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Kaoru Kobayashi

Publications and source records attributed to Kaoru Kobayashi.

At least 19 recordsLinked to original sources
PubMed2007

Clinicopathologic significance of intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation: a collaborative study with Member Institutes of The Japanese Society of Thyroid Surgery.

Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant tumor having histopathologic features similar to those of squamous cell carcinoma of the thyroid and other organs and a more favorable prognosis. It is thought to originate from ectopic thymic tissue or embryonic thymic rest in or adjacent to the thyroid. We investigated clinicopathologic features of 25 cases of ITET/CASTLE. The sensitivity and specificity of the pathologic diagnosis of ITET/CASTLE by immunohistochemical staining with CD5, a marker of carcinoma of thymic origin, were 82% and 100%, respectively. The 5- and 10-year cause-specific survival rates were 90% and 82%, respectively. Nodal metastasis and tumor extension predict a worse prognosis. Of 22 patients who had curative surgery, 10 (45%) underwent adjuvant radiation therapy, and no locoregional recurrence was seen in any of them. This is the first study demonstrating the survival curve for patients with ITET/CASTLE. Our findings suggest that curative resection followed by radiation therapy may effectively prevent locoregional recurrence and CD5 immunostaining is useful for diagnosing ITET/CASTLE.

Adult↗
PubMed2006

Epithelial-myoepithelial carcinoma of the submandibular gland with a high uptake of 18F-FDG: a case report and image diagnosis.

Epithelial-myoepithelial carcinoma (EMC) is a rare low-grade malignant salivary gland neoplasm typically found in the parotid gland. This report describes a case of EMC that arose from the submandibular gland, and gives special emphasis to the preoperative diagnostic value of positron emission tomography (PET) in combination with computed tomography (CT) and magnetic resonance imaging (MRI). Although a preoperative diagnostically specific image of EMC could not be established, the malignant nature of this tumor was detected by these combined examinations.

Aged↗
PubMed2006

Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation.

Diphenhydramine is widely used as an over-the-counter antihistamine. However, the specific human cytochrome P450 (P450) isozymes that mediate the metabolism of diphenhydramine in the range of clinically relevant concentrations (0.14-0.77 microM) remain unclear. Therefore, P450 isozymes involved in N-demethylation, a main metabolic pathway of diphenhydramine, were identified by a liquid chromatography-mass spectrometry method developed in our laboratory. Among 14 recombinant P450 isozymes, CYP2D6 showed the highest activity of diphenhydramine N-demethylation (0.69 pmol/min/pmol P450) at 0.5 microM. CYP2D6 catalyzed diphenhydramine N-demethylation as a high-affinity P450 isozyme, the K(m) value of which was 1.12 +/- 0.21 microM. In addition, CYP1A2, CYP2C9, and CYP2C19 were identified as low-affinity components. In human liver microsomes, involvement of CYP2D6, CYP1A2, CYP2C9, and CYP2C19 in diphenhydramine N-demethylation was confirmed by using P450 isozyme-specific inhibitors. In addition, contributions of these P450 isozymes estimated by the relative activity factor were in good agreement with the results of inhibition studies. Although an inhibitory effect of diphenhydramine on the metabolic activity of CYP2D6 has been reported previously, the results of the present study suggest that it is not only a potent inhibitor but also a high-affinity substrate of CYP2D6. Therefore, it is worth mentioning that the sedative effect of diphenhydramine might be caused by coadministration of CYP2D6 substrate(s)/inhibitor(s). In addition, large differences in the metabolic activities of CYP2D6 and those of CYP1A2, CYP2C9, and CYP2C19 could cause the individual differences in anti-allergic efficacy and the sedative effect of diphenhydramine.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed2006

A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes.

Monoubiquitination of endocytosed cell surface receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. The sorting of ubiquitinated proteins is executed by concerted actions of class E vacuolar protein sorting (Vps) proteins. Some proteins in the sorting machinery undergo monoubiquitination, suggesting that their functions are also regulated by ubiquitination. The Hrs-STAM complex, a class E Vps protein complex essential for the initial step of the sorting pathway, binds two deubiquitinating enzymes, UBPY and AMSH. Here we examined the effects of inactivating UBPY on protein ubiquitination at endosomes. Overexpression of a catalytically inactive UBPY mutant or depletion of UBPY by RNA interference resulted in the accumulation of ubiquitinated proteins on morphologically aberrant endosomes. Electron microscopy showed that they are aggregates of multivesicular endosomes. Among the sorting machinery proteins that undergo ubiquitination, Eps15 was monoubiquitinated at an elevated level in UBPY-inactivated cells. UBPY also deubiquitinated Eps15 in vitro, suggesting that Eps15 is a cellular substrate for UBPY. Furthermore, inactivation of UBPY caused the accumulation of Eps15 on the endosomal aggregates. These results suggest that UBPY regulates the level of protein ubiquitination on endosomes, which is required for maintaining the morphology of the organelle.

Adaptor Proteins, Vesicular Transport↗
PubMed2006

Host-guest complexation of endohedral metallofullerene with azacrown ether and its application.

Complexation of endohedral metallofullerene La@C(82)-A (1) with macrocyclic compounds, such as 1,4,7,10,13,16-hexaazacyclooctadecane (2), 1,4,7,10,13,16-hexamethyl-1,4,7,10,13,16-hexaazacyclooctadecane (3), mono-aza-18-crown-6 ether (4), 18-crown-6 ether (5), and p-tert-butylcalix[n]arenes (n = 4-8, 6-10), for the first time is examined. Among them, 1 forms a complex with azacrown ethers 2-4 while accompanying the electron transfer between them. This is characteristic of endohedral metallofullerene and caused by its low reduction potential. Activation energies, DeltaG(et), for the electron transfer from 2-4 to 1 are 4.6, 2.8, and 11 kcal/mol, respectively. These small DeltaG(et) values indicate that the electron transfer from the azacrown ethers to 1 is facile in the ground state. Furthermore, the selective isolation of lanthanum endohedral metallofullerenes from the extracts of soot is accomplished by utilizing the complexation of 1 with 2.

Journal Article↗
PubMed2006

Involvement of hepatocyte nuclear factor 4alpha in the different expression level between CYP2C9 and CYP2C19 in the human liver.

CYP2C9 and CYP2C19 are clinically important drug-metabolizing enzymes. The expression level of CYP2C9 is much higher than that of CYP2C19, although the factor(s) responsible for the difference between the expression levels of these genes is still unclear. It has been reported that hepatocyte nuclear factor 4alpha (HNF4alpha) plays an important role in regulation of the expression of liver-enriched genes, including P450 genes. Thus, we hypothesized that HNF4alpha contributes to the difference between the expression levels of these genes. Two direct repeat 1 (DR1) elements were located in both the CYP2C9 and CYP2C19 promoters. The upstream and downstream elements in these promoters had the same sequences, and HNF4alpha could bind to both elements in vitro. The transactivation levels of constructs containing two DR1 elements of the CYP2C9 promoter were increased by HNF4alpha, whereas those of the CYP2C19 promoter were not increased. The introduction of mutations into either the upstream or downstream element in the CYP2C9 gene abolished the responsiveness to HNF4alpha. We also examined whether HNF4alpha could bind to the promoter regions of the CYP2C9 and the CYP2C19 genes in vivo. The results of chromatin immunoprecipitation assays showed that HNF4alpha could bind to the promoter region of the CYP2C9 gene but not to that of the CYP2C19 promoter in the human liver. Taken together, our results suggest that HNF4alpha is a factor responsible for the difference between the expression levels of CYP2C9 and CYP2C19 in the human liver.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

Autoinduction of MKC-963 [(R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine] metabolism in healthy volunteers and its retrospective evaluation using primary human hepatocytes and cDNA-expressed enzymes.

MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6beta-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6beta-hydroxylation to extents similar to those observed with rifampicin in primary human hepatocytes. In addition, approximately 90% of the MKC-963 metabolism in human liver microsomes was estimated to be attributable to CYP3A4. These in vitro findings are in good agreement with the results of clinical study, suggesting that studies using human hepatocytes and cDNA-expressed human P450s are useful for assessing the autoinductive nature of compounds under development before starting clinical studies.

Administration, Oral↗
PubMed2006

Summary of recombinant human serum albumin development.

The methylotrophic yeast Pichia pastoris is well known as a host strain for the production of a variety of heterologous proteins. We have used P. pastoris for the production of recombinant human serum albumin (rHSA), for which we have developed efficient and specialized downstream processes. Results from structural analysis suggest that purified rHSA possesses an identical conformation to plasma derived human albumin (pdHA) and no difference from pdHA has been observed in neo-antigenicity. Host-cell-derived impurities (i.e. Pichia yeast component, DNA and mannan) have been evaluated in the purification process as well as in the drug substance and relevant specifications established. The efficacy and safety of rHSA have been tested in clinical studies and no difference from pdHA has been found in comparative study. Such studies have confirmed rHSA to have high efficacy with little or no adverse reaction.

Clinical Trials as Topic↗
PubMed2006

Clinical significance of metastasis to the central compartment from papillary microcarcinoma of the thyroid.

We previously demonstrated that for papillary microcarcinoma (PMC), (1) patients with lateral lymph node metastasis detected on preoperative ultrasonography (US) are more likely to develop recurrence, and (2) dissection of the lateral compartment does not improve the prognosis of patients without US-detectable lateral metastasis. In this study, we focused on metastasis from PMC to the central compartment. We investigated the clinical significance of lymph nodes in the central compartment using the same series of 600 patients as used in the previous study. Ultrasound-diagnosed central node metastasis could be found in 30 patients (20.0%). Although the specificity of US for detecting central node metastasis was 99.1%, sensitivity was only 10.9%. Neither US-diagnosed nor pathologically confirmed central node metastasis affected the disease-free survival (DFS) rate of PMC patients. Furthermore, in cases where PMC was located only in one lobe, central node dissection in the contralateral lobe did not improve the DFS rate. These findings suggest that, for PMC, (1) US is an insensitive technique for detecting the central node metastasis, (2) the presence of central node metastasis is unrelated to DFS of patients, and (3) when performing lobectomy for PMC involving only one lobe, dissection of the central compartment in the contralateral lobe is optional.

Adult↗
PubMed2006

Prognostic significance of extrathyroid extension of papillary thyroid carcinoma: massive but not minimal extension affects the relapse-free survival.

OBJECTIVES: Extrathyroid extension has been recognized as a prognostic factor in papillary thyroid carcinoma. In the most recent version of the UICC TNM classification system, extrathyroid extension has been classified into two grades, minimal extension (extension to sternothyroid muscle or perithyroid soft tissues) and massive extension (extension to subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve). In this study, we investigated the prognostic significance of each of the two types of extension. PATIENTS AND METHODS: One thousand and sixty-seven patients with papillary thyroid carcinoma without distant metastasis at surgery, who underwent surgical treatment in Kuma hospital between 1990 and 1995 and had been followed postoperatively for 60 months or more, were enrolled in this study. The grading of extrathyroid extension was based on both pathological findings and intraoperative surgical findings. RESULTS: In univariate analysis, although patients with massive extension showed a significantly worse relapse-free survival (RFS) rate than those with no or minimal extension (P < 0.0001), there was no difference in the RFS rate between patients with no extension and those with minimal extension. Among patients with massive extension, the RFS rate tended to be worse in those with posterior extension than in those with anterior extension (P = 0.0562). Furthermore, the RFS rate of patients with massive posterior extension only to the recurrent nerve demonstrated a better RFS rate than those with extension to other posterior organs (P = 0.0052). Multivariate analysis demonstrated that massive extrathyroid extension is recognized as an independent prognostic factor for RFS (P = 0.0003). CONCLUSIONS: These findings suggest that (1) upgrading of T category for tumors with massive extension is appropriate, whereas that for tumors with only minimal extension is not, and (2) careful surgical treatment and postoperative follow-up are required for tumors with massive extension to posterior organs other than the recurrent laryngeal nerve.

Adenocarcinoma, Papillary↗
PubMed2006

Sensitivity and specificity of intraoperative recurrent laryngeal nerve stimulation test for predicting vocal cord palsy after thyroid surgery.

INTRODUCTION: Recurrent laryngeal nerve (RLN) palsy after thyroidectomy, although infrequently encountered, can decrease quality of life. In addition to the hoarseness that occurs with unilateral RLN palsy, bilateral RLN palsy leads to dyspnea and often to life-threatening glottal obstruction. Therefore, intraoperative awareness of the nerve's status is of great importance. This study examined the sensitivity and specificity of a palpation technique to detect contraction of the posterior cricoarytenoid muscle (PCA) through the posterior hypopharyngeal wall while the RLN was being stimulated with a disposable nerve stimulator during thyroid surgery (the laryngeal palpation test) to predict postoperative RLN deficits. METHODS: A total of 2197 RLNs in 1376 patients were identified to be at risk of injury during thyroidectomy performed between July 2003 and August 2004. Postoperative RLN integrity was assessed using direct laryngoscopy or laryngofiberoscopy to visualize vocal fold mobility. RESULTS: Altogether, 76 RLNs failed to elicit a PCA contraction in response to nerve stimulation, and 80 cases of temporary vocal cord palsy and 21 cases of permanent vocal cord palsy were recognized on postoperative evaluation. For postoperative vocal cord palsy, the sensitivity and specificity of the laryngeal palpation test were 69.3% and 99.7%, respectively, with a positive predictive value of 92.1% and negative predictive value of 98.5%. For permanent vocal cord palsy, the sensitivity and specificity were 85.7% and 97.3%, respectively, with a positive predictive value of 23.7% and negative predictive value of 99.8%. CONCLUSIONS: The laryngeal palpation test is not a particularly useful method for predicting the level of RLN function after thyroidectomy. All patients must be examined postoperatively by direct laryngoscopy or laryngofiberoscopy to check vocal cord mobility. Even if there is no contraction of the PCA and we detect vocal cord palsy immediately after surgery, vocal cord palsy often recovers within 1 year when visual preservation of RLN is successful.

Adolescent↗
PubMed2006

A prophylactic infusion of calcium solution reduces the risk of symptomatic hypocalcemia in patients after total thyroidectomy.

BACKGROUND: Several risk factors have been associated with post-operative transient hypocalcemia after thyroid surgery. However, there are no studies evaluating preventive measures to avoid symptomatic postoperative hypocalcemia. Although intravenous infusion of calcium improves hypocalcemic symptoms, it is unknown whether prophylactic infusion prevents symptoms of postoperative hypocalcemia. PATIENTS AND METHODS: Five hundred and forty-seven patients underwent total thyroidectomy. Two groups were identified: group A (n = 243) received prophylactic intravenous drip infusion of 78-156 mg of calcium solution at 3-8 hours after operation, and group B (n = 304) received no prophylactic treatment. Prophylactic infusion was used only once if the patients did not have symptoms of hypocalcemia. Serum calcium (Ca) levels, intact parathyroid hormone (i-PTH) levels on the first postoperative day (1st POD), and the prevalence of symptoms of hypocalcemia were prospectively analyzed. RESULTS: The serum Ca levels at the 1st POD in group A patients (7.91 +/- 0.49 mg/dl, mean +/- SD) was significantly higher than group B patients (7.65 +/- 0.54, P < 0.0001), while the serum i-PTH levels were not significantly different between the two groups. The prevalence of numbness and/or tetany before noon on the 1st POD was significantly lower in group A patients. Prophylactic infusion of calcium solution reduced the prevalence of tetany from 8.6% to 2.1%. CONCLUSION: A prophylactic infusion of calcium solution after total thyroidectomy may be useful in reducing the development of symptomatic hypocalcemia and reduces the patients' risk of having discomfort and anxiety due to hypocalcemia.

Calcium↗
PubMed2006

Clinical significance of lymph node metastasis of thyroid papillary carcinoma located in one lobe.

BACKGROUND: Previous studies have shown that lymph node metastasis can be of prognostic value. In this study, we investigated the clinical significance of node metastasis focusing on metastasis in the central compartment for patients with papillary carcinoma located in one lobe. PATIENTS AND METHODS: We investigated the frequency of lymph node metastasis in 759 patients with papillary carcinoma to determine whether and how such metastasis affects disease-free survival (DFS). RESULTS: Central node metastasis was observed in 63% of patients, and the frequency was increased in relation to tumor size. The frequency of lateral node metastasis was 62.0%, which was also directly related to tumor size. On multivariate analysis of cases showing tumor larger than 1 cm, central node metastasis was recognized as an independent prognostic factor of DFS. The frequency of metastasis to the paratracheal nodes contralateral to the tumor was drastically elevated for tumors larger than 1 cm, but metastasis to this region did not independently predict worse DFS. CONCLUSION: Central node metastasis independently predicts a worse DFS for patients with papillary carcinoma larger than 1 cm.

Adult↗
PubMed2006

Minimal extrathyroid extension does not affect the relapse-free survival of patients with papillary thyroid carcinoma measuring 4 cm or less over the age of 45 years.

PURPOSE: In the most recent version of the UICC TNM classification system for thyroid carcinoma, tumors with minimal extrathyroid extension were classified as T3. In this study, we investigated whether this upgrading is appropriate for papillary thyroid carcinoma. METHODS: We investigated the difference in the relapse-free survival (RFS) rate between patients with tumors having no, minimal, and massive extrathyroid extension in a series of 502 patients over the age of 45 years. RESULTS: Patients with tumors showing massive extension showed a worse RFS rate except for those with tumors measuring 1 cm or less. However, there was no significant difference in RFS between tumors measuring 4 cm or less showing no or minimal extension. In an investigation of 409 patients without any clinically apparent node metastasis, the RFS of patients with tumors larger than 4 cm with massive extension was significantly worse than those with tumors measuring 4 cm or less, while the RFS of patients with tumors with either no or minimal extension did not depend on the tumor size. CONCLUSIONS: These findings suggest that tumors with minimal extension should be classified to have the same T grade as those without such extension, and upstaging of such tumors is therefore not appropriate.

Aged↗
PubMed2006

Delta Np73 expression in thyroid neoplasms originating from follicular cells.

AIMS: p73, a homologue of p53, is known as a negative regulator of tumour progression. However, delta Np73, an isoform of p73 lacking the NH2-terminal transactivation domain plays an oncogenic role by interfering with the activity of p53 and TA (full-length transactivating isoforms) p73. In this study, we investigated the expression of delta Np73 in human thyroid neoplasms originating from follicular cells. METHODS: We immunohistochemically investigated delta Np73 expression in 223 thyroid neoplasms. Delta Np73 expression level was evaluated as the sum of positivity score and intensity score. RESULTS: Normal follicular cells did not express delta Np73, but 27.3% of follicular adenoma, 85.4% of follicular carcinoma, 99.2% of papillary carcinoma, and 95.7% of anaplastic carcinoma were positive for the transcript. Delta Np73 expression level did not differ between widely invasive and minimally invasive follicular carcinomas. In papillary carcinoma, the level was inversely linked to tumour size, extrathyroid extension, and clinically apparent metastasis. Furthermore, in anaplastic carcinoma, delta Np73 expression level was significantly lower than that in papillary carcinoma. CONCLUSIONS: Our findings indicate that delta Np73 plays a role predominantly in the early phase of papillary carcinoma progression.

Adenocarcinoma, Follicular↗
PubMed2006

Usefulness of ultrasonography for diagnosis of malignant lymphoma of the thyroid.

BACKGROUND: Recent developments in ultrasonography (US) and the prevalence of ultrasound-guided fine needle aspiration biopsy (US-FNAB) has enabled physicians to detect and diagnosis thyroid diseases, including thyroid malignant lymphoma, much more easily. METHODS: We describe our diagnostic strategy for malignant lymphoma on US screening. We screened possible malignant lymphoma patients by US characteristics such as enhanced posterior echoes. RESULTS: Among 170 patients suspected of malignant lymphoma between 2000 and 2004, 74 (43.5%) were also diagnosed as having or suspected of lymphoma by US-FNAB. Five patients dropped out, and 67 of 69 patients who underwent surgical examination were pathologically diagnosed as having lymphoma. Finally, 79 (47.9%) of 165 US-suspected patients were confirmed as having lymphoma. Only 21.5% of lymphoma patients complained of rapidly growing goiter. CONCLUSION: US screening for goiters contributes markedly to diagnosis of lymphoma at an early phase, facilitating early initiation of therapy.

Adult↗