Tomoki Utsumi

Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis.

Thymoma and thymic carcinoma are the representative tumors arising from the thymic epithelium. Thymoma is well known for association with autoimmune diseases including myasthenia gravis, suggesting its biological activity. Herein, recent progress in research of thymoma is reviewed with reference to its immunological function. Myasthenia gravis is frequently associated with WHO type B1 and B2 thymomas. These types of thymomas hold a significant number of CD4+CD8+ double-positive T cells, and at the same time, the neoplastic epithelial cells express HLA-DR molecules at a slightly reduced level compared with the normal thymus. The impaired expression of HLA-DR molecules in neoplastic epithelial cells of thymomas possibly affects positive selection of CD4+CD8− single-positive T cells and may result in alteration of its repertoire. The function of thymoma neoplastic cells as the cortical epithelium of the thymus and the morphological resemblance of thymomas to the cortex suggest that thymoma is of cortical epithelial origin; this might imply that thymoma lacks the functional medulla where professional antigenpresenting cells are engaged in negative selection. These findings suggest that thymoma generates autoreactive T cells causing autoimmunity. Further investigation on immunological function of thymoma is supposed to elucidate the pathogenesis of thymoma-related autoimmunity and the high affinity of thymoma with myasthenia gravis. In addition, studying the biology of thymoma is also expected to contribute to further understanding of T-cell development and immunological tolerance in the human, because thymoma can be considered an acquired thymus.

Clinical and pathological aspects of thymic epithelial tumors

A histological classification of thymic epithelial tumors was presented by the World Health Organization (WHO) in 1999 and again in 2004 following slight modifications, in which thymic epithelial tumors were categorized as thymomas and thymic carcinomas. Whereas thymoma is defined as an organotypic (thymuslike) tumor, thymic carcinoma is a malignant epithelial neoplasm with a morphology similar to that of malignant neoplasms arising from other organs. Herein, the recent progress in research of thymic epithelial tumors is reviewed with reference to the WHO histological classification system, with the focus on thymomas. Thymomas are classified into five types—A, AB, B1, B2, B3—according to the shape and atypia of their epithelial cells as well as the abundance of lymphocytes. The invasiveness, prognosis, and genetic imbalance of thymomas have been shown to be related to this classification system. Myasthenia gravis is frequently associated with types B1 and B2. The WHO histological classification of thymomas is not only useful for treatment but reflects their biological characteristics, including genetic alterations. Advances are expected in future studies of thymomas from the standpoint of their clinical, pathological, and biological aspects.

Local IL-17 production and a decrease in peripheral blood regulatory T cells in an animal model of bronchiolitis obliterans.

Background. Recently, it has been reported that Th17 contributes to allograft rejection after transplantation. We investigated the alteration of Th17 and regulatory T cells (Treg) distribution in an animal model of bronchiolitis obliterans following ectopic tracheal transplantation model. Methods. Tracheal grafts from B6 mice transplanted into subcutaneous sites of C3H mice. Allografts were histologically evaluated, and expressions of CD4, CD8, CD25, CD28, CD127, CD152 and Foxp3, and intracellular interleukin (IL)-4, -6, -17, and interferon-&ggr;, in peripheral blood lymphocytes were analyzed. Tracheal graft IL-6 and -17 mRNA expression was assessed using a quantitative reverse-transcriptase polymerase chain reaction. All the data in allogenic transplantation was compared with those in isograft controls. In addition, the effect of IL-6 neutralization on the allograft was evaluated with histopathology and the IL-17 mRNA expression. Results. Treg was significantly lower in peripheral blood of allogenic mice, whereas no significant difference in Th17 in the CD4+ T-cell population was observed after allogenic or isogenic transplantation. Locoregional histologic examination revealed the presence of IL-6-producing lymphocytes and endothelium in the allograft, and the luminal obliteration by fibroblast proliferation. Both IL-6 and IL-17 mRNA levels were elevated in the allograft. Severity of tracheal obliteration and IL-17 mRNA level was significantly suppressed in the IL-6 neutralized allografts. Conclusions. After allograft in a mouse bronchiolitis obliterans model, IL-17 production increases locally without an alteration in peripheral blood Th17 cells, whereas peripheral Tregs decreases. Th17 cells, which can be regulated by IL-6 stimulation, may play a role in posttransplantation rejection of the allograft.

Clinicopathologic factors influencing postoperative prognosis in patients with small-sized adenocarcinoma of the lung.

OBJECTIVE Recent technologic developments in computed tomography have increased the incidence of surgical intervention for small-sized lung cancer. Although indications of a sublobar resection for early disease have been discussed, we occasionally encounter locally advanced small-sized lung cancer with node metastasis. The present study aimed to clarify the histopathologic factors influencing nodal involvement and prognosis of such patients. METHODS We studied 97 patients who underwent complete resection for an adenocarcinoma of 2 cm or less in diameter. Lymph node metastasis and necrosis were microscopically evaluated, whereas immunohistochemical studies were also performed with Ki-67 and D2-40 for proliferation activity and lymphatic invasion, respectively. In addition, carcinoembryonic antigen expression in the tumor and its level in serum were investigated. Survival analysis was then conducted by using these clinicopathologic factors. RESULTS The 5-year disease-free survival rate was 90%. Nodal involvement was significantly frequent in patients with tumors showing microscopic necrosis, a Ki-67 labeling index of greater than 5%, and an increased serum carcinoembryonic antigen level. Furthermore, 5-year disease-free survival was worse in patients with lesions showing microscopic necrosis (68%), a Ki-67 labeling index of greater than 5% (76%), and lymphatic invasion detected with D2-40 staining (77%). Multivariate analysis identified lymphatic invasion detected with D2-40 to be an independent predictor for postoperative recurrence. CONCLUSIONS These results indicate that microscopic necrosis, Ki-67 labeling index, and serum carcinoembryonic antigen level are predictors of nodal involvement. Careful postoperative follow-up examinations for recurrence are required for patients with tumors that show microscopic necrosis, high Ki-67 labeling index, and lymphatic invasion, even in those with stage IA disease.

Microvascular Permeability of the Non–Heart-Beating Rabbit Lung After Warm Ischemia and Reperfusion: Role of Neutrophil Elastase

BACKGROUND The duration of warm ischemia and reperfusion injury is a major limiting factor in the setting of lung transplantation with non-heart-beating donors (NHBD). We hypothesized that reperfusion with neutrophil elastase inhibitor or leukocyte-depleted blood has an inhibitory effect on the ischemia-reperfusion injury of NHBD rabbit lungs. METHODS To assess the lung injury, we used a perfused rabbit lung model and measured the hemodynamic parameters and filtration coefficient. The rabbit lungs after hypoxic cardiac arrest for 30, 50, and 60 minutes were harvested at room temperature, and ventilated lungs were reperfused for 1 hour at a constant flow (120 mL/min). The group with 60 minutes of warm ischemia and hypoxia was further divided into three groups to determine the effects of leukocyte-depleted reperfusion or neutrophil elastase inhibitor, (1) no other special treatment, (2) reperfusion with leukocyte-depleted blood, and (3) administration of 10 mg of specific neutrophil elastase inhibitor. The lungs reperfused immediately after harvest from the heart-beating donor were regarded as the control. RESULTS Sixty minutes of warm ischemia and hypoxia resulted in an increase in filtration coefficient (0.68+/-0.20 g x min(-1) x cm H2O(-1) per 100 g) compared with the control values of 0.13+/-0.03 g x min(-1) x cm H2O(-1) per 100 g. The increase in filtration coefficient after 60 minutes of warm ischemia and hypoxia in NHBD was remarkably suppressed by leukocyte depletion (0.23+/-0.07) and by neutrophil elastase inhibitor (0.21+/-0.08). The shunt fraction and histology results were also near normal. CONCLUSIONS These results suggested that leukocyte depletion or treatment with neutrophil elastase inhibitor during reperfusion reduces alveolar-capillary damage caused by lung ischemia-reperfusion injury in the NHBD lung transplantation setting. This effect might be mediated by inhibition of neutrophil elastase activity or sequestration, and thus may lead to the increased availability of NHBD lungs.

Clinical outcome of resected solid-type small-sized c-stage IA non-small cell lung cancer.

BACKGROUND The chances of pulmonary resection for small-sized lung cancer have increased because of the development of thin-slice computed tomography (CT). Though sublobar resection could be indicated for ground glass opacity (GGO)-dominant adenocarcinoma with low-grade behaviour, the malignant potential of solid-type, small-sized lung cancer has not been sufficiently assessed. We aimed to address the clinical outcomes of resected solid-type c-stage IA non-small cell lung cancer (NSCLC) smaller than 2 cm. METHODS A retrospective observational study involving 118 patients who had undergone a complete resection for lung cancer smaller than 2 cm with solid component more than 50% on CT was conducted, and their postoperative survival and recurrence pattern were analysed. RESULTS Thirty-five patients with solid component-dominant lesion (SCDL) and 83 patients with pure solid lesion (PSL) without GGO were enrolled. Lymph node involvement was found in 15 patients with PSL (18%). The 5-year disease-free survival (DFS) was 100% in SDCL patients and 83% in PSL patients. Multivariate analysis of PSL patients showed that lymph node metastasis and pleural invasion were independent negative prognostic predictors. The 5-year DFS was 88%, 80% and 46% in p-N0, p-N1 and p-N2 patients, respectively. The 5-year DFS was 33% for patients with pleural invasion, which was significantly worse than that for patients without pleural involvement. Postoperative recurrence was mainly observed as intrathoracic lesions within 3 years. CONCLUSIONS A proportion of solid-type NSCLC has malignant potential, even for tumours smaller than 2 cm. Periodic intrathoracic evaluation is required following complete resection.

Stage III thymoma: Relationship of local invasion to recurrence

OBJECTIVES We investigated the relationships of recurrence site with the involved organ and cell type in patients with Masaoka stage III thymomas. METHODS Records of 84 patients who underwent a complete resection of stage III thymomas between 1957 and 2005 were reviewed and then divided according to involved organ. The number of patients with cell types determined according to World Health Organization criteria were 2, 5, 7, 37, and 7 for types A, AB, B1, B2, and B3, respectively, whereas type was not determined in 25 patients. RESULTS Lung invasion occurred in 58 patients, followed by invasion of the pericardium in 47 and invasion of the great vessels in 23. Recurrence occurred in 23 patients, which included 12 with pleural dissemination and 8 with distant metastasis, mostly in the lung. Lung invasion was seen in 8 of the 12 patients with pleural recurrence, whereas vascular invasion was seen in 6 of the 8 patients with distant metastasis. Local recurrence was less common. Disease-free survival after 10 years for all subjects was 74.2%, whereas it was lower for those with vascular invasion (46.1%) compared with those without invasion (87.1%, P < .05). Of the 23 patients with recurrence, World Health Organization cell types B1, B2, and B3 were seen in 2, 11, and 3 cases, respectively, whereas type was not determined in 7 patients. CONCLUSIONS The pleural cavity and lung are common sites of recurrence of Masaoka stage III thymomas. It is important to establish an inclusive therapeutic strategy that considers the relationships of involved organs and sites of recurrence in these patients.

Increased nitric oxide levels in exhaled air of rat lung allografts

In organ transplantation nitric oxide has been reported to be involved in allograft rejection. We examined in a rat lung transplantation model whether nitric oxide is overproduced in acute rejection and can be detected in exhaled air. Thirteen rat right lung transplants were separated into three groups: group 1 (n = 5), untreated allografts (Brown-Norway [RT1n] to Lewis [RT1l]); group 2 (n = 4), cyclosporine-treated allografts; and group 3 (n = 4), isografts (Lewis to Lewis). We examined exhaled nitric oxide levels with a chemiluminescence analyzer and chest roentgenograms on days 2 through 5. Histologic samples were obtained on days 3 and 5. On day 5, the recipients were killed and we measured exhaled nitric oxide from the right and left lungs separately. Blood samples were also obtained for measurement of serum nitrite/nitrate. The exhaled nitric oxide level in untreated allografts increased significantly from day 5 (63.9 +/- 39.2 ppb, p = 0.0095) and was significantly higher than that in treated allografts (9.1 +/- 1.6 ppb) (p = 0.0085) and isografts (6.9 +/- 0.5 ppb) (p = 0.0068). The nitric oxide level in untreated allografts (826.5 +/- 416.1 ppb) was 75 times as high as that from the contralateral normal left lungs (11.2 +/- 2.6 ppb) (p = 0.0118). The level of exhaled nitric oxide correlated significantly with the histologic rejection grade (p = 0.0001). There was no significant difference in the serum nitrite/nitrate levels between allografts and isografts. These data suggest that increased exhaled nitric oxide levels might reflect acute rejection in lung transplants.

Nitric oxide production by bronchoalveolar cells during allograft rejection in the rat

BACKGROUND We reported the increased nitric oxide (NO) level in exhaled air of rat lung transplant recipients during acute rejection (AR). The aim of this study was to determine the site and level of NO production in the rejected graft. METHODS Rat lung transplantation was performed in isografts and allografts. RESULTS In isografts, no AR and no significant increase in NO production was identified. In allografts, grades I-II of AR was seen on postoperative day (POD) 3 and grade III on POD 5. NO produced by BAL cells increased on both POD 3 (11.8+/-2.0 parts per billion [ppb]) and POD 5 (115.3+/-66.9 ppb). There was a highly significant correlation between the level of NO and the severity of AR (p=0.862, P<0.005). BAL cells from allografts expressed iNOS mRNA. Among them, macrophages, lymphocytes and neutrophils were immunostained for iNOS. CONCLUSION NO produced by BAL cells was detected in the early stages of rejection. Therefore, it may serve as a sensitive indicator of AR in lung transplantation.

Clinical Study on Lung Cancer as a Second Primary Cancer

This study evaluates the effect of a previous cancer on the clinical characteristics and the outcome of lung cancer patients. The 313 primary lung cancer patients operated on in the Osaka University Hospital during the period 1984-1993 were reviewed. Of those, 37 had a history of previous cancer. In the lung cancer patients with a history of previous cancer, 20 had adenocarcinomas, 14 had squamous cell carcinomas, while 3 had other cancers. The previous malignancies included 13 gastric cancers, 10 head and neck cancers, 6 colorectal cancers, and 8 others. The pathological stage was 17 stage I, 1 stage II, 15 stage IIIA, 1 stage IIIB, and 3 stage IV. The 5-year survival rate was 37.9%. In patients without a history of previous cancer, there were 139 adenocarcinomas, 100 squamous cell carcinomas, and 37 others. The pathological stage was 126 stage I, 33 stage II, 74 stage IIIA, 23 stage IIIB, and 20 stage IV. The 5-year survival rate was 43.3%. There were no significant differences in the cell type, stage, or survival between the lung cancers found as the first and second cancers. Lung cancer patients with a history of previous cancer are expected to respond to a resection as well as those with lung cancer appearing as their first cancer.