Yoshitaka Fujii

A tentative tumor–node–metastasis classification of thymoma

To establish a tumor–node–metastasis (TNM) classification of thymoma, 207 thymoma patients seen at the First Department of Surgery, Osaka University, and the Second Department of Surgery, Nagoya City University, were evaluated. Lymphogenous and hematogenous metastases of thymoma were infrequent, but their frequency increased with the duration of the course. Lymphogenous metastasis was observed in few cases, but it was considered to progress from anterior mediastinal lymph nodes to intrathoracic and then to extrathoracic lymph nodes. No particular characteristics were observed in hematogenous metastasis. On the basis of these observations, a TNM classification of thymoma was established and applied it to 207 thymoma cases, but it had little advantage over conventional clinical staging. High percentages of thymic carcinomas and thymic carcinoids were in Stage IVB, and the TNM classification of these tumors was considered to be more useful.

Inversely correlated expression of p16 and Rb protein in non‐small cell lung cancers: An immunohistochemical study

Cdk4‐mediated phosphorylation of Rb protein is inhibited by p16, a product of a possible tumor suppressor gene. We examined the expression of p16 and Rb protein by means of immunohistochemistry in 61 non‐small cell lung cancers and have demonstrated an inverse relationship between the expression of p16 and Rb protein: 28/30 specimens that did not stain for p16 stained for Rb and 21/31 p16‐positive specimens did not stain for Rb. Only 1 of the p16‐negative specimens had a mutation of exon 2 of the CDKN2 gene. Our results indirectly support the theory that p16 expression is negatively regulated by the functional Rb protein.

Myasthenia Gravis with Thymoma: Analysis of and Postoperative Prognosis for 65 Patients with Thymomatous Myasthenia Gravis

Sixty-five patients with thymomatous myasthenia gravis were investigated. Thymomas were present in 44% of the male patients and 19% of the female patients with myasthenia gravis. The incidence of thymomatous disease in male patients was higher than in female patients in all age groups. Eighty percent of men more than 50 years old and women more than 60 years old had myasthenia gravis with thymoma. Germinal center formation in the thymus of patients with thymomatous myasthenia gravis was positive in 91% and was high grade. The prognosis for patients undergoing extended thymectomy of thymomatous myasthenia gravis was significantly better than in those having transsternal simple thymectomy, but it was worse than the prognosis for patients with nonthymomatous myasthenia gravis. No increase in the rate of remission or palliation was seen one year after thymectomy. It is concluded that early thymectomy is effective in control of myasthenia gravis in thymomatous myasthenia gravis.

Reversal of CD45R isoform switching in CD8^+ T cells.

Both CD4+ and CD8+ T cells express either CD45RA or CD45R0 isoform of CD45R in an exclusive way. Recent reports have shown that CD45RA+ T cells lose CD45RA and gain CD45R0 upon activation. This switching has been suggested to be irreversible although more recently, examples of reversal of CD45R isotype switching in CD4+ T cells have been reported. We report here that freshly isolated unprimed CD8+ T cells, when activated with PHA, temporarily lose CD45RA but reexpress an intermediate level of CD45RA 2-3 weeks after activation with PHA. This reversal seems to take place much more slowly in unprimed CD4+ T cells: the majority of CD4+ T cells that had lost CD45RA and gained CD45R0 remained CD45RA-CD45R0+ in 3 weeks after the stimulation. Also, long-term CD8+ CD45RA+ T cell lines stimulated with PHA or OKT3 showed even more rapid recovery of CD45RA while PPD-specific CD4+ T cell clones retained the original CD45R0 phenotype 3 weeks after stimulation with PPD or PHA.

Neoplastic epithelial cells express α-subunit of muscle nicotinic acetylcholine receptor in thymomas from patients with myasthenia gravis

We studied the expression of mRNAs coding for the α‐subunit of the muscle nicotinic acetylcholine receptor (AChR)in thymomas from patients with myasthenia gravis (MG). Northern blot analysis failed to detect the expression, but amplification of mRNAs derived from thymomas by reverse transcription and polymerase chain reaction produced the DNA fragments containing the nucleotide sequence coding of part of the α‐subunit. We further revealed that the α‐subunit mRNA was derived from neoplastic epithelial cells of thymoma. Our results support the hypothesis that AChR expressed in thymoma is a candidate for the primary antigen which induces autoimmune responses to muscle AChR. The close relationship between MG and thymoma may be at least in part explained by this hypothesis.

The immunologic role of thymectomy in the treatment of myasthenia gravis: implication of thymus-associated B-lymphocyte subset in reduction of the anti-acetylcholine receptor antibody titer

BACKGROUND AND PURPOSE Thymectomy is generally accepted as the major option of treatment for myasthenia gravis. To elucidate the biological role of thymectomy in the treatment of myasthenia gravis, the immunologic characteristics of the thymus was studied in association with the postoperative kinetics of the anti-acetylcholine receptor antibody titer. MATERIALS AND METHODS Thirty-four patients with nonthymomatous myasthenia gravis who had positive anti-acetylcholine receptor antibody titer and undergoing extended thymectomy were subjected to the study. Reduction of anti-acetylcholine receptor antibody titer was evaluated in terms of the proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy to that before the operation. The numbers of B lymphocytes (CD19(+) cells) and the germinal center B lymphocytes (CD19(+)CD38(high) cells) present in 1 g of the thymic tissue were calculated by flow cytometry. RESULTS The proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy ranged from 27.5% to 150%. The numbers of B lymphocytes and the germinal center B lymphocytes in 1 g of the thymic tissue ranged from 0.19 x 10(6)/g to 162.8 x 10(6)/g and from 0.09 x 10(6)/g to 33.4 x 10(6)/g, respectively. The proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy had a significant inverted correlation with the number of B lymphocytes (P =.002) as well as that of the germinal center B lymphocytes (P =.007). CONCLUSION Effectiveness of thymectomy was dependent on predominance of B lymphocytes and the germinal center B lymphocytes in the thymus, suggesting that one of the biological roles of thymectomy in the treatment of myasthenia gravis is removing the thymus-associated germinal centers.

Invasive thymoma with myasthenia gravis.

In 261 surgically treated patients with myasthenia gravis (MG), 26 had an invasive thymoma and 49 had a noninvasive thymoma. Invasive thymoma was seen in 41% of thymomatous MG patients older than 40 years of age, and 28% in patients younger than 40 years of age. Of 19 patients who underwent total or subtotal thymothymomectomy accompanied by irradiation (4000 rad), 17 were still alive on an average 6.5 years after surgery. The deterioration of MG by the irradiation was observed in 7 of 20 irradiated cases. Thus, postoperative irradiation is effective but should be done with attention to the deterioration of MG. The prognosis of MG in patients with an invasive thymoma was poorer than that in patients with a noninvasive thymoma.

Role of Systematic Mediastinal Dissection in N2 Non-Small Cell Lung Cancer Patients

The surgical results in patients with non-small cell lung cancer staged as N2 disease were historically analyzed. Twenty-six patients were confirmed to have N2 disease on the basis of histologic study of suspicious nodes without systematic mediastinal dissection (PI group), 50 patients underwent systematic mediastinal dissection (R2 group), and 17 patients had bilateral mediastinal dissection, 4 of whom were N3 positive (R3+ group) and 13, N3 negative (R3- group). The difference in the 5-year survival rate between the PI and R2 groups (8% and 16.3%, respectively) was not significant. All 4 patients in the R3+ group died of recurrence within 14 months after operation. Several findings suggest that some patients with N2 disease, especially those with three or more N2-positive stations, actually have N3 disease: The 3-year survival rate was higher in the R3- group (51.3%) compared with the R2 (32.6%; p = not significant) and PI groups (24%; p = 0.01); in the R2 group, the survival rate was significantly (p = 0.017) better for patients with N2 metastases in two stations or less than in patients with three or more N2-positive stations; and the rate of early postoperative death related to cancer correlated with the number of N2-positive stations. We conclude that accurate diagnosis of N2 and N3 disease, and therefore better evaluation of survival for patients with N2 disease, is possible by bilateral mediastinal dissection.

Acute Symptoms Due to a Huge Duplication Cyst Ruptured Into the Esophagus

A 36-year-old housewife complained of a tight feeling in the pharynx with increasing dysphagia, dyspnea, and mild fever. Chest roentgenogram was interpreted as a cystic mass in the middle mediastinum. Computed tomography showed a cystic mass compressing the carina and the esophagus. Ten days after onset, symptoms were suddenly relieved followed by a tarry stool. The chest mass shadow decreased. Esophagofiberscopy showed two fistulas communicating with a cyst that had two chambers. Thoracotomy performed 40 days after onset showed a true duplication of the esophagus with rupture into the esophagus. This is a rare case in which it was possible to observe the sequence of events of a ruptured intramural duplication cyst by means of chest roentgenography, computed tomography, esophagofiberscopy, and cystogram.

Acetylcholine receptor antibody-producing cells in thymus and lymph nodes in myasthenia gravis☆

Eleven patients with myasthenia gravis (5 with thymoma) were studied and spontaneous production of antibody to acetylcholine receptor (AChR) in vitro was found by thymus cells in 10 (and in all 5 with thymoma) and by lymph node cells in 8 (and in 3 with thymoma). The rate of AChR antibody production by thymus cells was greater than that by lymph node cells (10.7 +/- 11.6 and 1.4 +/- 1.5 fmol/10(6) cells/week, respectively, mean +/- SD, P less than 0.05 by paired t test), although the B-cell population was always smaller in the thymus than in the lymph nodes (9.5 +/- 9.4 and 31 +/- 12.7%, P less than 0.001), suggesting the principal role of the thymus in AChR antibody production. It is suggested that lymph nodes can be one of the main sites of AChR antibody production in myasthenia gravis but the antibody-producing cells may originate in the thymus.