Mizuto Otsuji

A Phase I Study of α-Galactosylceramide (KRN7000)–Pulsed Dendritic Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Purpose: Human Vα24 natural killer T (NKT) cells bearing an invariant Vα24JαQ antigen receptor, the counterpart of murine Vα14 NKT cells, are activated by a specific ligand, α-galactosylceramide (αGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of αGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Vα14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with αGalCer-pulsed DCs in lung cancer patients. Experimental Design: Patients with advanced non–small cell lung cancer or recurrent lung cancer received i.v. injections of αGalCer-pulsed DCs (level 1: 5 × 107/m2; level 2: 2.5 × 108/m2; and level 3: 1 × 109/m2) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases. Results: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of αGalCer-pulsed DCs, dramatic increase in peripheral blood Vα24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life. Conclusions: In this clinical trial, αGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.

A Phase I Study of In vitro Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Purpose: Human Vα24 natural killer T (Vα24 NKT) cells bearing an invariant Vα24JαQ antigen receptor are activated by a glicolipid ligand α-galactosylceramide (αGalCer; KRN7000) in a CD1d-dependent manner. The human Vα24 NKT cells activated with αGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-γ, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Vα24 NKT cell therapy. Experimental Design: Patients with advanced or recurrent non–small cell lung cancer received i.v. injections of activated Vα24 NKT cells (level 1: 1 × 107/m2 and level 2: 5 × 107/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Vα24 NKT cells, an increased number of peripheral blood Vα24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Vα24 NKT cells. The number of IFN-γ-producing cells in peripheral blood mononuclear cells increased after the administration of activated Vα24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. Conclusions: The clinical trial with activated Vα24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

Fluorescence bronchoscopy in the detection of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy

BACKGROUND A new strategy in the treatment of squamous cell carcinoma of the tracheobronchial tree is the detection and eradication of preinvasive bronchial lesions before they become invasive cancers. It is, however, difficult to detect preinvasive lesions by conventional white-light bronchoscopy alone. PURPOSE we conducted a detailed investigation on the use of fluorescence bronchoscopy in the detection of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. METHODS 64 participants with sputum cytology suspicious or positive for malignancy were examined with both white light and fluorescence bronchoscopy (LIFE group). Earlier to this study, before fluorescence bronchoscopy became available in our institute, 48 participants having sputum cytology suspicious or positive for malignancy were examined with white light bronchoscopy alone (control group). Biopsy specimens for pathological examinations were taken of all abnormal areas discovered by white light or fluorescence bronchoscopy examination. RESULTS In sputum cytology suspicious or positive for malignancy, the diagnosis of preinvasive bronchial lesions was greatly enhanced in the LIFE group as compared with the control group (45 vs. 7 lesions). The percentage of participants with preinvasive bronchial lesions was also significantly higher in the LIFE group than in the control group (40.6 vs. 12.5%, P = 0.00087, respectively). CONCLUSIONS Our study suggests that the use of fluorescence bronchoscopy in addition to conventional white-light examination could greatly enhance the detection and localization of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy.

Impact of interstitial lung disease on surgical morbidity and mortality for lung cancer: analyses of short-term and long-term outcomes

BACKGROUND This study investigated postoperative morbidity, mortality, and the long-term survival for patients with lung cancer who have interstitial lung diseases. METHODS A retrospective chart review of 931 patients with lung cancer who underwent pulmonary resection at Chiba University Hospital between 1990 and 2000 was undertaken. Interstitial lung disease was defined by medical history, physical examination, and abnormalities compatible with bilateral lung fibrosis on chest computed tomography or high-resolution computed tomography (36 patients: 3.9%, interstitial lung diseases group). The remaining 895 patients (96.1%) were categorized as non-interstitial lung disease group. RESULTS The incidence of postoperative pneumonia and acute or exacerbation of interstitial pneumonia was higher in the interstitial lung disease group (all P <.05). Thirty-day mortality was statistically equivalent between the interstitial lung disease and the non-interstitial lung disease groups (P =.30). The 5-year overall survivals were 62.5% (non-interstitial lung disease) and 35.6% (interstitial lung disease). Respiratory failure was the second main cause of death after the recurrence of primary cancer in the interstitial lung disease group. The risk factors for long-term mortality were interstitial lung diseases, advanced pathologic stage, male sex, high age, and positive smoking history (all P <.05). CONCLUSIONS Interstitial lung disease was a risk factor for developing postoperative morbidity and mortality and poor long-term survival due to the occurrence of respiratory failure.

Ki-67 immunostaining and other prognostic factors including tobacco smoking in patients with resected nonsmall cell lung carcinoma.

To estimate the effectiveness of expression of the tumor proliferative marker Ki‐67 antigen (Ki‐67) as a postoperative prognostic marker, the authors analyzed Ki‐67 expression and its correlation with postoperative survival and other clinicopathologic factors, including preoperative smoking habits, in patients with resected nonsmall cell lung carcinoma (NSCLC).

Overexpression of Collagen XVIII Is Associated with Poor Outcome and Elevated Levels of Circulating Serum Endostatin in Non–Small Cell Lung Cancer

Purpose: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non–small cell lung cancer (NSCLC). Experimental Design: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC. Results: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (± SD) serum endostatin level was 41.6 ± 34.4 ng/ml in the patient group and 16.3 ± 10.3 ng/ml in the control group (P < 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors. Conclusions: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.

Pleural Covering Application for Recurrent Pneumothorax in a Patient with Birt-Hogg-Dubé Syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary disease that presents with multiple lung cysts and recurrent pneumothorax. These cysts occupy predominantly the lower-medial zone of the lung field adjacent to the interlobar fissure, and some of them abut peripheral pulmonary vessels. For the surgical management of pneumothorax with BHDS, the conventional approach of resecting all subpleural cysts and bullae is not feasible. Thus, after handling several bullae by using a stapler or performing ligation as a standardized treatment, we applied to a pleural covering technique to thicken the affected visceral pleura and then to prevent recurrence of pneumothorax. We herein report the successful application of a pleural covering technique via thoracoscopic surgery to treat the recurrent pneumothorax of a 30-year-old man with BHDS. This technique is promising for the management of intractable pneumothorax secondary to BHDS.

Lymphangioleiomyomatosis with a Giant Bulla : Report of a Case

We report a case of lymphangioleiomyomatosis (LAM) with a giant bulla. A 33-year-old woman was referred to our department for treatment of dyspnea. Chest computed tomography showed a giant bulla with many smaller bullae. To obtain a definitive diagnosis and relieve the dyspnea, we performed a lung biopsy and bullectomy, after which her symptoms and pulmonary function improved remarkably. She was commenced on progesterone, which improved her condition even further. This case report retrospectively follows the progression of her disease from the onset of symptoms 5 years before she was referred to us for treatment.

Huge localized fibrous tumor of the pleura resembling a mediastinal tumor: report of a case.

A 67-year-old man was admitted to our hospital because of an abnormal chest echoic lesion detected incidentally by echocardiography. A chest roentgenogram showed the presence of a giant mass, and computed tomography of the chest confirmed the presence of a mass with a nonhomogeneous density in the left mediastinum, just adjacent to the left ventricle of the heart. Percutaneous aspiration cytology of the mass showed benign fibrous cells and a small amount of lymphocytes. The preoperative diagnosis of the tumor suggested a thymoma, and the patient underwent a thoracotomy. A pedunculated tumor arose from the visceral pleura of the left upper lobe of the lung, and it was capsulated within the pleura. The tumor measured 15 × 12 × 8 cm in size and it was successfully resected. The pathological diagnosis of the tumor was benign localized fibrous tumor of the pleura.

Long-Term Survival Achieved by Resection of Metastases in the Liver and Lung in a Patient with Recurrent Colonic Cancer: Report of a Case

Abstract A 58-year-old man who underwent a potentially curative resection of cancer of the sigmoid colon at another hospital was subsequently followed up at our hospital. A lateral segmentectomy was per-formed for a solitary hepatic metastasis, and partial resection of right S1 was later carried out for a pulmonary metastasis. Another pulmonary metastasis was found 6 years after his third operation and to minimize the area to be resected, bronchial arterial infusion chemotherapy was performed twice. A 51% reduction in the size of the tumor was achieved, so a right upper lobectomy and wedge resection of the bronchus were performed. The patient remains alive 14 years after the initial resection of colonic cancer. This case is considered noteworthy because it demonstrates the potential effectiveness of local adjuvant chemotherapy and the possibility of extended survival in a patient who has undergone resection of both hepatic and pulmonary metastases from colonic cancer.