Syoji Kuroki

Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer

The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Genetic analysis has demonstrated a critical role for the Hh pathway in mammary gland morphogenesis. Disruption of Patched1, a component of the Hh pathway, results in abnormal growth of mammary duct. Recent studies have shown constitutive activation of the Hh pathway in various types of malignancies. However, it remains unclear whether this pathway is activated in human breast cancer. Here, we determined the expression of the components, including Sonic Hh, Patched1, and Gli1, of the Hh pathway by immunohistochemical staining in a series of 52 human breast carcinomas. All of 52 tumors display staining of high intensity for Gli1 when compared with adjacent normal tissue. The nuclear staining ratio of Gli1 correlates with expression of estrogen receptor and histologic type. Exposure to cyclopamine, a steroidal alkaloid that blocks the Hh pathway, suppresses expression of Gli1 and the growth of the Hh pathway-activated breast carcinoma cells. These data indicate that the Hh pathway is a new candidate for therapeutic target of breast cancer.

Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer

Constitutive activation of signal transducer and activator of transcription (Stat) proteins has been demonstrated in a wide variety of malignancies. In this study, we elucidated the significance of Janus kinase (JAK) and the downstream transcription factor Stat3 signals on malignant potentials of pancreatic cancer. Electrophoretic mobility shift assay and immunohistochemical analysis revealed that Stat3 was constitutively activated in subsets of human pancreatic cancer tissues and cell lines (Panc1, Kp4, AsPC-1, BxPC-3). A JAK-specific inhibitor, tyrphostin AG490, markedly inhibited Stat3 activation and expression of cyclin D1, bcl-xL and vascular endothelial growth factor mRNAs estimated by RT-PCR, as followed by growth arrest (6.3-21.3% vs controls; P<0.001) of pancreatic cancer cells. Inactivation of Stat3 by dominant-negative Stat3 adenovirus partly suppressed the growth of pancreatic cancer cells on day 4 post-inoculation (P<0.05) but not the expression of these mRNAs. These results indicate that activation of the JAK/Stat3 signaling pathway plays an important role in the progression of pancreatic cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for pancreatic cancer.

Patterns of peripheral enhancement in breast masses : Correlation of findings on contrast medium enhanced MRI with histologic features and tumor angiogenesis

PURPOSE Our goal was to review patterns of peripheral enhancement on contrast-enhanced MRI of the breast and to correlate radiologic findings with pathologic features. METHOD We reviewed the MR images of 124 consecutive women with breast lesions. Peripheral enhancement was identified in 35 (32 malignant, 3 benign) lesions. MRI findings were correlated with pathologic features including microvessel density and distribution determined histologically. RESULTS Early peripheral enhancement with centripetal progression was seen in invasive carcinomas with a high peripheral and a low central microvessel density, associated with fibrosis and/or necrosis (n = 18; 15 with central fibrosis, 2 with fibrosis and necrosis, and 1 with necrosis alone). Early peripheral enhancement with minimal or no change in enhancement was seen in both malignant (n = 10) and benign (n = 3) lesions. Delayed peripheral enhancement with centrifugal progression was seen in carcinomas that had an expansive growth pattern and a high marginal vessel density with or without a vascularized rim of connective tissue (n = 4). CONCLUSION Early peripheral enhancement with centripetal progression appears to be fairly specific for carcinomas, whereas early enhancement with minimal or no centripetal progression, although more common in malignant tumors, may be seen in some benign lesions as well.

Video-assisted thyroid lobectomy through a small wound in the submandibular area

BACKGROUND Endoscopic thyroidectomy has not gained wide acceptance because of the expertise required, the long operation time, the wide dissection, and the extra cost of specialized instruments. We developed a video-assisted hemithyroidectomy procedure that requires only one small incision at the upper neck. METHODS Hemithyroidectomy was performed through a 25 to 30 mm transverse incision made in the upper lateral neck for the treatment of benign thyroid nodule. No gas or external lift dissection was needed. RESULTS The mean age of 39 patients was 33.8 years. The tumor size ranged from 1.9 to 5.5 cm (mean 3.1 cm). All patients underwent total lobectomy without conversion to traditional cervicotomy. The mean operation time was 56 minutes (range 36 to 90). Follicular adenoma was the final pathologic diagnosis in 25 patients and adenomatous goiter in 14. Transient recurrent laryngeal nerve palsy was seen in 1 patient. CONCLUSIONS Our technique is safe, minimally invasive, less time consuming, and cosmetically excellent.

The internal biliary fistula--reappraisal of incidence, type, diagnosis and management of 33 consecutive cases.

To reevaluate the current features of spontaneous internal biliary fistulas, we reviewed 1,929 consecutive patients who had been treated for biliary tract diseases during the recent 12-year period. Thirty-three patients had internal biliary fistulas and the incidence was 1.9%. Of 33 patients, 20 were women and 13 were men with the average age 63 years, and their mean duration of illness was 4 years. A total of 37 fistulas were found and the most common type was choledochoduodenal (62%), followed by cholecystoduodenal (19%), cholecystocholedochal (11%) and cholecystocolonic (8%) fistulas. Internal biliary fistulas of thirty-one patients were caused by biliary stones and those of two patients by malignant tumors. All of the 17 bile samples examined were bacteria positive and the majority of calculi were brown pigment stones. All of the choledochoduodenal fistulas were correctly diagnosed by endoscopic retrograde cholangiography. In 14 patients with cholecystoenteric or cholecystocholedochal fistulas, direct evidence of the internal fistula was obtained only in 7 patients (50%) preoperatively. Pneumobilia, a small atrophic gallbladder adherent to the neighboring organs and a history of spontaneous disappearance of jaundice in elderly patients may indicate the presence of a cholecystoentric fistula. Since the preoperative diagnostic rate for internal biliary fistula involving the gallbladder is still low, care is necessary before and at the time of surgery especially during laparoscopic cholecystectomy for elderly patients with cholelithiasis.

Preoperative Internal Biliary Drainage Is Superior to External Biliary Drainage in Liver Regeneration and Function After Hepatectomy in Obstructive Jaundiced Rats

OBJECTIVE To examine the differences in regeneration rates and functions of the liver at the time of and after hepatectomy in obstructive jaundiced rats with preoperative external and internal biliary drainage. SUMMARY BACKGROUND DATA The significance of biliary drainage before surgery is controversial in patients with obstructive jaundice. METHODS After biliary obstruction for 7 days, rats were randomly divided into three groups: obstructive jaundice and hepatectomy (OJ-Hx), external biliary drainage and hepatectomy (ED-Hx), and internal biliary drainage and hepatectomy (ID-Hx). The OJ-Hx group underwent hepatectomy without biliary drainage; the other two groups underwent hepatectomy after biliary drainage for 7 days. At the time of hepatectomy, all rats were provided with internal biliary drainage. On days 0, 1, 2, 3, and 7 after hepatectomy, the DNA synthesis rate and the concentrations of adenine nucleotides and malondialdehyde in the liver were determined as markers of the hepatic regeneration rate, energy status, and lipoperoxide concentration, respectively. Portal endotoxin concentrations were measured and serum hyaluronic acid concentrations were determined as an indicator of hepatic endothelial function. RESULTS The relative liver weight was significantly higher in the ID-Hx group than in the OJ-Hx group on days 1, 3, and 7 after hepatectomy and than in the ED-Hx group on days 1 and 2. The rate of hepatic DNA synthesis was significantly higher in the ID-Hx group than in the OJ-Hx and ED-Hx groups on day 1. The rate was similar in the ED-Hx and ID-Hx groups on day 2 but was significantly higher than in the OJ-Hx group. The hepatic malondialdehyde concentration was significantly higher on day 1 in the ED-Hx group than in the other two groups. It was lowest in the ID-Hx group throughout the study. Both biliary drainage procedures lowered the portal endotoxin concentration and serum hyaluronic acid concentration at the time of hepatectomy. The serum hyaluronic acid concentration was lowest in the ID Hx group. Hepatic adenine triphosphate concentrations and energy charge levels were similar among the three groups. CONCLUSION Although both external and internal biliary drainage before hepatectomy improved serum liver function tests, portal endotoxin concentration, and serum hyaluronic acid concentration at the time of surgery, preoperative internal biliary drainage was superior to external drainage, as evidenced by the better liver regeneration and function after hepatectomy.

Esterified and total 7 alpha-hydroxycholesterol in human serum as an indicator for hepatic bile acid synthesis.

Serum levels of 7 alpha-hydroxycholesterol and activities of hepatic microsomal cholesterol 7 alpha-hydroxylase in surgical patients were analyzed by capillary gas-liquid chromatography-selected ion monitoring technique using a new internal standard, 5 alpha-cholestane-3 beta, 7 beta-diol. We found that concentrations of 7 alpha-hydroxycholesterol obtained after alkaline hydrolysis were higher than those without alkaline hydrolysis, indicating that a considerable amount of 7 alpha-hydroxycholesterol in human serum is present in esterified form. Esterified 7 alpha-hydroxycholesterol could also be quantitatively hydrolyzed with cholesterol esterase, suggesting that fatty acid is bound at the 3 beta-position of the cholestenediol. The serum levels of esterified and free 7 alpha-hydroxycholesterol in patients with cholelithiasis were 198.0 +/- 90.3 and 48.3 +/- 19.8 pmol/ml (mean +/- SD), respectively, and were similar to those in patients without hepatobiliary diseases. After treatment with chenodeoxycholic acid (300 mg per day) for 7 to 10 days, esterified and free 7 alpha-hydroxycholesterol levels decreased to 64.9 +/- 33.6 and 20.5 +/- 11.1 pmol/ml, respectively. Activity of cholesterol 7 alpha-hydroxylase was also inhibited. Treatment with ursodeoxycholic acid (600 mg per day) for 7 to 10 days had no inhibitory effect on serum 7 alpha-hydroxycholesterol levels and the enzyme activity. In all groups, high correlations were found between the activity of cholesterol 7 alpha-hydroxylase and serum levels of 7 alpha-hydroxycholesterol: free (r = 0.71, n = 38, P less than 0.001); esterified (r = 0.87, n = 38, P less than 0.001); total (r = 0.87, n = 38, P less than 0.001). Esterified and total 7 alpha-hydroxycholesterol was more highly correlated with the enzyme activity than the free form. We conclude that a significant amount of 3 beta-acyl esters of 7 alpha-hydroxycholesterol is present in human serum and that serum levels of esterified and/or total 7 alpha-hydroxycholesterol are likely to reflect the activity of hepatic cholesterol 7 alpha-hydroxylase and thus the amount of primary bile acids synthesized in the liver.

Infrasternal mediastinoscopic thymectomy in myasthenia gravis: surgical results in 23 patients

BACKGROUND Infrasternal mediastinoscopic surgery is a new approach to resection of the anterior mediastinal mass. METHODS We evaluated this new approach in 23 patients with myasthenia gravis who underwent total thymectomy assisted by infrasternal mediastinoscopy between 1998 and 2000. The results were analyzed with special reference to morbidity and short-term improvement of the disease severity determined according to quantitative myasthenia gravis (QMG) scores. RESULTS Complete removal of the thymic gland with the pericardial adipose tissue was accomplished through an infrasternal mediastinoscopic approach in 21 of the 23 (91.3%) patients. The remaining 2 patients required conversion to sternotomy, the one for insufficient sternal lifting with vascular tape and the other for invasion of a thymoma to the innominate vein. There was no related mortality and only one complication, a phrenic nerve injury in 1 patient (4.3%). Significant clinical improvement of disease was achieved in the short term and several advantages were apparent. CONCLUSIONS Infrasternal mediastinoscopic thymectomy is safe and feasible for patients with myasthenia gravis.

Granulomatous Mastitis Diagnosed and Followed up by Fine-Needle Aspiration Cytology, and Successfully Treated by Corticosteroid Therapy: Report of a Case

A 36-year-old woman presented to our hospital with a rapidly growing lump in her left breast. Fine-needle aspiration (FNA) cytology of the mass revealed many epithelioid cells admixed with multinucleated Langhans-type giant cells, neutrophils, lymphocytes, and stromal cells, leading to a diagnosis of granulomatous mastitis. This report describes the clinical course of this patient in whom granulomatous mastitis was successfully treated with corticosteroid therapy. Special reference is made to the usefulness of FNA cytology in the diagnosis and follow-up of this disease.

Inhibition of inducible nitric oxide synthase prevents hepatic, but not pulmonary, injury following ischemia-reperfusion of rat liver

The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.