 32 (67%) were in the head of the pancreas and 16 (33%) in the body or tail in group 2 (p = 0.0007). A unique endoscopic finding, excretion of mucin from the patulous orifice of the papilla, was present in two (9%) of the 21 mucinous cystic tumours and in 21 (45%) of the 47 intraductal papillary-mucinous tumours examined (p = 0.006). Metachronous or synchronous malignant diseases were found in the pancreas or other organs in one (5%) of the 21 patients with mucinous cystic neoplasm and in 13 (27%) of the 48 with intraductal papillary-mucinous tumours (p = 0.03). The three- and five-year survival rates of 11 patients with mucinous cystadenocarcinoma were 45% and 27%, while those of 15 with intraductal papillary-mucinous carcinoma were 85% and 42%. These findings suggest that mucinous cystic neoplasm and intraductal papillary-mucinous tumours are different clinicopathological entities. Aggressive surgery with peripancreatic lymph node dissection is recommended, particularly for mucinous cystadenocarcinoma, and postoperative follow-up with attention given to the presence of other malignancy is necessary as well as to local recurrence and haematogenous spread.

Hepatectomy combined with colectomy is the preferred treatment for patients with synchronous colorectal cancer and hepatic metastasis. However, the effects on hepatic reserve function of combining colectomy with hepatectomy are unclear. The purpose of this study was to determine liver regeneration and functions after hepatectomy with and without colectomy. 23 rats underwent 70% hepatectomy (Hx group) and 23 rats underwent 70% hepatectomy with ileocecal resection (HCx group), and 6 rats just after surgery (day 0) underwent simple celiotomy. On days 0, 1, 2, 3 and 7 after surgery, the remnant liver weight, DNA synthesis rate, malondialdehyde concentration, hepatic Adenosine monophosphate, ADP, ATP, serum hyaluronic acid concentration and endotoxin level in the portal blood were measured. In HCx group, the hepatic DNA synthesis rate on day 1 (p < 0.01) and the liver weight on day 7 (p < 0.05) were significantly lower, hepatic malondialdehyde concentration on days 1 and 2 (p < 0.05) was significantly higher and serum hyaluronic acid and portal endotoxin levels on day 1 were significantly higher (p < 0.01 and p < 0.05, respectively). Addition of colectomy to hepatectomy impairs regeneration and endothelial cell function of the remnant liver; the impairment is associated with increased levels of portal endotoxin and hepatic lipoperoxide.

Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with fecal immunochemical tests (FIT) widely utilized for CRC screening in Japan. To evaluate the importance of repeated FIT screening, the incidence of CRC was compared in patients undergoing initial and repeated screening. Participants aged ≥40 years in Saga, Japan, were invited to undergo a 2-day FIT. FIT positive subjects were verified by colonoscopy to evaluate the CRC incidence rates. From 2005 to 2007, 55,595 individuals were invited to undergo CRC screening, including 47,168 undergoing repeated and 8,427 undergoing initial screening. Of the 5,832 FIT-positive subjects, 4,615 were assessed by colonoscopy, with 114 diagnosed as having CRC. Of these 114 patients, 67 had early and 47 had advanced CRC. The risk of CRC was 63% lower in the repeated than in the initial screening group (p<0.0001). Of the 67 patients with early CRC, 42 underwent endoscopic resection, with the rate significantly higher in the repeated than in the initial screening group (p = 0.01). Overall survival was longer in screened subjects than in those who visited hospitals with clinical symptoms. Repeated CRC screening with FIT reduced the incidence of CRC in Saga, Japan.

BACKGROUND/AIMS: Even with the recent advances of diagnostic and therapeutic modalities, the clinical course of patients with pancreatic cancer remains dismal. Five-year survivors are rare, cure is exceptional, and the operative mortality rate is significant. In this study, univariate and multivariate retrospective analyses were performed with regard to the prognostic parameters to clarify the problems in order to improve survival rates after surgical resection.METHODOLOGY: Clinical courses of 60 Japanese patients with pancreatic cancer who underwent surgical resection in one Japanese University Hospital were reviewed to scrutinize the influence of 22 prognostic (9 host-side, 5 operative and 8 tumor-side) factors. A special reference was made on intra-operative radiation therapy, portal vein resection, lymph node dissection around the aorta, and conventional pancreatoduodenectomy versus pylorus-preserving pancreatoduodenectomy in pancreatic head cancer.RESULTS: Univariate analysis showed that operation time, comprehensive stage, comprehensive curability, histopathologic grade of differentiation and histopathologic venous invasion were statistically significant factors. Multivariate Cox regression analysis regarding the 5 profound factors showed that histopathologic grade of differentiation and histopathologic venous invasion were independently significant factors. The 1- and 3-year survival rates of 18 patients with intra-operative radiation therapy were 56% and 39%, while those of 36 patients without intra-operative radiation therapy were 54% and 18%. The 1- and 3-year survival rates of 43 patients with PV0,1 were 58% and 28%, while those of 17 with PV2,3 were 50% and 10%. Three patients with PV2 in 1 and PV3 in 2 underwent a portal vein resection. Two of the 3 patients were dead from liver metastasis 3 and 5 months after a surgical resection of liver metastasis. The 1- and 3-year survival rates of 17 with radical lymph node dissection including the para-aortic area were 61% and 26%, while those of 27 without para-aortic lymph node dissection were 66% and 25%. Of the 17 patients, the para-aortic lymph node was metastasized in 1 patient. The 1- and 3-year survival rates of 31 with pancreatoduodenectomy were 53% and 18%, while the 1- and 3-year survival rates with pylorus preserving pancreatoduodenectomy were 68% and 28%, respectively.CONCLUSIONS: These findings suggest that the clinical outcome after surgical resection of pancreatic carcinoma depends on tumor-side factors not operative parameters or host-side parameters. The clinical course seems to rely upon the nature of pancreatic cancer not upon the operative procedure.

INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120 mg TOR(HD-TOR) has been used for recurrent breast cancer in Japan, but there is still insufficient evidence regarding the efficacy of HD-TOR.PATIENTS AND METHODS: HD-TOR was administered for recurrent or metastatic breast cancer between January 2003 and May 2012. The primary end point of the study was the tumor response rate. Bone metastasis cases were excluded from the efficacy analysis, but were included in the safety population.RESULTS: A total of 21 patients registered in the study and the 2 patients with bone metastasis only were excluded from the efficacy analysis. The median follow-up period was 8. 3 months. None of the patients in the study had a CR, 4 had a PR(21. 1%), 9 had SD(47. 4%), and 6 had PD(31. 6%). Eight of the 9 SD cases had a long-term SD. The ORR was 21. 1% and the CB rate was 63. 2%. The median TTP of CB cases was 18. 3 months. None of the patients discontinued treatment because of a grade 3 or grade 4 adverse effects.CONCLUSION: In summary, the current study showed that HD-TOR may lead to a CB for recurrent breast cancer in first- or second-line treatment rather than thirdline. In particular, HD-TOR may give a benefit in highly endocrine-sensitive cases.

Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second most common cause of cancer-related death worldwide and is thus a significant global health problem. The best means of improving the survival of GC patients is to screen for and treat early lesions. However, GC is often diagnosed at an advanced stage and is associated with a poor prognosis. Current diagnostic and therapeutic strategies have not been successful in decreasing the global burden of the disease; therefore, the identification of reliable biomarkers for an early diagnosis, predictive markers of recurrence and survival and markers of drug sensitivity and/or resistance is urgently needed. The initiation and progression of GC depends not only on genetic alterations but also epigenetic changes, such as DNA methylation and histone modification. Aberrant DNA methylation is the most well-defined epigenetic change in human cancers and is associated with inappropriate gene silencing. T...

The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversial, because of the high surgical morbidity and mortality. Splenectomy has been reported to be useful for patients with hypersplenic thrombocytopenia, but the timing and route of splenectomy and hepatic resection remains unclear. This report evaluated the efficacy of laparoscopic surgery for simultaneous splenectomy and hepatic resection in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. Among 65 patients with hypersplenic thrombocytopenia who underwent hepatic resection for hepatocellular carcinoma, 20 patients underwent simultaneous splenectomy and hepatic resection. Initially, ten patients underwent the procedure by conventional laparotomy (open group) and ten patients underwent by laparoscopy (laparoscopic group). The clinicopathological results from the two groups were compared retrospectively. The blood loss in the laparoscopic group was significantly l...

In common with other investigators, we have reported the constitutive activation of transcription factor nuclear factor-kappaB (NF-kappaB) in a variety of carcinomas, but there is no definite information on its clinical significance. NF-kappaB p65 activation was determined by immunohistochemical analysis of surgically resected specimens from 63 gastric carcinomas. The 63 patients were divided into a high NF-kappaB group (21 patients) and a low NF-kappaB group (42 patients). Forty-seven of the 63 patients underwent curative resection. The 47 patients consisted of 13 high NF-kappaB patients and 34 low NF-kappaB patients. The high NF-kappaB group demonstrated a shorter overall survival rate compared with the low NF-kappaB group (p=0.015). In the 47 patients who underwent curative resection, the high NF-kappaB group also showed a poor survival prognosis (p=0.032). Multivariate analysis indicated that NF-kappaB activation is a potential prognostic factor in gastric carcinoma. Constitutiv...

Intraoperative radiation therapy has been introduced to improve survival rates after resection of biliopancreatic cancer. Early and late effects of intraoperative radiation on the exocrine and endocrine functions of the residual pancreas were examined in 54 patients with pancreatic head resection. Of the 54 patients, 20 underwent intraoperative radiation (A group) and the other 34 did not (B group). Fasting blood sugar level, a 120-min value of the 75-g oral glucose tolerance test, N-benzol-L-tyrosyl-p-aminobenzoic acid (BT-PABA) excretion value (a pancreatic exocrine function test), and amount of postoperative pancreatic juice drainage were compared between groups A and B at preoperative and early and late postoperative times. Fasting blood sugar level and a 120-min value of the 75-g oral glucose tolerance test (OGTT) showed no change at the early (<2 months) postoperative period of the two groups. At the late (>6 months) postoperative period, fasting blood sugar showed no al...

The effects of treatment with chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) on nucleation time, biliary lipid concentration, and vesicular lipid composition were studied. Gallbladder bile was collected at the time of surgery from 33 cholesterol gallstone patients who were divided into three groups: 16 untreated, 9 pretreated with CDCA (400 mg/day), and 8 pretreated with UDCA (600 mg/day) for 1-3 weeks before surgery. Control bile samples were also collected from nine patients without cholelithiasis. Nucleation time was prolonged significantly in both CDCA- and UDCA-treated groups [12.6 +/- 8.5 (SD) and 21.0 +/- 0 days, respectively] compared with the untreated gallstone group (3.3 +/- 3.2 days). Both treatments significantly decreased the proportion and concentration of both cholesterol and phospholipids present in the vesicular phase. Treatment with UDCA decreased the cholesterol saturation index more than did CDCA at the dose used in this study. In the CDCA-treated g...

The morphological spectrum of gallbladder carcinoma is broad and variable. Most of these tumors are tubular adenocarcinomas. There are some tumors with unusual morphology that may be difficult to classify due to their rarity. One of such tumors is the signet-ring cell carcinoma, which is a highly aggressive, mucin producing variant of gallbladder adenocarcinoma predominantly or exclusively composed of signet-ring cells. Histologically, these tumors are similar to their counterparts in other organs such as stomach, colon and breast, and should not be misinterpreted as metastatic carcinoma from one of these primary sites. The literature about this variant of carcinoma is sparse and little is known about it. We found only three cases of signet-ring cell carcinoma of the gallbladder previously reported. We present the case of an 86-year-old woman with signet-ring cell carcinoma of the gallbladder and discuss the potential diagnostic dilemmas

It has been shown that the hedgehog (Hh) signaling pathway is activated in gastric cancer. To investigate the viability of the Hh pathway as a therapeutic target, we analyzed activation of the Hh pathway in gastric cancer. Surgically resected gastric carcinoma specimens and lymph nodes were analyzed immunohistochemically. We used the percentage of cancer cells with nuclear translocation of Gli1 as a marker of Hh pathway activation. Nuclear localization of Gli1 was higher in 28 undifferentiated-type tumors than in 30 differentiated-type tumors. Eighteen of the fifty-eight cancer specimens consisted of a mixture of a histologically predominant part and a small area with different histology. In these 18 tumors, the percentage of cells showing nuclear staining of Gli1 was higher in the undifferentiated-type part than in the differentiated-type part. Nuclear staining of Gli1 in primary tumors was positively correlated with lymph node metastasis. The Gli1 nuclear staining percentage of metastatic lymph nodes correlated closely with that of each primary carcinoma. Cyclopamine, a Hh pathway inhibitor, suppressed the growth of gastric cancer cells in vitro. The Hh pathway may be a useful therapeutic target for such as undifferentiated-type gastric cancer with lymph node metastasis.

Two patients with intraductal papillary-mucinous adenoma of the pancreas were successfully treated by ductal branch-oriented minimal pancreatectomy. We propose this novel less invasive ductal branch-oriented pancreatectomy, as indicated for benign ductal ectasia of the pancreas. The cystically dilated branch duct is identified by intraoperative ultrasonography, intraoperative balloon pancreatography, and injection of indigocarmine into the cyst. The cystically dilated branch is resected from the surrounding pancreas together with minimal removal of the pancreatic parenchyma. The communicating duct and cutting margins are tightly ligated to prevent pancreatic juice leakage and fistula. A drainage tube is placed in the main pancreatic duct whenever possible. Histopathologic examination of the transected branch duct is necessary to check for mucosal extension of dysplastic epithelium. This ductal branch-oriented minimal pancreatectomy is the least invasive pancreatectomy and a suitable operation for branch-type ductal ectasia of the pancreas, which is usually benign.

An inflammatory polyp of the gallbladder is a rare variant of benign gallbladder polyp. Differentiation between an inflammatory polyp and polypoid gallbladder carcinoma is difficult when the polyp is more than 1 cm in diameter. We report a rare case of a large inflammatory polyp of the gallbladder masquerading as gallbladder carcinoma in a 37-year-old Japanese woman who was incidentally diagnosed with a large gallbladder polyp, measuring 1 cm in diameter, by ultrasonography. She was asymptomatic and physical examination was unremarkable. Abdominal ultrasonography and endoscopic ultrasonography revealed three polypoid lesions in the gallbladder. One lesion was an isoechoic polyp, measuring 15 x 8 mm, showing a nodular surface and located in the fundus of the gallbladder. The other two lesions were hyperechoic polyps, measuring 5 x 5 mm, in the body of the gallbladder. Computed tomography and magnetic resonance imaging revealed marked enhancement of the largest polypoid lesion by dynamic study, and no lymph node enlargement was noted. Endoscopic retrograde cholangiography revealed a 12 x 8 mm polyp with an irregular surface in the fundus of the gallbladder. Superselective angiography of the cystic artery revealed neovascularity and a tumor stain in the fundus of the gallbladder. Cholecystectomy with lymph node dissection was performed. Intraoperative frozen section diagnosis of the largest polyp was an inflammatory polyp of the gallbladder. The other two polyps were cholesterol polyps. Inflammatory polyp should be considered as a differential diagnosis of hypervascular gallbladder polyps that measure more than 1 cm in diameter.

To examine the differentiating parameters between cholesterol and pigment gallstones, we compared the nucleation times, concentrations of biliary lipid and protein, and the distribution of vesicular cholesterol in gallbladder bile of 16 patients with cholesterol, eight patients with black pigment gallstones, and nine gallstone-free control patients. Cholesterol monohydrate crystals were present in the fresh bile of only the cholesterol gallstone group. The nucleation time was significantly faster in the cholesterol stone group (3.3 +/- 3.2 days) than in the other two groups (pigment stone: 15.8 +/- 6.6, control: 16.9 +/- 5.7). The cholesterol saturation indices and the distribution of vesicular cholesterol were significantly higher in the cholesterol gallstone group than those in the other two groups. The total biliary protein concentration was significantly (P < 0.01) higher in the cholesterol gallstone group [2.57 +/- 1.91 (SD) mg/ml] than that in the black pigment stone group (1.09 +/- 0.59). All parameters in patients with black pigment gallstone were essentially similar to the controls. We conclude that the presence of cholesterol crystals, rapid nucleation time, high vesicular cholesterol distribution, elevated cholesterol saturation index, and high protein concentration are associated with cholesterol gallstones but not with black pigment gallstones.

To examine the hypothesis that the chemical activity of cholesterol molecules reflects the amount of cholesterol phasing out from bile associating with cholesterol monohydrate crystal nucleation, the cholesterol activities in human gallbladder biles from cholesterol gallstone patients, either untreated or treated with ursodeoxycholic acid, and from gallstone-free patients were determined in relation to the nucleation time and vesicular lipid composition. The cholesterol activity (nmol/disc/h) determined by the polyethylene disc uptake method was higher in the untreated gallstone group than the gallstone-free group (P less than 0.05) and the ursodeoxycholic acid treated group (P less than 0.01). The cholesterol activity correlated negatively with the nucleation time (P less than 0.01) and positively with both the vesicular cholesterol concentration (P less than 0.05) and the cholesterol/phospholipid ratio in vesicles (P less than 0.05). After the separation of vesicles from micelles by gel filtration, the cholesterol activity in the vesicular phase was found to be similar to that in the micellar phase. Interestingly, both the activities of cholesterol in the vesicular and micellar phases were significantly higher in the untreated gallstone group than in the gallstone-free group (P less than 0.05). These results suggest that cholesterol activity represents the amount of thermodynamically unstable cholesterol in bile.

To the authors' knowledge detailed morphometric changes in lymph nodes with and without metastasis in patients with early gastric carcinoma remain undocumented. Histologic slides of 1847 lymph nodes dissected from 115 consecutive patients who underwent gastrectomy for early gastric carcinoma were examined histologically and measured using computer morphometry with the public domain National Institutes of Health Image program. Quantitative data were analyzed in relation to preoperative and intraoperative clinical assessments and postoperative pathologic diagnosis. Metastasis was found in 11 lymph nodes (0.6%) from 8 patients (7.0%). Metastatic lymph nodes showed a mean maximum dimension of 4.8 mm, a mean area of 14.4 mm(2), and a mean ratio of maximum/minimum dimension of 1.36; the corresponding values for nonmetastatic lymph nodes were 4.7 mm (P = 0.45), 13.2 mm(2) (P = 0. 13), and 1.66 (P = 0.10), respectively. The lymph node with a metastasis was not necessarily the largest of the dissected lymph nodes from each patient, and histologically each lymph node with a metastasis showed pericancerous fibrosis in > 10% of its area. The sensitivities of preoperative computed tomography, abdominal ultrasonography (US), endoscopic US, and intraoperative assessments to diagnose metastasis were 0%, 13%, 0%, and 13%, respectively, and the sensitivities of these modalities to detect lymph nodes > 10 mm in dimension were 18%, 10%, 3%, and 10%, respectively. Digital quantitative analysis is useful and widely applicable to clinicopathologic evaluation. The diagnostic sensitivity of lymph node metastasis in patients with early gastric carcinoma in the current study was very low with preoperative and intraoperative assessments because lymph node metastases were small and showed subtle histologic changes of pericancerous fibrosis.