Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results.

BACKGROUND AND AIMS: Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules. METHODS: Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months). RESULTS: Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months). CONCLUSIONS: Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.

[Small sclerosing hemangioma combined with primary lung cancer; report of a case].

A 56-year-old woman underwent a surgery for right breast cancer when she was 51-year-old. In February 2002, computed tomography (CT) was performed as a part of a follow-up study and showed 2 small nodules in the lower lobe of her right lung: one was 10 mm nodule in S9, and another was 5 mm in S6. On a follow-up CT in March 2005, the S9 nodule had enlarged to 19 mm and was looked as ground glass opacity (GGO). We thought it was primary lung cancer. In contrast, the nodule in S6 had not enlarged and it was thought to be benign. In May 2005, right lower lobectomy was performed. The S9 nodule was diagnosed as adenocarcinoma, and the S6 nodule as sclerosing hemangioma.

[Mediastinal granular cell tumor: report of a case].

Mediastinal granular cell tumor is rare. We report a case of 16-year-old woman with a granular cell tumor in the right upper-middle mediastinum. Chest computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 4.0 x 2.5 x 5.5 cm well circumscribed mass in the right upper-middle mediastinum. Tumor resection was performed. It was found that the tumor involved right vagus nerve. The tumor was completely excised with combined resection of the right vagus nerve peripheral to the right recurrent nerve. Histopathologically, the tumor consisted of round to polygonal cells with abundant eosinophilic granular cytoplasm, and diagnosed a granular cell tumor.

[Positron emission tomography (PET)-computed tomography (CT) suggesting small intestinal metastasis from lung cancer; report of a case].

A 75-year-old man admitted to our hospital due to an abnormal X-ray shadow detected during an annual health check-up. Chest computed tomography (CT) revealed 3.0 cm solid nodules with chest wall invasion in the left lung. We could not get a definitive diagnosis by transbronchial lung biopsy or CT-guided needle biopsy. Positron emission tomography (PET)-CT revealed positive findings in the tumor, aortopulmonary window lymph node and splenic flexure. Under a diagnosis of suspected lung cancer, thoracotomy was performed. As intraoperative diagnosis revealed a moderately differentiated squamous cell carcinoma, the patient underwent a left upper lobectomy, mediastinal lymph node dissection, and combined chest wall resection. Pathological stage was T3N2M0, stage IIIA. Ten days after surgery, the patient suffered from ileus and emergent surgery was performed. Subsequent pathological examination revealed lung cancer metastasis in the small intestine.

[Surgical resection of metachronous multiple lung cancer after complete response of small cell lung cancer; report of a case].

A 76-year-old man underwent combination chemotherapy with cisplatin and etoposide and 50 Gy radiotherapy for left-sided small cell lung cancer in 1999. He achieved clinical complete response and showed no sign of recurrence on follow-up study. In December 2004, chest computed tomography (CT) revealed a 1 cm nodule in the right lung. Although no diagnosis could be made by bronchoscope, we suspected metachronous multiple lung cancer because of high 18fluorodeoxyglucose uptake with positron emission tomography (PET). The patient underwent video-assisted thoracoscopic surgery in May 2005; the frozen section diagnosis was adenocarcinoma.

Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2.

AIMS: Hypomagnesemia has been implicated in adversely affecting diabetic complications. This is a retrospective study designed to determine whether there is any association between serum magnesium concentration [Mg2+] and the rate of renal function deterioration, as determined by the slope of serum creatinine reciprocals versus time (1/SCr-vs-t), in patients with diabetes mellitus type 2 (DM2). MATERIALS AND METHODS: DM2 patients without known kidney disease seen at Olive View-UCLA Medical Center for any reason during January-March 2001 were included. For each patient, all available data from our electronic database for [Mg2+], hemoglobin A(1C) (HbA(1C), serum creatinine (SCr), lipid profiles, routine urinary analysis, as well as history of hypertension and pharmacy profiles were retrieved. The average of all parameters obtained and linear regression analyses for the slope of 1/SCr-vs-t plot were performed for each patient. Patients were stratified by gender and divided into four groups based on increasing [Mg2+]. Correlations between each parameter including the slope of 1/SCr-vs-t and the four magnesium groups were analyzed. RESULTS: 252 males and 298 females with a mean follow-up of 62.6 +/- 22.5 months were included. Patients belonging to lower [Mg2+] groups for both genders had significantly worse slopes of 1/SCr-vs-t plot independent of the presence of hypertension and use of ACEI/ARB, diuretics, HMG-CoA enzyme inhibitors or aspirin. In a multivariate regression analysis controlling for age, HbA(1C) and various components of the lipid profile, [Mg2+] remained an independent predictor for the slope of 1/SCr-vs-t. A trend for worse proteinuria based on routine urinary analysis was observed among patients belonging to the lowest [Mg2+] group. CONCLUSIONS: Lower [Mg2+] is associated with a faster renal function deterioration rate in DM2 patients.

Role of women in medicine: a look at the history, the present condition and the future status of women in the surgical field, especially neurosurgery.

We have analyzed the historical background of women's progress in medicine in Japan and the role of female neurosurgeons as models for the next generation. Female neurosurgeons were asked to complete a questionnaire regarding their professional life in detail and the problems they are facing while managing their personal life after getting married and having a child. Some feel that there remain some constraints at work for being a female, due to their male colleagues who are not so understanding in nature. The younger generation is not so keen on joining the neurosurgical branch as their life career due to hard work and complete dedication demanded by neurosurgery. It is not easy for all to manage a neurosurgical career along together with a married life and children. Hence it is now time for those successful female neurosurgeons to become role models. Government can play an important role in these social reforms by coming up with programs to give social security to females and initiate programs for child care for married females pursuing such a demanding profession. Certain measures to encourage females to take up surgery are providing more time by arranging care for babies and families, flexibility in working hours, in addition to having a considerate husband and a considerate chief of department and senior staff. Departmental policies need to be completely impartial and should promote everyone based on their skills and knowledge. Women neurosurgeons need to get together and discuss all these issues so that the younger generation will not hesitate to take up this profession and become stalwarts of neurosurgery like their male counterparts.

Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas.

BACKGROUND: Multiple lesions of intraductal papillary-mucinous tumor of the pancreas (IPMT) in the same pancreas often are encountered. To elucidate field (multicentric) cancerization and clonality of IPMT, clonal analyses of IPMT and its precursor lesion of ductal hyperplasia were performed. K-ras codon 12 mutations and X-chromosome inactivation of human androgen receptor gene (HUMARA) were investigated. METHODS: Paraffin embedded tissue samples from the pancreata of 37 patients who underwent resection for IPMTs were microdissected manually or by laser capture microdissection. Multiple samples from each surgical specimen were microdissected representing each IPMT and discrete ductal hyperplasias. DNA was extracted, and K-ras codon 12 mutations were examined by two-step polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mutations were analyzed by direct DNA sequence. The HUMARA locus was digested with or without HpaII and HhaI prior to amplification. The HUMARA assay was conducted by fluorescence-labeled PCR-RFLP and was analyzed with specialized software. RESULTS: All 37 pancreata had at least two lesions of ductal hyperplasia, and 23 of 37 pancreata (62%) had K-ras codon 12 mutations in these precursor lesions. Of 23 pancreata with mutated K-ras hyperplasia, 15 (65%) had multiple, distinct mutations in different lesions of hyperplasia in the same pancreas, suggesting a field defect. Thirty-two of 37 IPMTs (86%) had K-ras codon 12 mutations. Among these, 16 IPMTs (50%) had multiple, distinct mutations at K-ras codon 12. The HUMARA assay showed that 12 of 15 IPMTs were informative, and 9 were considered polyclonal and/or oligoclonal origin in origin. With the combined results of multiple K-ras mutation detection and the HUMARA assay, 12 of 15 IPMTs from female patients (80%) were considered polyclonal and/or oligoclonal in origin. CONCLUSIONS: The current results suggest that multiple, distinct K-ras mutations of different ductal hyperplasias in a given pancreas are due to a field (multicentric) cancerization effect in IPMTs. Thus, most of IPMTs are polyclonal and/or oligoclonal in origin, i.e., IPMTs may originate from multiple (molecularly distinct) precursor lesions.

Requirement of c-jun N-terminal kinase for apoptotic cell death induced by farnesyltransferase inhibitor, farnesylamine, in human pancreatic cancer cells.

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with "amine" which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually "cytostatic" rather than "cytotoxic", we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced "cytotoxic" effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without "amine." Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.

Riboflavin transport by isolated perfused rabbit renal proximal tubules.

Rabbit renal proximal tubular transport of riboflavin (RF) was examined by using the in vitro isolated tubule perfusion technique. We found that proximal tubules actively reabsorbed (J(lb)) and secreted (J(bl)) RF. At 0.1 microM RF concentration, J(bl) was significantly higher than J(lb), resulting in a net secretion. This net secretion of RF was decreased at 0.01 microM RF concentration and increased at 1 microM RF concentration. Both J(lb) and J(bl) were inhibited by lowering temperature or by adding iodoacetate, a metabolic inhibitor, and lumichrome, an RF analog, suggesting the involvement of carrier-mediated transport mechanisms. J(bl) was inhibited by probenecid, an anion transport inhibitor, and by para-aminohippuric acid, an organic anion, suggesting the relevance of RF secretion to renal organic anion transport. J(bl) was also inhibited by alkaline pH (8.0) and by the calmodulin inhibitor trifluoperazine, indicating the influence of pH and Ca(2+)/calmodulin-dependent pathway on RF secretion. Finally, we found that addition of chlorpromazine, a phenothiazine derivative, inhibited both J(lb) and J(bl), raising the concern about the nutritional status in patients receiving such a type of medication.

Riboflavin uptake by human-derived colonic epithelial NCM460 cells.

Normal microflora of the large intestine synthesize a number of water-soluble vitamins including riboflavin (RF). Recent studies have shown that colonic epithelial cells possess an efficient carrier-mediated mechanism for absorbing some of these micronutrients. The aim of the present study was to determine whether colonic cells also possess a carrier-mediated mechanism for RF uptake and, if so, to characterize this mechanism and study its cellular regulation. Confluent monolayers of the human-derived nontransformed colonic epithelial cells NCM460 and [(3)H]RF were used in the study. Uptake of RF was found to be 1) appreciable and temperature and energy dependent; 2) Na(+) independent; 3) saturable as a function of concentration with an apparent K(m) of 0.14 microM and V(max) of 3.29 pmol x mg protein(-1) x 3 min(-1); 4) inhibited by the structural analogs lumiflavin and lumichrome (K(i) of 1.8 and 14.1 microM, respectively) but not by the unrelated biotin; 5) inhibited in a competitive manner by the membrane transport inhibitor amiloride (K(i) = 0.86 mM) but not by furosemide, DIDS, or probenecid; 6) adaptively regulated by extracellular RF levels with a significant and specific upregulation and downregulation in RF uptake in RF-deficient and oversupplemented conditions, respectively; and 7) modulated by an intracellular Ca(2+)/calmodulin-mediated pathway. These studies demonstrate for the first time the existence of a specialized carrier-mediated mechanism for RF uptake in an in vitro cellular model system of human colonocytes. This mechanism appears to be regulated by extracellular substrate level and by an intracellular Ca(2+)/calmodulin-mediated pathway. It is suggested that the identified transport system may be involved in the absorption of bacterially synthesized RF in the large intestine and that this source of RF may contribute toward RF homeostasis, especially that of colonocytes.

Epithelial cell proliferation and gene mutation in the mucosa of gallbladder with pancreaticobiliary malunion and cancer.

The significant association between pancreaticobiliary malunion (PBM), especially undilated-type PBM, and a high risk of gallbladder cancer is known. Reflux and stasis of pancreatic juice induce various epithelial changes in the gallbladder. Recently, epithelial hyperplasia of the gallbladder was shown to be significantly and frequently associated with undilated-type PBM, and it is suggested that the majority of epithelial hyperplasia may exist at birth or be acquired in early childhood, and thereafter present throughout the lives of PBM patients. Cell kinetic studies demonstrated a significant stepwise increase in cellular proliferative activity from normal gallbladder mucosa, through epithelial hyperplasia to cancer. Epithelial hyperplasia with increased proliferative activity may predispose the mucosa to mutational events, thereby increasing cancer risk in PBM patients. K-ras mutations were frequently detected in gallbladder cancer in PBM patients and in epithelial hyperplasia as well. Epithelial hyperplasia is demonstrated to be an important premalignant lesion of gallbladder cancer. A multistep process of carcinogenesis as a consequence of multiple genetic alterations of oncogenes and tumor suppressor genes has been demonstrated in various organs; however, there is limited information on the molecular mechanism in gallbladder carcinogenesis with PBM. Recent findings support the idea that epithelial hyperplasia plays an important role in gallbladder carcinogenesis with PBM and also support the concept that neoplastic development in gallbladder with PBM also evolves through a multistep process associated with hyperproliferation and genetic alterations.

Chloride dependency of renal brush-border membrane phosphate transport.

In our present study, we examined the effect of Cl(-) on rabbit renal brush-border membrane (BBM) phosphate (P(i)) uptake. It was found that the Na(+)-dependent BBM (32)P uptake was significantly inhibited by Cl(-) replacement in the uptake solution with other anions, or by Cl(-) transport inhibitors, including DIDS, SITS, diphenylamine-2-carboxylate (DPC), niflumic acid (NF), and 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB). Intravesicular formate or Cl(-) increased BBM (36)Cl(-) uptake but did not affect BBM (32)P uptake. BBM (22)Na(+) uptake was lowered by Cl(-) replacement in the uptake solution but not by Cl(-) transport inhibitors. Changes in transmembrane electrical potential altered BBM (36)Cl(-) and (32)P uptake in directions consistent with a net inward movement of negative and positive charges, respectively. However, the Cl(-)-dependent BBM P(i) uptake was not affected by changes in transmembrane electrical potential. Finally, a similar Cl(-) dependency of P(i) uptake was also found with BBM derived from rat and mouse kidneys. In summary, our study showed that a component of Na(+)-dependent P(i) uptake was also Cl(-) dependent in rabbit, rat, and mouse renal BBM. The mechanism underlying this Cl(-) dependency remains to be identified.

Epithelial hyperplasia of the gallbladder in children with anomalous pancreaticobiliary ductal union.

BACKGROUND/AIMS: Few data are available on the fate and incidence of epithelial hyperplasia throughout the life of anomalous pancreaticobiliary ductal union (APBD) patients. The pathological study in pediatric APBD patients is less recognized. METHODOLOGY: Ten resected gallbladders obtained from children with APBD and control patients without APBD were examined histologically, and immunohistochemically for the detection of Ki-67 (as a proliferative marker) and p53. K-ras mutations in codon 12 were also examined. Epithelial hyperplasia was classified into high-grade and low-grade hyperplasia. RESULTS: Six (60%) of 10 patients with APBD had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. Diffuse epithelial hyperplasia was observed in 1 (50%) of 2 undilated-type APBD and 5 (63%) of 8 dilated-type. Two (33%) of 6 patients with epithelial hyperplasia exhibited high-grade hyperplasia. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. K-ras mutations and p53 overexpression were not detected in hyperplastic and normal mucosa. CONCLUSIONS: Epithelial hyperplasia of the gallbladder accompanied by increased proliferative activity exists at birth or is acquired in childhood with APBD patients and may be an important factor predisposing to the development of gallbladder carcinoma.

Effects of Duraflo II heparin-coated cardiopulmonary bypass circuits on the coagulation system, endothelial damage, and cytokine release in patients with cardiac operation employing aprotinin and steroids.

The effects of Duraflo II heparin coated cardiopulmonary bypass circuits, low-dose aprotinin, and steroids on the coagulation system, endothelial damage, and cytokine release were evaluated by comparing those treated with low-dose aprotinin and steroids. Twenty-four adult patients undergoing coronary artery bypass grafting, aortic valve replacement, or valve repair surgery were randomly assigned to 2 groups: either heparin-coated (Duraflo group, n = 12) or noncoated equipment (noncoated group, n = 12) groups. In the Duraflo group, the cardiopulmonary reservoir was also coated with heparin. There were no significant differences in age at the time of operation, aortic cross-clamp time, cardiopulmonary bypass time, and rectal temperature during cardiopulmonary bypass. Standard systemic heparinization was performed. Methylpredonisolone and low-dose aprotinin were given in both groups of patients. Serum XIIa factor, TAT, and IL-6 were significantly higher in the control group than in the Duraflo group during cardiopulmonary bypass (p < 0.01). Serum IL-8 was significantly higher in the control group than in the Duraflo group at 24 h after cardiopulmonary bypass (p < 0.05). No significant difference was found in serum thrombomodulin and TNF-alpha; both were within normal during the study period. These results indicate that the use of Duraflo II heparin coated equipment and a heparin-coated cardiopulmonary reservoir suppressed excess coagulation and inflammatory reaction induced by cardiopulmonary bypass.

Riboflavin transport by rabbit renal basolateral membrane vesicles.

The present study examined riboflavin (RF) uptake by isolated rabbit renal basolateral membrane (BLM). RF uptake was linear during the initial 10 seconds and leveled off thereafter with longer incubation. Studies on RF uptake as a function of incubation medium osmolarity indicated that the BLM RF uptake was the results of transport (approximately 45%) into the intravesicular space as well as binding (approximately 55%) to membrane surfaces. The RF binding to BLM was Na+-dependent so that replacement of Na+ by other cations eliminated the binding component of RF uptake. The process of BLM RF uptake was saturable as a function of substrate concentration and was significantly inhibited by cis-addition of its structural analogs, lumiflavin and lumichrome, indicating the involvement of a carrier-mediated process. The BLM RF uptake was affected by changes in extravesicular pH so that, as compared to pH 7.5, RF uptake was lower at pH 6.5 and higher at pH 8.5. The effect of extravesicular pH persisted when the transmembrane H+ gradient was dissipated by FCCP, indicating the direct effect of pH on BLM RF uptake. The BLM RF uptake was not affected by alterations of the transmembrane electrical potential, induced by either the presence of anions with different membrane permeability (Cl-=NO-3>SO-4>gluconate-) or using nigericin (10 microg/mg protein) with an outwardly or inwardly directed transmembrane K+ gradient. The BLM RF uptake was, however, inhibited by probenecid and p-aminohippurate, and was enhanced by trans-RF. In summary, these results demonstrate the existence of a Na+-dependent BLM binding of RF and a membrane-associated carrier system for RF uptake by renal BLM.