Reducing mortality due to lung cancer deaths is the most important issue in the fight against cancer. As a practical solution the authors propose a completely new paradigm for cancer diagnosis. This approach calls for the popularization of lung cancer screening CT to cover over 50% of the entire Japanese population aged between 40 and 84 by 2025 and the treatment of the early-stage lung cancer thus detected by the single-dose carbon ion radiotherapy modality developed by the authors. By this means it would be possible to reduce the lung cancer mortality rate by over 22%. The strategic installation of carbon ion radiotherapy facilities exclusively dedicated to the treatment of lung cancer throughout Japan would permit lung cancer treatment on a large scale at a lower cost than with current surgery.

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In 1999, the World Health Organization (WHO) categorized large cell neuroendocrine carcinoma as a variant of large cell carcinoma. It is important not only to classify histological types of large cell carcinomas of the lung in detail but also to understand that histological subtypes of lung carcinomas are closely related to prognoses. Among large cell carcinomas, large cell neuroendocrine carcinomas are not rare and are more frequently diagnosed by clinicians as recognition of this entity widens. Since Travis et al. first reported LCNEC in 1991, many authors have reported that LCNECs are aggressive tumors and patients with LCNEC have very poor prognoses. Although LCNEC is categorized as a variant of large cell carcinomas, the biological behavior of LCNEC tumors is very similar to those of small cell lung carcinomas, thus LCNEC tumors should be classified as high-grade neuroendocrine tumors. Because of the poor prognosis, surgery alone is not sufficient to cure LCNEC tumors, and patients with LCNEC must receive multimodality therapies including adjuvant chemotherapy even if the pathological stage is IA.

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Objective. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various in vitro tumor studies. However de novo expression of TRAIL and TRAIL-receptor 1 (TRAIL-R1) in cancer tissues is not well documented, and few data are available on their effect on the clinical outcome of non-small cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the expression of TRAIL and TRAIL-R1 proteins in cancer tissues surgically resected from patients with NSCLC by scoring the immunoreactivity, and to examine the correlation between the expression of these proteins and clinical findings of NSCLC. Methods. Cancer tissues and normal tissues were obtained from patients with NSCLC. The expression of TRAIL and TRAIL-R1 proteins was examined by immunohistochemical studies. Results. Significantly higher immunostaining scores for TRAIL and TRAIL-R1 were observed in cancer tissues compared with normal tissues of patients with NSCLC (P<0.0001 for both). There was a significantly positive correlation between the immunostaining score of TRAIL or TRAIL-R1 and pathological T-factor in these patients (P=0.021 and P=0.009, respectively). Conclusion. The majority of NSCLCs expressed TRAIL and TRAIL-R1, which may play a role in regulating the progression of NSCLC.

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Objective. The objective was to determine the histological features related to acute exacerbation of usual interstitial pneumonia pattern (UIP lesion). Materials and methods. The subjects were 12 patients with a diffuse (dense fibrosis extending more than 1 cm from the pleura) or a focal (less than 1 cm) UIP lesion showing acute exacerbation following lobectomy or more for lung cancer (exacerbation group), and 24 comparable patients without acute exacerbation (stable group). The exacerbation group: all men, mean±SD 68±7 years, 7 diffuse and 5 focal UIP lesions. We quantitatively examined the activity and tissue damage related to the UIP lesion on 3 representative histological slides by hematoxylin and eosin staining and by immunohistochemical staining using anti-EMA antibody and anti-ubiquitin antibody. Results. Significant differences (<0.05) were demonstrated: a. the thickness of interstitial inflammation continuous with dense fibrosis; exacerbation group 2.4±1.3, stable group 1.3±1.3 mm, b. number of granulation tissue in and next to dense fibrosis; 21.4±12.2, 12.6±9.1, c. quantification of interstitial inflammatory change with granulation tissue apart from dense fibrosis; 7±5.9, 3.7±3, d. quantification of acute interstitial inflammatory change with fibrin exudation; 1.6±3.2, 0.25±0.6, respectively. Conclusion. The above findings suggestive of UIP activities might be background factors in acute exacerbation.

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Objective. VATS lobectomy is not a standard operative procedure for lung cancer at present because there are various technical approaches and evaluation methods of VATS lobectomy. Therefore, we retrospectively compared clinical outcomes of thoracoscopy-assisted and completely thoracoscopic VATS lobectomy for primary lung cancer. Methods. We treated 80 cases with clinical Stage IA lung cancer with VATS lobectomy with lymphadenectomy. Of these, 42 were performed using a thoracoscopic light guide of through a 10-cm thoracotomy with a rib retractor, from June, 1999 to October, 2005 (group A: thoracoscopy-assisted). In 38 cases, we only watched the monitor without a rib retractor to reduce operative stress on the chest wall from April, 2003 to December, 2005 (group P: completely thoracoscopic procedure). Surgery in both groups was carried out basically in the same way except the difference related to the level of VATS lobectomy. In both groups, dissection of upper mediastinal nodes was performed in cases with upper lobectomy and that of subcarinal nodes was performed in cases with lower lobectomy. In cases of right middle lobectomy, both nodes were dissected. In group P, various devices and ideas were employed with access to improve technical maneuvers and safety. A 4-cm thoracotomy was made and three ports were inserted to complete the surgery via a flexible thoracoscope. Results. Operation time was 248 minutes in group P, which was significantly longer than the 202 minutes in group A (P=0.0001). Blood loss was 146 gram versus 263 gram, which was not significantly different between the two groups. Numbers of dissected upper mediastinal nodes were 11.0 in group P versus 7.2 in group A, respectively. Numbers of dissected subcarinal nodes were 4.7 in group P versus 4.8 in group A, respectively. There was no significant difference between the two groups. Length of hospital stay, total amount of chest tube drainage, and dose of suppository pain killer (diclofenac sodium) were 8.0 days in group P versus 15.0 days in groups A (P<0.0001), 746 ml in group P versus 1015 ml in groups A (P=0.031), and 15 mg in group P versus 45 mg, in groups A (P<0.001), respectively. They were significantly less in group P compared with those in group A. Three cases (7.9%) were converted to open thoracotomy in group P because of technical reasons in two cases and injury to the pulmonary artery in one case. Postoperative morbidity was observed in 5 cases (13.2%) in group P versus 11 cases (26.2%) cases in group A, respectively. Prolonged air leakage was similarly observed in 3 cases (7.9%) in group P versus 5 cases (11.9%) in group A, respectively. Three patients with chest pain required consultation with anesthesiologists in group A. No operative or hospital death was seen in either group. The 2-year survival rate was 87.7% in group P and 90.5% in group A. Conclusion. Minimum operative stress on the chest wall achieves reduction of chest pain after completely thoracoscopic VATS lobectomy. Establishment of a standard procedure is anticipated for future randomized control trials to provide objective evidence and revise the Japanese Guidelines of lung cancer treatment, in which VATS lobectomy still only has a grade C recommendation.

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Objective. To evaluate long-term safety, median overall and progression-free survival, of gefitinib by enrolling patients from clinical studies that had been completed or closed who may benefit from continued gefitinib monotherapy. Methods. A total of 77 patients worldwide (from 9 parent gefitinib trials), mainly with advanced NSCLC (n=61), were enrolled into this extension trial between December 1999 and January 2002; the data cut-off was December 2002. Patients received gefitinib treatment once daily. Results. The safety profile of gefitinib reported in this trial was similar to that reported in earlier gefitinib clinical trials; no new safety issues were identified and gefitinib-related toxicity was predictable, with diarrhea and skin-related adverse events being the most common. For patients entering this trial from IDEAL 1 and 2 (n=48), similar results for both the 250 mg and 500 mg doses were observed for median overall survival (22.2 and 20.8 months, respectively) and progression-free survival (13.7 and 14.0 months, respectively). Conclusions. No new safety issues were identified following long-term treatment with gefitinib and clinical benefit observed in the parent trial was maintained in the majority of patients.

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Background. Cerebrovascular events after chemotherapy for lung cancer are relatively rare. Case. A 50-year-old man with advanced lung cancer (squamous cell carcinoma, T4N3M0 stage III B) had chemoradiotherapy (cisplatin+docetaxel) since November 2004. After temporary reduction, tumor regrowth occurred, and then second line chemotherapy (carboplatin+paclitaxel) was started in June 2005. The day after initiation of second line chemotherapy, left hemiparesis and speech disturbance appeared, but the symptoms totally disappeared in 1 hour. Because brain MRI and MRA, electrocardiography, and echocardiography were not able to detect the cause of the cerebrovascular event, it was diagnosed as a transient ischemic attack (TIA). He received vinorelbine in October 2005, a third line chemotherapy, and he had a TIA again the next day after initiation of vinorelbine administration. He is now receiving best supportive care and has had no TIA or cerebral ischemic stroke since then. Conclusion. We must be aware of cerebrovascular events as adverse effects of chemotherapy for lung cancer.

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Background. Gefitinib showed response rate of 10-20% in chemorefractory non-small cell lung cancer cases, while even in patients who responded, tumor recurrence can appear during the therapy. There are only a few reports about patients successfully retreated with gefitinib. Here we report a case of adenocarcinoma of the lung with a favorable response to retreatment with gefitinib. Case. A 37-year-old woman presented with left chest pain, cough, and dyspnea on exertion in February 2004. Her chest radiograph and CT revealed multiple nodular shadows throughout both lung fields. Adenocarcinoma of the lung was diagnosed (cT1N2M1). Because of progressive disease after two courses of chemotherapy with cisplatin and gemcitabine, she was given gefitinib therapy in May 2004 and a partial response was achieved. However, gefitinib was discontinued after 6 months of treatment, due to regrowth of the tumors. The tumors continued to grow even after further chemotherapy (four courses of cisplatin and docetaxel, followed by three courses of carboplatin and paclitaxel). She was retreated with gefitinib in June 2005, with a partial response once again. Conclusion. Retreatment with gefitinib may yield good results in patients with non-small cell lung cancer who are refractory to chemotherapy.

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Background. It is widely accepted that metastatic pulmonary tumors from synovial sarcoma can be resected with a curative intent. To the best of our knowledge, a pleuropneumonectomy for pulmonary metastases with dissemination from synovial sarcoma has never been reported. Case. A 26-year-old woman who had undergone extensive resection for synovial sarcoma in the right thigh suffered left back pain. Although she was treated with rehabilitation and medication, the pain persisted. Abdominal ultrasonography revealed a huge intrathoracic mass on the right diaphragm. A chest computed tomography (CT) showed multiple masses occupying the left side of the thoracic cavity. A needle biopsy confirmed the diagnosis of metastases from synovial sarcoma. After combined chemotherapy with adriacin and ifosfamide, a pleuropneumonectomy was carried out to remove all metastases. The pericardium and a diaphragm were partially resected because of the invasion. Histological findings confirmed the diagnosis of metastases from synovial sarcoma and invasion to the surface of the pericardium and diaphragm. There was no evidence of pulmonary metastasis within the histological investigation. The postoperative course was satisfactory and she was discharged from the hospital on the 8th postoperative day. She was then treated with an additional chemotherapy with 2 cycles of the same regimen. Six months postoperatively, multiple nodules were found in the right lung on a chest CT scan. She was treated with chemotherapy and has been doing well with remaining disease for 1 year after the surgery. Conclusion. Our experience suggested that pleuropneumonectomy for disseminated metastatic disease contribute to the quality of life and prolonged survival.

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Background. Solitary fibrous tumor is a rare mesenchymal neoplasm. We report a rare case of multiple metastases 11 years after resection of the initial tumor. Case. A 75-year-old woman was admitted to our hospital with swelling of the right parotid gland. Computed tomographic scanning revealed a tumor, 20 mm in diameter, in the right parotid gland. In spite of negative aspiration cytology, the tumor had enlarged in the previous year and was resected. Simultaneously, radiographic examination of the chest revealed three pulmonary nodules. Under the suspicion of metastatic tumor, we resected all of these tumors. These tumors showed hypercellularity of spindle cells with markedly atypical nuclei, immunoreactive with CD34 and bcl-2. Histopathologically, a diagnosis of solitary fibrous tumor was made. These tumors showed the same histological features as the tumors resected from the retroperitoneal space 11 years previously. Conclusion. From the histopathologic features and the clinical course, we concluded that the solitary fibrous tumor in the retroperitoneal space had metastasized to the lung and parotid gland. Long-term follow-up is recommended for solitary fibrous tumors, because of its potential malignancy.

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Background. It is difficult to localize ectopic ACTH-secreting tumors. This is particulary true in small tumors. We report a case where somatostatin receptor scintigraphy was useful in the localization of ACTH-producing tumor. Case. A 34-year-old man was found to have Cushing's syndrome with ectopic ACTH production. Although CT, MRI and FDG-PET failed to reveal the ectopic source of ACTH, ¹¹¹In-pentetreotide scintigraphy demonstrated marked accumulation in the right middle lobe. We therefore performed a thin-sliced chest CT, and an intrabronchial tumor was found in the right middle branch (B⁴a). Preoperative diagnosis of ACTH-producing bronchial carcinoid was made by bronchoscopic biopsy. Plasma ACTH and serum cortisol levels decreased immediately after resection of the right middle lobe. ACTH production by tumor cells was confirmed by immunohistochemistry. Conclusion. This case indicates that ¹¹¹In-pentetreotide scintigraphy may be useful to identify and localize ectopic ACTH-producing tumors.

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[in Japanese]

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[in Japanese]

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