Involvement of brown adipose tissue in subcutaneous fat necrosis of the newborn.

BACKGROUND: Subcutaneous fat necrosis (SCFN) of the newborn is a rare condition that manifests within days after birth. The interscapular region, axillae and shoulders are the most commonly affected sites, corresponding to anatomic sites of brown adipose tissue (BAT) in newborns. OBJECTIVE: We postulated a specific involvement of BAT in SCFN and searched for brown adipocytes at affected sites. METHODS: Biopsy specimens were immunostained with antibodies against uncoupling protein 1 (UCP-1) and examined by electron microscopy. We also examined BAT by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography and computed tomography (PET-CT) scanning. RESULTS: A few cells in biopsy specimens from two patients bound antibodies against UCP-1, and brown adipocytes were detected at several stages of degeneration. PET-CT scans revealed lower uptake of (18)F-FDG at major sites of SCFN. CONCLUSION: SCFN and BAT can be found at the same sites, suggesting a pathophysiological connection.

Phase I/II study of irinotecan and UFT for advanced or metastatic colorectal cancer.

UNLABELLED: The aim of this study was to determine the recommended dose of irinotecan in combination with the fixed dose of oral UFT as first-line therapy in patients with advanced or recurrent colorectal cancer, and to evaluate the response rate and overall survival as a phase II study. PATIENTS AND METHODS: Thirteen patients were recruited into a phase I trial. Four doses of irinotecan ranging from 60 to 150 mg/m2/day were administered intravenously on day 1 and day 16 in combination with UFT given orally from day 2 to day 15. In a phase II study, 53 patients received at least one cycle of this therapy. RESULTS: The recommended dose of this combination was determined as irinotecan 120 mg/m2/day and UFT 400 mg/m2/day. Dose-limiting toxicities were neutropenia and prolonged leucopenia. On an intent-to-treat analysis, the response rate in the phase II study was 24.5% (95% confidence interval 13.8% to 38.2%). The median overall survival time was 20.3 months (95% confidence interval, 15.0-22.8 months). Out of 20 patients with stable disease, 17 who received more than 4 cycles of the regimen lived longer than the other 3 patients who received fewer than 3 cycles (p = 0.0353). Hematological adverse events were mainly grade 3/4 neutropenia observed in 6 out of 53 patients. Grade 3 non-hematological toxicities, such as diarrhea, anorexia, nausea/vomiting and alopecia were observed in 6 patients. CONCLUSION: Irinotecan combined with oral UFT was effective and well-tolerated. This regimen may be considered as a first-line therapy for advanced or metastatic colorectal cancer and may result in fairly long survival, even for patients with stable disease.

Combined effects of cholecystectomy and lithocholic acid on pancreatic carcinogenesis of N-nitrosobis(2-hydroxypropyl)amine in Syrian golden hamsters.

The effects of cholecystectomy and/or lithocholic acid (LCA) on the composition of biliary bile acid and on pancreatic carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine (BHP) were examined in male Syrian golden hamsters. Cholecystectomy was performed 1 wk before BHP initiation. BHP (250 mg/kg of body weight) was injected s.c. once a wk for 5 wk. A diet containing 0.5% LCA was begun 1 wk after the final BHP injection. All hamsters were sacrificed 36 wk after cholecystectomy, and the pancreas was examined histologically. Only the LCA treatment but no other treatment influenced the bile acid composition, i.e., the increase in LCA and decrease in cholic acid. The incidence of pancreatic carcinoma was 23 of 30 (76.7%) in hamsters receiving cholecystectomy plus BHP followed by LCA diet. The tumor incidence was five of 18 (27.8%) with BHP followed by basal diet, ten of 18 (55.6%) with cholecystectomy plus BHP followed by basal diet, and six of 18 (33.3%) with BHP followed by LCA diet, respectively. The total number of pancreatic carcinomas in hamsters receiving cholecystectomy and BHP followed by LCA diet also increased significantly. These results indicate that combined treatments of cholecystectomy and dietary LCA enhanced BHP-inducing pancreatic carcinogenesis in hamsters.

A prospective study on primary gastric stump cancer following partial gastrectomy for benign gastroduodenal diseases.

A prospective study was made on 3827 Japanese patients who had undergone partial gastrectomy for benign gastroduodenal diseases to examine whether they are at a high risk of mortality from primary gastric stump cancer (PGSC) and whether the risk is determined by the surgical procedure. The patients were followed up from the time of surgery (from 1948 to 1970) to June 30, 1981. Of 3,701 patients (96.7%), the vital status at the end of observation was determined, the total person-years at risk being 62,286.33. The observed deaths were compared with the expected deaths calculated from the mortality rates of Japan. An elapsed time of 10 years from operation to death was set not only to exclude possible recurrent, remaining, or multiple cancers but also to allow a certain latency period for the development of PGSC. The observed and expected deaths from PGSC were 11 and 52.85, respectively, the ratio being 0.21 (p less than 0.01). The ratios were uniformly less than 1 for both sexes and across three operative groups: Billroth I, Billroth II with Braun's anastomosis; or Billroth II without Braun's anastomosis. No difference was observed between the death rates from PGSC by operation type. The possible role of the postoperative nonphysiological (pathological) environment or duodenogastric reflux in gastric stump carcinogenesis was not detected in the present study.

Metabolism of intravenously administered 7 alpha-hydroxycholesterol-3 beta-stearate in the hamster.

In order to investigate the metabolic fate of serum esterified 7 alpha-hydroxycholesterol, [4-14C]7 alpha-hydroxycholesterol-3 beta-stearate was synthesized from labeled cholesterol and administered to bile fistula hamsters intravenously. Bile samples were collected at every 20 min for 7 h. Radioactivity was detected in bile 40 min after the beginning of the infusion of the labeled compound and 56.5 +/- 5.7% (48.7-66.0%) of the administered radioactivity was recovered in bile during 7 h. The liver contained appreciable radioactivity (19.5 +/- 7.6% of the administered dose) at the time of sacrifice. Only a trace amount of radioactivity was detected in urine and blood. Cumulative recovery of the radioactivity was 76.3 +/- 8.6% (63.3-90.4%). Major radioactive metabolites in the bile samples were identified to be taurine- and glycine-conjugated cholic acid and chenodeoxycholic acid by radioactive thin-layer chromatographic analysis of the bile samples before and after enzymatic hydrolysis and 3 alpha-hydroxysteroid dehydrogenase treatment. The conversion was nearly complete and we could not detect neutral metabolites, such as the mother compound, free 7 alpha-hydroxycholesterol and bile alcohols, as well as glucuronidated or sulfated bile acids. It is concluded that serum esterified 7 alpha-hydroxycholesterol could be effectively taken up by the liver, hydrolyzed by cholesterol esterase and metabolized via the normal biosynthetic pathway to taurine- or glycine-conjugated primary bile acids to be excreted into bile.

Type of gallstones and deaths from stroke and coronary heart disease among cholecystectomized patients.

A total of 841 Japanese patients who had undergone cholecystectomy for choleithiasis (550 for cholesterol stones and 291 for pigment stones) from 1951 to 1970 were investigated on death from stroke, coronary heart disease (CHD) and heart disease other than CHD in relation to the type of gallstones. Compared to patients with pigment stones, those having cholesterol stones had a 50% lower risk of dying from stroke which was statistically significant. The findings support the idea that westernization of Japanese diets may be responsible both for the decline in stroke mortality and for the changing pattern of gallstones in this country. The risk of CHD among cholesterol-stone patients was higher, but not significantly so, than that of pigment-stone patients whereas mortality from heart disease other than CHD did not differ much between the two groups. There were, however, few deaths from these diseases and the findings were therefore not conclusive.

An outbreak of foodborne hepatitis A in a factory: a possible shift in age of patients in Japan.

We investigated extensively an outbreak of hepatitis A at a factory in suburban Nagoya. Epidemiological study indicated a foodborne outbreak by a supplier of lunches. Serologically, all the employees younger than 30 years of age had been susceptible to hepatitis A virus, but the highest morbidity was observed in the 40-44 age group. The age difference in morbidity from foodborne hepatitis and susceptible populations suggests a shift in mean patient age linked to a shift in antibody prevalence to hepatitis A virus. In communities where the prevalence started shifting after development of sanitary systems, effective prophylaxis for foodborne hepatitis A will be necessary to prevent the disease in an increasing number of older patients in a few decades.

Gallbladder carcinoma in the era of laparoscopic cholecystectomy.

OBJECTIVE: To assess the usefulness of laparoscopic cholecystectomy for unsuspected and suspected gallbladder carcinoma. DESIGN: Retrospective review with a mean follow-up of 27 months, ranging from 1 to 47 months. SETTING: University hospital and 8 affiliated hospitals. PATIENTS: Of 2616 laparoscopic cholecystectomies performed over 4 years, 24 gallbladder carcinomas were treated by laparoscopic cholecystectomy and retrospectively reviewed. RESULTS: The clinical course depended on the histopathologic depth of invasion of gallbladder carcinoma. All 6 cases of pathologic tumor (pT) stage in situ (pTis) gallbladder carcinoma and 2 cases of pT1 gallbladder carcinoma showed no invasion to the lymphatic, venous, or perineural spaces, and these 8 patients were all doing well from 2 to 19 months (mean, 11 months) after laparoscopic cholecystectomy. Sixteen cases of pT2 or pT3 gallbladder carcinoma invaded the subserosal layer or the liver, and 5 of the 16 patients were dead of liver dysfunction, abdominal wound recurrence, or liver metastasis 5 days and 7, 12, 15, and 18 months after operation, although additional resection of the liver bed with lymph node dissection was performed after laparoscopic cholecystectomy in 4 of these 5 patients. Abdominal wall recurrence in the absence of distant metastasis was present in 3 (19%) of the 16 patients with pT2 or pT3 gallbladder carcinoma due to inoculation of cancer cells in the abdominal stab wounds where the gallbladder or laparoscope was removed. CONCLUSIONS: Gallbladder carcinoma at the pTis or pT1 stage removed laparoscopically needs no other treatment. We recommend that the gallbladder be removed by vinyl bag and port sites be excised or washed with normal saline to prevent port site recurrence in patients with laparoscopic cholecystectomy for pT2 or pT3 carcinoma.

Effects of pravastatin and ursodeoxycholic acid on cholesterol and bile acid metabolism in patients with cholesterol gallstones.

To investigate the effects of pravastatin and ursodeoxycholic acid (UDCA) on cholesterol and bile acid metabolism in humans, 41 patients with cholesterol gallstone disease were allocated to four groups and treated with pravastatin (20 mg/day), UDCA (600 mg/day), both pravastatin and UDCA, or neither drug (control) for 1-2 weeks prior to elective cholecystectomy. Cholesterol 7 alpha-hydroxylase activity and serum levels of total 7 alpha-hydroxycholesterol were significantly increased by pravastatin and unaffected by UDCA. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was markedly increased by pravastatin and decreased by UDCA. UDCA significantly decreased biliary cholesterol concentration and the cholesterol saturation index and prolonged the nucleation time; however, pravastatin alone had little effect on biliary lithogenicity. Serum total and low-density lipoprotein (LDL)-cholesterol levels were reduced most by the combined administration of pravastatin and UDCA. In conclusion, at a dose of 20 mg/day, pravastatin increased bile acid synthesis but did not decrease biliary lithogenicity. UDCA had no significant effect on bile acid synthesis, but markedly decreased biliary lithogenicity.

Multiseptate gallbladder: biliary manometry and scintigraphy.

A 30-year-old man with multiseptate gallbladder, a very rare congenital anomaly, is presented. His presenting symptom was epigastric pain. A hypoplastic gallbladder with multiple septa was demonstrated by ultrasonography and endoscopic retrograde cholangiography. An injection of cerulein reproduced pain, and simultaneous biliary manometry and scintigraphy showed impairment of gallbladder filling and emptying. Laparoscopic cholecystectomy resulted in complete relief of the pain. Biliary manometry and scintigraphy are useful to determine the operative indication in a symptomatic patient with this entity.

Deconjugation of bilirubin accelerates coprecipitation of cholesterol, fatty acids, and mucin in human bile--in vitro study.

To examine the initial step of brown pigment gallstone formation, sterile human gallbladder bile samples were incubated with or without beta-glucuronidase in vitro. Enhanced bilirubin deconjugation achieved by adding beta-glucuronidase significantly accelerated the formation of a precipitate that contained bilirubin (28.2 +/- 3.8% of dry weight), cholesterol (14.3 +/- 5.2%), free fatty acids (12.0 +/- 1.3%), and glycoprotein (10.0 +/- 6.7%). Both the composition and scanning electron microscopic appearance of the precipitate were similar to these features in brown pigment gallstones. The cholesterol saturation index and nucleation time in the supernatant did not change with various incubation periods. The weight ratios of bilirubin to cholesterol in the precipitates correlated with those in bile (r = 0.76; P = 0.017). Gel chromatography of the precipitate showed high molecular weight glycoprotein to be the major constituent. Bilirubin, cholesterol, fatty acids, and mucin were found to coprecipitate in accordance with bilirubin deconjugation, which process may play an important role in an early stage of the formation of brown pigment gallstones.

The relationship between homovanillic/vanillylmandelic acid ratios and prognosis in neuroblastoma.

A total of 44 cases with neuroblastoma cases (excluding true positive cases detected in mass screenings) who were born from 1979 to 1991, and had data concerning the clinical stage and values of vanillylmandelic acid (VMA) and homovanillic acid (HVA) at diagnosis (microg/mg creatinine) were followed up until the end of 1994. Deaths were confirmed using the record of vital statistics of the Hokkaido Government. The 60-month survival rate of those who had an HVA/VMA ratio of 1-2 was 80.0%. Conversely, those with ratios <1 or >2 had respective survival rates of 24.1% and 5.3%. Most of those with a ratio >2 died within 24 months of diagnosis. Many of the cases with a ratio <1 lived over 12 months but died within about 36 months. Many tumors of those cases with a ratio of 1-2 originated in extra-adrenal glands, and had negative n-myc amplification. Most of the patients with a ratio >2 were diagnosed at 1 year of age or older. The HVA/VMA ratio at diagnosis is useful in estimating both the survival period and the prognosis.

Carcinoma of the ampulla of Vater synchronously associated with early gastric cancer--a report of two cases.

We report two cases of carcinoma of the ampulla of Vater synchronously associated with early gastric cancers. The gastric lesions were diagnosed pre-operatively in one patient and at the time of examination of the resected specimen following pancreatoduodenectomy in the other. Specific problems in the diagnosis and management of these multiple primary carcinomas are discussed. Careful evaluation of the stomach prior to the surgical treatment for ampullary carcinoma is recommended.

Composite glandular-endocrine cell carcinoma of the extrahepatic bile duct: immunohistochemical study.

A composite glandular-endocrine cell carcinoma of the extrahepatic bile duct in a 64 yr old Japanese man is reported. A nodular polyp measuring 1.9 x 1.1 cm was located in the confluence of the extrahepatic bile duct. Histologically, the tumor was composed of well differentiated tubular adenocarcinoma and small cell neuroendocrine carcinoma with a transition between the 2 components. The 2 areas of the tumor immunohistochemically revealed a clear-cut difference in functional differentiation. Tumor cells in the glandular component were immunoreactive to both carcinoembryonic antigen (CEA) and CAM 5.2, while those in the small cell area were immunoreactive to neuroendocrine markers such as neuron specific enolase (NSE), chromogranin A and serotonin. These results suggest that the tumor arose from a multipotential stem cell capable of differentiation in 2 directions.

Laparoscopic adrenalectomy: review of 14 cases and comparison with open adrenalectomy.

We reviewed 14 cases of laparoscopic adrenalectomy and compared the results with those of a recent series of 15 consecutive patients undergoing a traditional open adrenalectomy for a benign tumor. The laparoscopic adrenalectomy group included nine patients with primary aldosteronism, three with Cushing's syndrome, one with pheochromocytoma, and one with a nonfunctioning incidentaloma. In the patient with pheochromocytoma, a good operative field was safely obtained by a combination of pneumoperitoneum at less than 6 mm Hg insufflation pressure and the abdominal wall-lift method. In both groups, the tumors were removed successfully in all cases. Laparoscopic adrenalectomy, which required neither a large skin and muscle incision nor any resection of the ribs, offered a lower morbidity and earlier recovery in spite of the longer operation time. The most important complication observed in laparoscopic adrenalectomy was that of pneumothorax secondary to an injury of the diaphragm and pleura during the dissection of the left adrenal gland using electrocautery. However, the injury wound was small, and the pneumothorax was resolved by suturing the tear under laparoscopy. These results suggest that laparoscopic adrenalectomy is a minimally invasive alternative to traditional open adrenalectomy and thus has the potential soon to become a standard procedure for the treatment of benign adrenal tumors.

Is the mass screening for neuroblastoma ineffective?

Though a recent study (Schilling et al. 2002) concluded that the mass screening for neuroblastoma targeting children age 12 months was ineffective, we pointed out several serious problems and reestimated its effectiveness using their data. They employed the subjects in the "control area" as controls, not the "non-participants" whose biases are fewer because their area is the same as that of the participants. The incidence of neuroblastoma among the subjects in the "control area" was about 25% smaller than that of the "non-participants". This leads to underestimation of the effectiveness of the mass screening. They combined false negatives with true positives to calculate the incidence of the "screened group". But since many spontaneous regression cases are included in the true positives, this method inflates the incidence of the "screened group", leading to underestimation of the effectiveness of the mass screening. When the false negatives are compared with the non-participants, the incidence of the cases in stage 4 among the latter is about 40% of that of the former, and the mortality is less than two-thirds. The percentage of spontaneous regression cases among the true positives is estimated to be about 40%. These results are better than those of the Japanese screening programs (targeting infants age 6 months), supporting the effectiveness of mass screening for neuroblastoma.

Contribution of HPLC mass screening for neuroblastoma to a decrease in mortality.

The aim of this study is the estimation of the contribution of HPLC mass screening for neuroblastoma to the decrease in deaths due to this disease. The mortality rates of malignant neoplasms of the adrenal glands (ICD 9, 1940; ICD 10, C74; virtually all the cases of these codes are neuroblastoma during childhood) at 1-4 years of age in cohorts born in 1979-1984, 1985-1988, and 1989-1992 in the whole of Japan were calculated, using data obtained from the Ministry of Health and Welfare. The numbers of infants screened by HPLC in the cohorts were estimated through the reports of the Ministry of Health and Welfare and the database of the Japanese Society for Mass-screening. The mortality of the cohort born in 1989-1992, in which 77.8% of the live births were screened by HPLC, was 1.73 per 100,000 live births. This is about half of that (3.26) of the cohort born in 1979-1984, in which few infants were screened. On the assumption that cases of the 1985-1988 and 1989-1992 cohorts died according to the mortality rate of the 1979-1984 cohort, the expected numbers of deaths were estimated; that for the 1985-1988 cohort was 178.51 (of them, that for the infants screened by HPLC was 39.65), and that for the 1989-1992 cohort was 159.78 (of them, that for the infants screened by HPLC was 124.33). The observed numbers of deaths were 145 and 85, respectively. Assuming that non-HPLC methods have no effects and using 2 unknown quantities x (contribution of HPLC) and y (other factors), simultaneous equations (1) 178.51 - 39.65x - 178.51y = 145 and (2) 159.78 - 124.33x - 159.78y = 85 were made. Solving them, x = 0.5041 and y = 0.0757 were obtained. In conclusion HPLC screening targeting infants aged 6 months reduces death of adrenal neuroblastomas at 1-4 years of age by about 50%.

Induction of osteoclast-like cells derived from the synovial lavage fluids of patients with temporomandibular joint disorders.

OBJECTIVE: Although biochemical studies have examined the synovial fluid (SF) of patients with temporomandibular joint (TMJ) disorders (TMDs), the details of the molecular mechanism of bone destruction and remodeling remain unknown. In this study, we induced and characterized osteoclast-like cells from the SF of patients with TMD and investigated the participation of these cells in the pathogenesis of TMD. METHODS: We collected SF cells from patients with TMD after a pumping procedure, cultured osteoclast-like cells, and examined their characteristics, including osteoclast markers and bone resorption activities. In addition, we obtained fibroblastic cells from the SF of TMD patients by continuous sub-culturing. Using these fibroblastic cells, we examined fibroblast markers using immunocytochemical staining and analyzed the receptor activator of nuclear-factor-kappaB ligand (RANKL) mRNA levels. Detection of soluble form of RANKL (sRANKL) in the SF was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Osteoclast-like cells were induced from the SF cells of patients with TMD by adding recombinant human (rh) macrophage colony stimulating factor (M-CSF) and either 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] or prostaglandin E2 (PGE2). These multinucleated giant cells were positive for tartrate-resistant acid phosphatase (TRAP) and had the ability to absorb bone. The fibroblastic cells from the SF of TMD patients were positive for fibroblast markers and RANKL mRNA was up-regulated. Detection of sRANKL in SF of patient group was significantly higher than control group. CONCLUSION: The results suggest that the joint-infiltrating SF cells from TMD patients play important roles in the pathogenesis of these disorders, which is characterized by progressive bone destruction or remodeling.