Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice.

Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2(h4) mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell-mediated autoimmune diseases in general.

B cell-targeted therapy with anti-CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism.

Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 µg/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-γ, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody-producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.

[Metastatic lung cancer origin from osteosarcoma of mandible invading tracheal lumen].

A 52-year-old woman underwent the surgical treatment for osteosarcoma of the left mandible in 2003 and was followed up afterward. She suffered from dry cough and bloody sputum, and was admitted to our hospital in April 2007. Computed tomography (CT) revealed several nodules in bilateral lung, and bronchofiberscopy showed the endobronchial tumor obstructing in the right main bronchus. The metastatic tumor progressed in the right main bronchus from the right S6 lung segment. The tumor rapidly progressed in the right bronchus in comparison with the CT findings in about 2 weeks, and the possibility of the tracheal obstruction was considered. She underwent the right middle and lower lobectomy, and the endobronchial tumor was pulled through the right main bronchus. The postoperative course was uneventful, the patient was discharged on 14th postoperative day, and the chemotherapy using cisplatin (CDDP) and adriamycin (ADR) is on-going.

[Thymic carcinoma involving aortic arch; report of a case].

Adenocarcinoma of the thymus is a very rare malignant tumor. The standard treatment for advanced thymic carcinoma has not yet been established, and the prognosis is poor. We report a case of thymic carcinoma that involving the aortic arch and the innominate vein. A 78-year-old woman was admitted to our hospital complaining of hoarseness in April 2007. The computed tomography (CT) scan showed an anterior mediastinal tumor contiguous to the aortic arch and the innominate vein with swelling lymphnodes. Microspcopic examinations of specimens obtained by CT-guided needle biopsy revealed poorly differenciated adenocarcinoma. The carcinoembryonic antigen (CEA) level of serum elevated at 54.9 ng/ml. Thymic carcinoma was diagnosed. The chemoradiotherapy [concurrent, carboplatin (CBDCA) + paclitaxel(TXL)-->vinorelbine (NVB), 60 Gy] was performed, but the effect of the therapy was limited. The resection of the tumor with a part of aortic arch and other peripheral tissues was performed in Augast 2007. The postoperative course was uneventful and the CEA level of serum lowered to the normal. She was discharged 30 days after surgery.

[Right lung cancer with right aortic arch].

An abnormal shadow was detected on chest X-ray mass screening in an asymptomatic 63-year-old man. The further examinations revealed the shadow to be primary lung cancer (Rt. S6. adenocarcinoma, cT2N0M0, c-stage IB) with right aortic arch. We used 3 dimentional-computed tomography (3D-CT) to assess an anatomical feature of vessels in detail. The right lower lobectomy and the dissection of medi astinal lymph nodes was performed. We confirmed no abnormal anatomy of pulmonary artery and vein at surgery, and it was possible to perform right lower lobectomy with the common procedure. Since lymph node was found by intraopetrative pathological examination, since no metastasis from interlobar to subcarinal lymph node was found, we did not perform dissection of upper mediastinal dissection, which was equivalent to ND2a lymph nodes dissection of the left lung cancer in General Rule for Clinical and Pathological Record of Lung Cancer. The patient with right aortic arch is known to have variant anatomy of other intrathoracic vessels occasionally. 3D-CT was quite useful in assessing anatomical feature, and enabled us to perform safe operation.

Inhibitor of vascular endothelial growth factor receptor tyrosine kinase attenuates cellular proliferation and differentiation to mature neurons in the hippocampal dentate gyrus after transient forebrain ischemia in the adult rat.

Neurogenesis in the adult hippocampal dentate gyrus is promoted by transient forebrain ischemia. The mechanism responsible for this ischemia-induced neurogenesis, however, remains to be determined. It has been suggested that there may be a close relationship between neurogenesis and the expression of vascular endothelial growth factor, an angiogenic factor. The purpose of the present study was to examine the relationship between vascular endothelial growth factor and cell proliferation in the dentate gyrus after transient forebrain ischemia. The mRNA expression of vascular endothelial growth factor was increased in the dentate gyrus on day 1 after ischemia. Immunohistochemical analysis on day 9 after ischemia, when a significant increase in cell proliferation was seen, showed that the cerebral vessel space in the subgranular zone of the dentate gyrus had not been affected by the ischemia. Neither were the vascular densities on days 1 and 3 after ischemia altered compared with those of non-operated naïve control rats. Furthermore, the distance from the center of the proliferative cells to the nearest cerebral vessel of ischemic rats was comparable to that of the sham-operated rats. We demonstrated that transient forebrain ischemia-induced cell proliferation and differentiation to mature neurons in the hippocampal dentate gyrus was attenuated by the i.c.v. administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor. These results suggest that vascular endothelial growth factor receptor at the early period of reperfusion may contribute to neurogenesis rather than to angiogenesis in the hippocampal dentate gyrus.

Laparoscope-assisted anal sphincter-preserving operation preceded by transanal procedure.

BACKGROUND: Transanal intersphincteric resection (ISR) was introduced and has been increasingly performed as an ultimate surgical treatment for extremely low rectal cancer. We considered that high quality and less invasive surgery could be achieved if ISR and laparoscopic surgery were combined. METHODS: Between December 2003 and June 2004, we performed laparoscope-assisted ISR for two patients with very low rectal cancer and total colectomy for two patients with ulcerative colitis complicated by colorectal cancer. In all patients, the transanal procedure was preceded by trans-abdominal laparoscopic rectal excision. RESULTS: Preceding transanal dissection facilitated muscle layer-oriented curative dissection, and more importantly, made subsequent laparoscopic rectal excision effortless as a result of penetrating to the dissected pelvic cavity. All patients showed favorable recovery including postoperative anal function with no complication or recurrent disease. CONCLUSIONS: This procedure is feasible and has favorable short-term results for radical treatment of very low rectal disease, while preserving anal function.

Importance of lymph vessels in gastric cancer: a prognostic indicator in general and a predictor for lymph node metastasis in early stage cancer.

BACKGROUND: Metastasis to regional lymph nodes (LNs) through lymphatic vessels is common in cancer progression and is an important prognostic factor in many cancers. Recent evidence suggests that tumour lymphangiogenesis promotes lymphatic metastasis. AIMS: To study the role of lymph vessel density (LVD) in gastric cancer and investigate whether LVD is associated with LN metastasis/prognosis. METHODS: Lymphatics of 117 primary human gastric cancer cases were investigated by quantitative immunohistochemical staining for podoplanin. The relation between LVD and LN metastasis and other established clinicopathological parameters was analysed. The relation between LVD and prognosis was also studied. RESULTS: Mean LVD of "hot spots" was 11.6/case. LVD significantly correlated with LN and podoplanin positive lymphatic invasion. High LVD was associated with worse overall survival. In multivariate analysis, positive LVD was a significant independent predictor of overall survival, depth of invasion, and TNM stage. LVD significantly correlated with LN metastasis at surgery and podoplanin positive lymphatic invasion. In multivariate analysis, positive LVD was an independent significant predictor of LN metastasis. CONCLUSIONS: Increased podoplanin expression is significantly associated with LN metastasis, and may play an important role in detecting LN metastasis in gastric cancer. Furthermore, LVD may be a significant prognostic factor in gastric cancer at any stage. In addition, LVD and lymph vessel invasion detected by podoplanin immunohistochemistry are associated with LN metastasis in T1 early gastric cancer. LVD assessment by podoplanin immunohistochemistry may become a useful predictor of LN metastasis in T1 early gastric cancer and may influence the decision making process for additional surgery.

Cyclic mechanical strain regulates the PTHrP expression in cultured chondrocytes via activation of the Ca2+ channel.

The association between mechanical stimulation and chondrocyte homeostasis has been reported. However, the participation of PTHrP (parathyroid-hormone-related protein) in the mechano-regulation of chondrocyte metabolism remains unclear. We determined whether mechanical stimulation of chondrocytes induces the expression of PTHrP and, further, whether the mechano-modulation of PTHrP is dependent on the maturational status of chondrocytes. Cyclic mechanical strain was applied to rat growth plate chondrocytes at the proliferating, matrix-forming, and hypertrophic stages at 30 cycles/min. Cyclic mechanical strain significantly increased PTHrP mRNA levels in chondrocytes at the proliferating and matrix-forming stages only. The induction of PTHrP was dependent on loading magnitude at the proliferating stage. Using specific ion channel blockers, we determined that mechano-induction of PTHrP was inhibited by nifedipine, a Ca2+ channel blocker. These results suggest that mechanical induction of PTHrP possibly provides the environment for greater chondrocyte replication and matrix formation that would subsequently affect cartilage formation.

Removal of 137Cs in Japanese catfish during preparation for consumption.

Japanese catfish contaminated by (137)Cs have been used to investigate how dressing and cooking methods affect the removal of radioactivity from the fish. During the dressing, 6.0% of the initial (137)Cs activity in live fish was removed by washing them, and a further 30.3% of this activity relative to the washed fish was removed by discarding the nonedible body parts (such as the skeleton, fins, visceral mass, liver, and kidney) and by washing the chopped edible remains. Fish curry was cooked with various spices, vegetable oil, and greens and other vegetables following a method commonly used in Southeast Asian and East Asian countries. The cooking process removed a further 61.6% of the (137)Cs activity relative to the activity in dressed fish. Taken together, this normal domestic fish dressing and culinary process removed 74.7% of the initial (137)Cs activity that had been present in the live fish. During the cooking, the radioactivity removed from the fish pieces was found to be distributed throughout the ingredients of the curry. The cooked pieces retained, on average, 38.5% of the radioactivity present in the raw dressed pieces. Among the ingredients, the gravy was found to contain an average of 34.8% of the activity of the dressed fish. The activity in greens and vegetables was found to vary from 4.0% (in cauliflower) to 7.2% (in potatoes). It may be concluded that normal home preparation and culinary processes removed much of the radioactivity from the fish.

RGD-CAP (betaig-h3) exerts a negative regulatory function on mineralization in the human periodontal ligament.

In our previous studies, RGD-CAP/betaig-h3 was isolated from a fiber-rich fraction of cartilage and was found to have a negative function on mineralization of hypertrophic chondrocytes. However, the expression and biological function of RGD-CAP in the periodontal ligament (PDL) are not known. We hypothesized that RGD-CAP could be expressed in the PDL and regulate its mineralization. To test this, we investigated the expression of RGD-CAP in human PDL and the effects of RGD-CAP on mineralization of cultured PDL cells. RGD-CAP was detected in the human PDL as multimeric proteins greater than 200 kDa. The RGD-CAP mRNA level decreased in cultured PDL cells exposed to 10(-8) M dexamethasone or 10(-8) M 1alpha,25-dihydroxyvitamin D(3) when these steroids increased alkaline phosphatase (ALP) activity. Furthermore, exogenous RGD-CAP suppressed the ALP activity and bone nodule formation of cultured PDL cells. These findings suggest that RGD-CAP in the PDL modulates the mineralization which affects adjacent alveolar bone metabolism.

Relation between ultrasonographic and histologic findings of tracheal invasion by differentiated thyroid cancer.

Between 1988 and 1999 a total of 24 patients with differentiated thyroid cancer invading the airway underwent various types of tracheal resection at the Osaka Police Hospital. Preoperative ultrasonographic (US) findings in these patients were compared with postoperative histologic results of the resected specimens to confirm the relation between the preoperative and postoperative diagnoses and to determine the indications for operative procedures. Preoperative US revealed cancer invasion to the adventitia in 2 cases, to the intercartilage space in 13, and to the tracheal mucosa in 9. Histologically, cancer invasion to the adventitia was confirmed in 4, to the intercartilage space in 10, and to the mucosa in 10. Among 13 cancer invasion instances to the intercartilage revealed by US, overdiagnosis occurred in 3 cases and underdiagnosis in 1. The actual overall diagnostic rate by US was 83.3%, which is a great improvement over other available methods. In conclusion, preoperative US findings of the trachea agreed with the histologic findings of the resected specimens, indicating US to be the first choice when making decisions about resecting the trachea and about the operative procedure.

Video-assisted thoracic lobectomy by the substernal hand-assisted method for a metastatic lung tumor.

In lobectomy by video-assisted thoracic surgery (VATS), the surgeon is required to have experience and a high degree of skill in performing the operation. We applied substernal hand-assisted thoracoscopic lobectomy to remove a metastatic lung tumor that originated from colon cancer in one patient and obtained satisfactory results. This method compensates for a current limitation of VATS lobectomy, namely, the fact that the surgeon cannot touch the lesion. The reported method is safe and useful for thoracoscopic surgery. It can be performed easily, even if the surgeon is not experienced in performing VATS lobectomy.

Hand-assisted thoracoscopic resection for anterior mediastinal masses.

We report three cases of anterior mediastinal disease (pericardial cyst, thymoma, and myasthenia gravis) in which we used a hand-assisted method in combination with thoracoscopic resection via an infrasternal approach in order to improve the maneuverability and safety of the operation. This technique combines the advantages of both thoracoscopic and incisional resection. It shows promise of becoming a less invasive operation that can be used to treat certain mediastinal tumors, both malignant and benign.

Hepatic resection for intrahepatic cholangiocarcinoma: relation to gross tumor morphology.

BACKGROUND/AIMS: The aim of this study was to investigate the clinicopathologic features and biological behaviors related to the gross appearance of intrahepatic cholangiocarcinoma. METHODOLOGY: Fourteen patients with intrahepatic cholangiocarcinoma who underwent hepatic resection between 1986 and 1998 were divided into four groups according to the gross appearance of the tumor: ID (intraductal growth) type (n = 1), PD (periductal-infiltrating) type (n = 4), MF (mass-forming) type (n = 5), MF-with-PD type (n = 4). RESULTS: Overall survival at 1, 5, and 10 years was 50.0%, 35.7%, and 35.7%, respectively. All three long-term survivors without recurrence had tumors unassociated with vascular invasion, intrahepatic metastasis, or lymph node metastasis. The MF and MF-with-PD tumors were more frequently associated with vascular invasion and/or lymph node metastasis than the ID or PD type. The Ki-67-positive grade of the cancer cells was clearly higher in the MF and MF-with-PD tumors than in the ID or PD type. All of the cases of MF-with-PD tumors were stage IV-A and had a poor outcome. CONCLUSIONS: Extended hepatic resection with a sufficient surgical margin yielded good results in intrahepatic cholangiocarcinoma patients without vascular invasion, intrahepatic metastasis, or lymph node metastasis. However, it is necessary to develop a new effective strategy for advanced intrahepatic cholangiocarcinomas, such as the MF-with-PD type.

Video mediastinoscopic division of a congenital esophagobronchial fistula with esophageal diverticulum by a paraesophageal approach.

We treated a patient with an esophagobronchial fistula accompanied by stomach cancer. Using an endo-stapling technique, the fistula was divided video mediastinoscopically by a paraesophageal approach through the esophageal hiatus in the diaphragm.

Three-dimensional MR imaging of mammographically detected suspicious microcalcifications.

BACKGROUND: The purpose of this study was to evaluate the diagnostic value and clinical significance of three-dimensional MR imaging of the breast in patients with mammographically detected suspicious microcalcifications. METHODS: Forty patients with suspicious microcalcifications on mammography were evaluated with three-dimensional MR imaging. MR findings were grouped mainly by distribution of abnormal enhancement (linear, focal-clumped, segmental-clumped, segmental-stippled and diffuse-stippled). These findings were compared with the mammography findings according to the criteria of the Breast Imaging Reporting and Data System (BI-RADS) and histopathologic data. RESULTS: Twenty patients had proven malignancies, most frequently ductal carcinoma in situ. For all the cases, linear (100%) and segmental-clumped type (100%) enhancement on MR imaging showed a significantly higher risk for malignancy. Diffuse stippled type (7%) and no enhancement (0%) on MR imaging indicated the lowest possibility of malignancy. 3D-MR imaging showed a sensitivity of 90%, a specificity of 95% and an overall accuracy of 93% in this study. CONCLUSIONS: Three-dimensional MR imaging of the breast can more accurately diagnose ductal carcinoma in situ. Combined with mammography, this procedure is useful for reducing the number of false-positive biopsies and helpful for deciding the better management of patients with mammographically detected suspicious microcalcifications.

Merits and demerits of operative procedure to the trachea in patients with differentiated thyroid cancer.

Local radical thyroidectomy, including cervical lymph node dissection and combined circumferential resection of the trachea, has been performed over the past 20 years in 31 patients with differentiated cancer invading the trachea. The 5- and 10-year survival rates for these patients were 77.4% and 66.7%, respectively. In 19 of the 31 (61%) cases the recurrent nerve was resected because of direct cancer invasion. Bilateral recurrent nerve palsy occurred in 12 patients, 3 of whom were managed postoperatively using a T-shaped tube for preservation of the larynx. Hoarseness remained in 21 patients. In two patients with recurrent cancer invasion of the larynx, partial laryngectomy and hemilaryngectomy were performed, and reconstruction was done using ear cartilage without postoperative dyspnea or dysphagia. Parathyroid function is an important factor in regard to the quality of life of patients. In 22 patients at least one of the parathyroids was preserved. Postoperative calcium administration was necessary in 14 patients. Our long-term observations indicate that local radical thyroidectomy with combined resection of the trachea can serve as a useful treatment for advanced differentiated cancer invading the airway.