Shigeki Hitomi

Correlation of Expression of H/LeY/LeB Antigens with Survival in Patients with Carcinoma of the Lung

BACKGROUND The level of expression of H/Le(y)/Le(b) antigens is high in various histologic types of lung cancer, a feature that may be related to deletion of A and B blood-group antigens. We evaluated the possibility that expression of this antigen, which can be defined by the monoclonal antibody MIA-15-5, might be of prognostic value, as suggested by our previous observation that MIA-15-5 inhibits tumor-cell motility and metastasis. METHODS We used MIA-15-5 to stain tissue sections from 149 patients with primary lung cancer whose clinico-pathological histories were well documented. The survival curves for patients whose tumors stained positively were compared with the curves for those whose tumors stained negatively. Multivariate analyses were performed with a Cox proportional-hazards regression model. RESULTS Among the 149 patients studied, five-year survival in the 91 patients with MIA-positive tumors was significantly lower than survival in the 58 with MIA-negative tumors (20.9 percent vs. 58.6 percent, P less than 0.001). Among the 67 patients with squamous-cell carcinoma, the rates also differed significantly (10.5 percent vs. 62.1 percent, P less than 0.001). The difference in survival between patients with MIA-positive tumors and those with MIA-negative tumors was significant among patients with blood groups A and AB (P less than 0.001), but not among those with blood group B or O (P = 0.071 and 0.068, respectively). Multivariate analysis with the Cox regression model indicated that positivity best correlated with five-year mortality, followed by lymph-node status (N stage) and tumor size status (T stage), whereas sex, age, and blood group did not correlate with mortality. CONCLUSIONS Positivity for MIA (i.e., immunohistologic staining by MIA-15-5, which defines H/Le(y)/Le(b) antigens) is inversely correlated with survival among patients with primary lung cancer and may be of prognostic value.

Extended operation for non-small cell lung cancer invading great vessels and left atrium.

OBJECTIVE We analyzed the results of surgical treatment in patients with non-small cell lung cancer invading the great vessels (GV) and left atrium (LA) by direct extension and without distant metastases. METHODS From 1976 to 1993, 42 patients (37/male, 5/female) with lung cancer invading the GV and LA were treated surgically, 13 had invasion of the superior vena cava and innominate vein, 15 of the aorta and subclavian artery, and 14 of the left atrium. In all 42 the diagnosis was confirmed by pathological examination. Surgical resection included pneumonectomy (16 patients) and lobectomy (26 patients). The histologic type was squamous cell carcinoma in 27 patients, adenocarcinoma in 12, and large cell carcinoma in 3. Preoperatively, 13 patients were treated with radiation and chemotherapy. Postoperatively, further treatment was given to 22 patients. All were staged according to the international TNM staging system. Survival was calculated by the Kaplan-Meler method. RESULTS A total of 15 patients underwent complete resection. Reliability of clinical N factor was 80%. The overall survival was 17% at 3 years (median survival time (MST), 14 months). The operative mortality was 2.4%. Patients with lung cancer invading GV (MST, 19 months) had significantly longer survival than did those with cancer invading LA (MST, 10 months, P = 0.036). There were significant prognostic differences between N0-1 and N2-3 (MST, 22 months; MST, 9 months, respectively, P = 0.0013). Cox regression analysis identified pathological N factor, completeness of resection, and pre- and postoperative radiotherapy as important in affecting survival. CONCLUSIONS We conclude that patients with pathological N0-1 non-small cell lung cancer invading great vessels can achieve long-term survival with adequate surgical treatment.

Postoperative adjuvant chemotherapy with PVM (Cisplatin+Vindesine+Mitomycin C) and UFT (Uracil+Tegaful) in resected stage I–II NSCLC (non-small cell lung cancer): a randomized clinical trial

OBJECTIVE The West Japan Study Group For Lung Cancer Surgery (WJSG) conducted a randomized controlled trial in order to assess the usefulness of adjuvant chemotherapy for NSCLC. METHODS Patients with completely resected NSCLC (stages I and II) were enrolled in the trial. These patients were randomized into two groups: a surgery alone group; and a chemotherapy group which received intravenous administration of two courses of 4-week PVM chemotherapy (80 mg/m2 of Cisplatin on day 1, 2-3 mg/m2 of Vindesine on day 1 and/or day 8, and 8 mg/m2 of Mitomycin C on day 1), after which they took 400 mg/day of UFT (Uracil + Tegaful) orally for 1 year. RESULTS Among 229 patients registered for the study from August 1988 to July 1990, 225 were available cases (116 patients in the surgery alone group, and 109 patients in the chemotherapy group). No bias in prognostic factors could be found between the two groups. The 5-year survival rate was 71.1% for the surgery-alone group and 76.8% for the chemotherapy group with no significant difference observed. However, subset analysis demonstrated that PVM therapy improved the post operative survival of pT1N0 patients (the 5-year survival rate: 75.3% for the surgery alone group, and 90.7% for the chemotherapy group P<0.05). CONCLUSIONS It is interesting to find that among pT1N0 patients, who were not regarded as a target of chemotherapy, those receiving chemotherapy showed significantly better prognostic results. These findings suggest the necessity of further studies on the adjuvant chemotherapy, even in the early stages.

Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded

BACKGROUND We analyzed the operative outcome of extensive surgery for invasive thymoma, especially in those with thymomas invading the superior vena cava, the left innominate vein, or both. METHODS We treated 41 patients with invasive thymoma, including 34 stage III, 5 stage IVa, and 2 stage IVb thymomas. Thirty-eight patients received radiotherapy preoperatively or postoperatively. In 12 patients with invasion of the superior vena cava or innominate vein, we performed angioplasty, reconstruction, or both. RESULTS The overall 5-year survival rate was 77% and the 10-year survival rate was 59%. In the stage III group, there was a significant difference between those with complete and those with incomplete resection. Ten of 12 patients who had angioplasty with or without reconstruction of the superior vena cava or innominate vein survived without recurrence of the tumors. CONCLUSION Angioplasty and vascular reconstruction are recommended because successful treatment for invasive thymomas depends on complete resection of the tumors.

High-dose irradiation prevents rejection of canine tracheal allografts

We investigated the possibility of immunosuppressant-free transplantation of the trachea using high doses of 60Co gamma irradiation of the graft before transplantation. Twenty mongrel dogs were used. Five rings of the trachea were removed from the donors and irradiated with 60Co gamma rays. Five corresponding rings were removed from the thoracic trachea of the recipient dogs, and the irradiated trachea was transplanted. Five animals were placed in each of four dosage groups: group A, no irradiation; group B, 20,000 cGy; group C, 50,000 cGy; and group D, 100,000 cGy. The anastomotic site and graft were covered with a pedicled greater omentum graft. No immunosuppressants were given. In group A, all the animals died within 1 month of tracheal stenosis caused by graft rejection. In groups B and C, one animal in each group survived for a long period, but all the others died of tracheal stenosis caused by graft rejection. In group D (100,000 cGy), the graft became incorporated into the recipient tissue in four of the five animals, and three are still alive (more than 1 year later). These findings indicate that allotransplantation of the trachea without the use of immunosuppressants is possible with pretransplantation irradiation of the graft at the dose of 100,000 cGy.

Amelioration of ischemia-reperfusion injury by human thioredoxin in rabbit lung

Human thioredoxin is a polypeptide with thiol groups, possessing reducing activity, which is proved to have the ability to reduce active oxygens. This study evaluated the effect of human thioredoxin on the ischemia-reperfusion lung injury and the roles of human thioredoxin on active oxygens by chemiluminescence examination. The left hilum of the lung of Japanese white rabbits was occluded for 110 minutes and then reperfused for 90 minutes. Ten, 30, 60, and 90 minutes after reperfusion the right hilum was occluded for 5 minutes and the pulmonary functions of the left lung were examined. The animals were divided into four groups, three ischemia groups and a sham group (without occlusion; n = 6). The ischemia groups received human thioredoxin, 60 mg/kg (n = 10), N-acetylcysteine, 150 mg/kg (n = 7), or saline solution (control, n = 10) during reperfusion. Three rabbits in the human thioredoxin group and the control group were used to measure active oxygens with a cypridina luciferin analog. An additional group of reperfused lungs (n = 3) that were given superoxide dismutase after 110 minutes of ischemia was established to identify chemiluminescence examination. Compared with the sham group, reperfusion after 110 minutes of ischemia produced a significant lung injury in the control group. Among the ischemia groups, the human thioredoxin group showed significantly higher arterial oxygen tension at 30, 60, and 90 minutes after reperfusion than the control group, although there was no significant difference between the N-acetylcysteine and control groups. Histologically, intraalveolar exudation, interstitial thickening, and cellular infiltration were seen in the control group, whereas in the thioredoxin group alveolar structure was well preserved. In the measurement of active oxygens the chemiluminescence in the human thioredoxin group was less than that in the control group and as little as that in the group administered superoxide dismutase. We concluded human thioredoxin attenuated ischemia-reperfusion injury by involving active oxygens in rabbit lungs.

Time trends and survival after operations for primary lung cancer from 1976 through 1990

To assess the time trends and survivals after operations for primary lung cancer, the cases of 845 consecutive patients who underwent thoracotomy between 1976 and 1990 were retrospectively reviewed by groups corresponding to year of the operation (the early period was 1976 to 1980, n = 208; the middle period was 1981 to 1985, n = 291, and the late period was 1986 to 1990, n = 346). The 5-year survivals at the early, the middle, and the late periods were 31.5%, 39.0%, and 54.0%, respectively, with significant improvement particularly at the late period (p < 0.05 for the early period vs the middle period, p < 0.01 for the early or middle period vs the late period); the improvement was caused by increase in the ratio of patients with stage I disease (20.7% at the early period, 32.0% at the middle period, 44.2% at the late period), increase in the rates of complete tumor resection with lymph node dissection (57.2%, 68.0%, 74.3%, respectively), and decrease in the rates of operation-related death (3.8%, 3.4%, 0.9%, respectively). The postoperative prognosis of patients with stage II disease at the late period (5-year survival 74.8%) showed significant improvement compared with the other periods. Moreover, the prognosis of patients with stage IIIa, pN2 disease (5-year survival 41.5%) showed significant improvement, which was caused by the significant decrease in patients with pT3 N2 M0 disease and poor prognosis.

Attenuation of ischaemia reperfusion injury by human thioredoxin.

BACKGROUND--Active oxygen species are thought to play a part in ischaemia reperfusion injury. The ability of a novel agent, human thioredoxin (hTRX), to attenuate lung damage has been examined in a rat model of ischaemia reperfusion injury. METHODS--Twenty eight animals were studied. At thoracotomy the left main bronchus and the left main pulmonary artery were clamped for 75 minutes and the lung was then reperfused for 20 minutes. Phosphate buffered saline was administered intravenously to nine control animals and hTRX (30 micrograms/g body weight) was given intravenously to another group of nine animals. Two experiments were carried out. The first (Exp 1) was a time matched pair experiment (five treated, five controls), and the second (Exp 2) was performed under controlled conditions (four treated, four controls; temperature 25 degrees C, humidity 65%). In another 10 nonischaemic rats and those in Exp 1 biochemical measurements of lipid peroxide, superoxide dismutase, and glutathione peroxide levels were performed. RESULTS--In both experiments rats perfused with hTRX survived longer than controls. In Exp 1 the arterial oxygen tension (PaO2) on air in the hTRX group was higher at 20 minutes than at one minute after reperfusion. In Exp 2 PaO2 at 20 minutes was higher in the hTRX group than in the controls. Lipid peroxide, superoxide dismutase, and glutathione peroxide levels in the control group were higher than in the hTRX group and in the non-ischaemic groups. Histological examination showed less thickening and oedema of the alveolar walls in the hTRX group than in controls. CONCLUSIONS--These results suggest that hTRX is effective as a radical scavenger and can limit the extent of ischaemia reperfusion injury of the lungs of experimental animals.

Alpha‐fetoprotein and human chorionic gonadotropin‐producing lung cancer

A 73‐year‐old man had primary lung cancer that produced both alphafetoprotein (AFP) and human chorionic gonadotropin (HCG). The preoperative serum AFP level of 1039 ng/ml decreased to the normal range 8 weeks after surgery. The preoperative serum HCG level of 11 mIU/ml, which temporarily decreased to the normal range after operation, soon increased thereafter. The serum HCG level decreased, however, to the normal range after postoperative mediastinal radiation therapy. During relapse, only the serum HCG level increased gradually to 26,000 mIU/ml 7 weeks before his death. The lung cancer was classified histologically as poorly differentiated adenocarcinoma. Immunohistochemically, AFP was detected in the mononuclear tumor cells of the primary tumor in the lung, and HCG was found in the giant cells of the subcarinal metastatic lymph node. The concanavalin A non‐reactive fraction rate for AFP was 81.3%, and appeared to differ from those of hepatocellular carcinoma and yolk sac tumor. Cancer 59:227–232, 1987.

Loss of heterozygosity (LOH) at 17q and 14q in human lung cancers

Our recent linkage study of urethane-induced pulmonary adenomas in SMXA RI strains of mouse revealed two host resistance genes, Par1 (chromosome 11) and Par3 (chromosome 12). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24, based on synteny between mouse and human. In this study, we examined the loss of heterozygosity (LOH) in these two homologous human chromosomal regions in 30 primary lung adenocarcinoma samples with matched normal DNA. Using 15 highly polymorphic markers, two commonly deleted regions were identified on human chromosomes 14 and 17, respectively. At 17q21, nine (53%) of 17 informative tumors showed LOH between D17S588 and D17S518. On the other hand, at 14q11-12, seven (32%) of 22 informative tumors showed LOH at loci between D14S261 and D14S80. Subsequently, we examined 25 squamous cell carcinomas (SQ) and 24 small cell carcinomas (SCC). At 14q11-12, six (38%) of 16 informative SQ and five (42%) of 12 informative SCC showed LOH. In contrast, at 17q11-23, one (7%) of 15 informative SQ and two (14%) of 14 SCC showed LOH. Therefore, the gene on 17q seemed to affect selectively adenocarcinomas, whereas the other gene on 14q, all three types of lung carcinomas. These observations indicate that a comparative genetic analysis provides a promising approach to survey genes involved in multifactorial process of human lung carcinogenesis.