Dosimetric evaluation of compensator intensity modulation-based stereotactic body radiotherapy for Stage I non-small-cell lung cancer.

OBJECTIVE: To evaluate the dosimetry of compensator intensity modulation-based stereotactic body radiotherapy (SBRT) [non-coplanar intensity-modulated radiotherapy (ncIMRT)], its use was compared with that of three-dimensional conformation-based SBRT, for patients with Stage I non-small-cell lung cancer (NSCLC). METHODS: 21 consecutive patients with Stage I NSCLC were treated with ncIMRT or SBRT at Tokyo Medical University. To compare the two techniques, ncIMRT and SBRT plans for each patient were generated, where the planning target volume (PTV) coverages were adjusted to be equivalent to each other. The prescribed dose was set as 75 Gy in 30 fractions. PTV coverage, conformity index, conformation number (CN) and homogeneity index (HI) were used to compare the two strategies. RESULTS: There was no statistically significant difference between PTV coverage for the 100%, 95% and 90% dose levels in the SBRT plan and those in the ncIMRT plan. The CN values were 0.53 ± 0.13 in the SBRT plan and 0.72 ± 0.10 in the ncIMRT plan. These values were significantly better than those of the SBRT plan (p < 0.001). The HI in the ncIMRT plan was 1.04 ± 0.03%, which was also significantly better than that of SBRT. CONCLUSION: The ncIMRT plan provided superior conformity and reduced the doses to the lung for patients with Stage I NSCLC. ADVANCES IN KNOWLEDGE: The delivery technique with compensator intensity modulation-based SBRT was evaluated. Concerning target motion, this is thought to be more robust and safer than SBRT for early-stage NSCLC.

Patients with severe emphysema have a low risk of radiation pneumonitis following stereotactic body radiotherapy.

OBJECTIVE: To evaluate the risk of radiation pneumonitis (RP) after stereotactic radiotherapy (SBRT) for patients presenting with severe pulmonary emphysema. METHODS: This study included 40 patients with Stage I non-small-cell lung cancer who underwent SBRT, 75 Gy given in 30 fractions, at the Tokyo Medical University, Tokyo, Japan, between February 2010 and February 2013. The median age of the patients was 79 years (range, 49-90 years), and the male:female ratio was 24:16. There were 20 T1 and 20 T2 tumours. 17 patients had emphysema, 6 had slight interstitial changes on CT images and the remaining 17 had no underlying lung disease. The level of emphysema was classified into three groups according to the modified Goddard's criteria (severe: three patients, moderate: eight patients and mild: six patients). Changes in the irradiated lung following SBRT were evaluated by CT. RESULTS: On CT images, RP was detected in 34 (85%) patients, and not in 6 (15%) patients, during a median observation period of 313 days. Of the six patients, three had severe emphysema and three had no underlying lung disease. Patients with severe emphysema had lower risk of RP than those with moderate emphysema (p = 0.01), mild emphysema (p = 0.04) and no underlying lung disease (p = 0.01). CONCLUSION: Patients with severe emphysema had a low risk of RP following SBRT. ADVANCES IN KNOWLEDGE: Little is known about the association between RP and pulmonary emphysema. Patients with severe emphysema had lower risk of RP than those with no underlying lung disease.

[A case of bronchogenic cyst which developed from negative findings to a thin-walled cavity for about 6 years].

A 56-year-old man whose chest radiograph in 1993 was normal was referred to our hospital because of a productive cough in 1997. Chest radiographs showed a thin-walled cavity filled with air. We followed his condition radiographically for three years and observed enlargement of the diameter of the lesion and appearance of an air fluid level, and we therefore decided to perform thoracoscopic middle lobe resection in 1999. Histological examination showed a communication between the cavity and a bronchus. As far as we know, there are no previous reports about intrapulmonary bronchogenic cysts which on radiographic observation developed from negative findings to a thin-walled cavity filled with air over a 6-year period.

Dendritic cell maturation overrules H-2D-mediated natural killer T (NKT) cell inhibition: critical role for B7 in CD1d-dependent NKT cell interferon gamma production.

Given the broad expression of H-2 class Ib molecules on hematopoietic cells, antigen presentation pathways among CD1d expressing cells might tightly regulate CD1d-restricted natural killer T (NKT) cells. Bone marrow-derived dendritic cells (BM-DCs) and not adherent splenocytes become capable of triggering NK1.1(+)/T cell receptor (TCR)(int) hepatic NKT cell activation when (a) immature BM-DCs lack H-2D(b)-/- molecules or (b) BM-DCs undergo a stress signal of activation. In such conditions, BM-DCs promote T helper type 1 predominant CD1d-restricted NKT cell stimulation. H-2 class Ia-mediated inhibition involves more the direct H-2D(b) presentation than the indirect Qa-1(b) pathway. Such inhibition can be overruled by B7/CD28 interactions and marginally by CD40/CD40L or interleukin 12. These data point to a unique regulatory role of DCs in NKT cell innate immune responses and suggest that H-2 class Ia and Ib pathways differentially control NKT cell recognition of DC antigens.

Efficient gene transduction by RGD-fiber modified recombinant adenovirus into dendritic cells.

Dendritic cells (DC) are important antigen-presenting cells in the development of an anti-tumor T cell response. To extend the range of current immuno / gene therapies, we tested luciferase-expressing RGD-adenovirus (Ad) (Ad5lucRGD)-mediated transduction into DC. Phenotypically characterized DC were generated from peripheral blood CD14(+) cells by incubation with granulocyte-macrophage colony-stimulating factor, interleukin-4 and tumor necrosis factor alpha. On the 7th day of culture, the cells became mature DC with a CD1a(+), CD11c(+), CD80(+), CD83(+), CD86(+), human leukocyte antigen (HLA)-DR(+), CD14- phenotype. The expression of alpha( v)beta(3) integrin was enhanced on day 3 and returned to the basal level on day 7. We then compared the transduction efficiency of an Ad5lucRGD system to that using conventional Ad, in cells harvested on days 1, 3 and 7 of culture. Luciferase activity was negligible in AdCMVLuc, but remarkable in cells processed with Ad5lucRGD. Activity was maximal in cells that had been cultured for 3 days. Recombinant Ad5 fiber knob protein blocked AdCMVLuc- and Ad5lucRGD-mediated gene transduction by 90% and 20%, respectively. Surface markers and cytokine production were not affected by Ad5lucRGD-mediated transduction.

[Spinal cord sarcoidosis without abnormal shadows on chest radiography or chest CT diagnosed by transbronchial lung biopsy].

The patient was a woman aged 56 years. In February 1998, she complained of fatigability of the right upper limb and disturbed extension of the right fourth finger. Because her condition deteriorated gradually and myelopathic signs such as difficulty in walking developed, she was hospitalized in May 1999 for close examination and appropriate treatment; and she was a few days later transferred to our hospital because of progressive myelopathy. In T2-weighted MR images of the cervical spine, the high-intensity area ranged between C2 and Th1, and in Gd-DTPA enhanced MRI the high-intensity area was seen between C3 and C7. Although chest radiographs and chest CT scans were normal, spinal cord sarcoidosis could not be ruled out, and therefore, bronchoscopic examination was performed. Specimens obtained from transbronchial lung biopsy (TBLB) revealed non-caseating epithelioid cell granulomas, and so and the disease was diagnosed as spinal cord sarcoidosis. Both symptoms and MRI findings were improved by treatment with corticosteroids. It is suggested that, in patients suspected of spinal cord sarcoidosis from MRI findings. TBLB should be aggressively attempted, even if chest radiographs and chest CT scans are normal.

Production of hepatocyte growth factor from human lung microvascular endothelial cells induced by interleukin-1beta.

To investigate the possible role of hepatocyte growth factor (HGF) in the reconstruction process following inflammatory damage in lung tissue, we compared HGF production of human lung microvascular endothelial cells (HLWECs) and human umbilical vein endothelial cells (HUVECs) after stimulation by interleukin(IL)-1beta. In an HLMEC-conditioned medium, large amounts of total (single and 2-chain) HGF were detected, and were 26- to 28-fold higher than those in HUVECs or human lung fibroblasts. The production of total HGF increased in a dose-dependent manner (4.7 to 9.2 times) with IL-1beta. In contrast, the amount of HGF in an HUVEC-conditioned medium was unaffected by IL-1beta treatment. The amount of cell-associated HGF also showed a dose-related increase (140% to 160%) in HLMECs, but not in HUVECs with IL1beta. In addition, HGF and c-met (HGF receptor) mRNAs in HLMECs and HUVECs were examined by the RT-PCR method. HGF and c-met mRNAs were clearly detected in HLMECs before and after treatment with IL-1beta, but not in HUVECs. These results suggest that increases in HGF production from HLMECs may play a role in the reconstruction process following inflammatory damage in lung tissue.

Cytokines production of U5A2-13-positive T cells by stimulation with glycolipid alpha-galactosylceramide.

We have previously established and reported a novel monoclonal antibody (mAb), U5A2-13, which recognizes a phenotypically similar population of natural killer (NK)-like T cells. Using U5A2-13 mAb, we now describe the functional properties of U5A2-13(+) T cells in both NK1.1-positive or -negative mouse strains. Similar to NK1.1(+) T cells, hepatic U5A2-13(+) T cells of C57BL/6 (NK1.1(+) strain) mice, but not U5A2-13(-) T cells, could be induced to produce large amounts of IL-4 and IFN-gamma by stimulation with glycolipid alpha-galactosylceramide (alpha-GalCer) present on dendritic cells (DC) in a dose-dependent manner. The abundant production of these cytokines from U5A2-13(+) T cells of BALB/c (NK1.1(-) strain) mice is similar to that noted in C57BL/6 mice. Cytokine production by cultures stimulated with DC of beta2-microglobulin-deficient mice was significantly less than that of cultures stimulated with DC of intact mice. Overall, U5A2-13(+) T cells recognize alpha-GalCer presented by CD1d, indicating that U5A2-13(+) T cells can be used to analyze NK-like T cell function in various strains of mice.

Establishment and usefulness of an anti-human CD57 IgG1 monoclonal antibody.

In the present study we established a new monoclonal antibody, JNK-1, which recognizes all cells recognized by CD57/HNK-1 mAb. JNK-1 and CD57 mAbs inhibited the binding of each other, suggesting that the molecules they recognize are either identical or sufficiently close to cause steric hindrance in the binding assay. JNK-1 mAb detected the 110-kDa protein, which is identical to the protein recognized by CD57/HNK-1 mAb in Western immunoblot analysis combined with immunoprecipitation. Therefore, JNK-1 mAb appears to recognize homogeneous molecules identified by the currently available CD57 mAb. Notably, JNK-1 mAb is composed of mouse IgG1 heavy chains, and thus can be used easily in immunoprecipitation, which cannot easily be performed with the available CD57 mAb because it is an IgM isotype. Thus, JNK-1, which is an IgG isotype, may present a useful tool to elucidate the CD57 protein.

[Pulmonary actinomycosis with "balls-in-a hole" appearance diagnosed by examination of bronchial lavage fluid].

A 49-year-old man was referred to our hospital because of abnormal chest X-ray findings. Chest X-ray films showed infiltrative opacities in the right lung, and histological findings of a transbronchial biopsy specimen showed non-specific inflammation. The patient was treated with Ofloxacin for one month. After the treatment, chest X-ray films showed that the infiltrative opacities in the right upper lobe had decreased, but that opacities in the right lower lobe had increased, with an air meniscus sign. A chest computed tomography scan at the same time revealed that the remaining opacities contained multiple mass-like lesions within a cavity in the right S6, appearing as "balls in a hole". One year after the first visit, the patient visited the hospital again because of cough and sputum. A chest X-ray film showed that the size of the cavity in the right lower lobe had increased. The histological findings from a fresh transbronchial biopsy specimen revealed a non-specific inflammation again; however, black clots obtained from bronchial lavage fluid after biopsy were histologically identified as sulfur granules, a classic pathological indication of actinomycosis. This confirmed the diagnosis of pulmonary actinomycosis. The patient was treated with penicillin, and the opacities in the right lower lobe subsided.

[Pneumonia caused by granulomatous Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome].

A 54-year-old man was admitted to the hospital because of fever and general fatigue. A chest roentgenogram on admission showed lobular opacities and ill-defined opacities in both lower lobes. The pneumonia was successfully treated with antibiotics. The acquired immunodeficiency syndrome was diagnosed because ELISA and PCR tests for antibodies to the human immunodeficiency virus were positive and the CD 4+ lymphocyte count was 39 per cubic millimeter. Examination of bronchoalveolar lavage fluid revealed no Pneumocystis carinii. Trimethoprim and sulfamethoxazole were given prophylactically, but were withdrawn because of a rash. The patient began to receive aerosolized pentamindine and was discharged. On the next day, he was readmitted to the hospital because of a high fever. A chest roentgenogram showed diffuse miliary opacities. Chest CT scan also showed diffuse small nodular opacities in both lungs. Examination of a transbronchial biopsy specimen revealed well-defined, noncaseating granulomas with pneumocystis organisms in their centers. Cultures for tuberculosis and fungi were all negative. We diagnosed granulomatous pneumonia caused by Pneumocystis carinii, which is an atypical manifestation of Pneumocystis carinii pneumonia. The patient died of sepsis and cardiac tamponade. Microscopically, the lung tissue was found to have foamy intra-alveolar exdates, which is a typical histological feature of Pneumocystis carinii pneumonia.

Sarin poisoning on Tokyo subway.

On the day of the disaster, 641 victims were seen at St. Luke's International Hospital. Among those, five victims arrived with cardiopulmonary or respiratory arrest with marked miosis and extremely low serum cholinesterase values; two died and three recovered completely. In addition to these five critical patients, 106 patients, including four pregnant women, were hospitalized with symptoms of mild to moderate exposure. Other victims had only mild symptoms and were released after 6 hours of observation. Major signs and symptoms in victims were miosis, headache, dyspnea, nausea, ocular pain, blurred vision, vomiting, coughing, muscle weakness, and agitation. Almost all patients showed miosis and related symptoms such as headache, blurred vision, or visual darkness. Although these physical signs and symptoms disappeared within a few weeks, psychologic problems associated with posttraumatic stress disorder persisted longer. Also, secondary contamination of the house staff occurred, with some sort of physical abnormality in more than 20%.

[Palliative intubation of esophageal prosthesis in two patients with lung cancer].

Case one: A 61-year-old man was admitted to the hospital because of coughing. Adenocarcinoma of the lung was diagnosed. The patient was treated with bronchial artery infusion of cisplatin and mitomycin C, followed by irradiation; and there was a partial response. Eighteen months later he was admitted to the hospital because of dysphagia. An esophageal prosthesis was inserted because of esophageal stenosis surrounded by local recurrent tumor. After intubation, the patient was able to eat and was discharged. Although the patient died 5 months later, the tube was patent and functional until that time. Case two: A 63-year-old man was admitted to the hospital because of coughing. Adenocarcinoma of the lung was diagnosed. The patient was treated with 3 cycles of chemotherapy consisting of cisplatin, vindesine, and mifomycin C, which were followed by irradiation; and there was a partial response. Six months later he was admitted to the hospital because of dysphagia. An esophageal prosthesis was inserted because of esophageal stenosis surrounded by mediastinal lymph nodes. Although the patient was able to eat, bilateral pleuritis and mediastinitis developed and he died ten days after intubation. At autopsy the esophagus was found to have been perforated. Palliative intubation of an esophageal prosthesis can be effective in patients with esophageal stenosis due to lung cancer, but care must be taken to prevent fatal complications.

[Lymphangiomyomatosis with chylous ascites treatment successfully by peritoneo-venous shunting].

A 49-year-old woman was admitted to our hospital because of coughing and dyspnea. A chest roentogenogram showed emphysematous changes and a diffuse reticular shadow. A high-resolution CT scan of the chest showed many small cysts throughout the lungs. Lymphangiomyomatosis was diagnosed after examination of a specimen obtained by transbronchial biopsy. Abdominal distention due to chylous ascites developed during the hospital stay despite anti-estrogen therapy. Because the ascites was resistant to conservative therapy, we decided to begin peritoneo-venous shunting with a Denver Shunt system. After the operation, the abdominal distention was controlled for 1 year and 11 months, at which time the patient died of respiratory and heart failure with pneumonia. At autopsy, the shunt was patent and functional although about 900 ml of serous ascites fluid was present. An adenocarcinoma was found in the upper lobe of the right lung, but it may not have been related to the lymphangiomyomatosis. Peritoneovenous shunting with a Denver Shunt can be used to treat chylous ascites due to lymphangiomyomatosis when conservative therapy is insufficient.

Ultrastructural features of alveolitis in sarcoidosis.

Seventy-nine specimens of lung parenchyma from 61 patients with sarcoidosis were examined ultrastructurally with a focus on alveolitis, and they were compared with specimens of hypersensitivity pneumonitis (HP) and the percentage of lymphocytes in bronchoalveolar lavage fluid (BALF). Lymphocytes and monocytes were frequently observed in the capillary lumina, and these cells and macrophages were found in the interstitium of the alveolar walls in the specimens with alveolitis of sarcoidosis and HP. Increases in the percentage of lymphocytes in BALF correlated with the degree of alveolitis. Swelling and bleb formation of the endothelium of alveolar capillaries and changes in the capillary basement membrane were commonly found and were significantly increased in the specimens with alveolitis. The frequency of bleb formation was significantly higher in alveolitis of sarcoidosis than in that of HP. However, the changes in alveolar epithelium were not significant in sarcoidosis. Microvascular changes in alveolitis are not specific for sarcoidosis, but they are observed in other interstitial lung diseases. These alterations may play an important role in the development of pulmonary sarcoidosis.

[Causes of idiopathic interstitial pneumonia (IIP): inhaled dust as environmental problem].

We have reported that patients with IIP can be roentgenologically grouped into two subtypes, typical (type-A) and atypical (type-B). The characteristic feature of X-ray findings in type-A is marked restriction of the lung, especially of the lower lobes, and in type-B is emphysematous changes in addition to the findings of type-A. In this study, to clarify the pathological findings of these two subtypes, 60 IIP patients in whom open lung biopsy and/or autopsy were performed were studied both clinically and pathologically. The following results were obtained. 1) Pathological features of type-A were alveolitis, marked restriction of the lung secondary to atelectasis and fibrosis of lung parenchyma, and honeycombing as a result of remodeling. 2) The features of type-B were intra-alveolar organization and secondary emphysema after intra-alveolar inflammation (pneumonia) overlapped the pathological changes of type-A. 3) Patients with a history of dust inhalation were much more frequently observed in type-B than in type-A (p < 0.01). These results suggest that inhaled dust may be a causative factor of IIP, especially of type-B.

Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy cases.

We examined pulmonary vascular involvement in 40 autopsy cases of sarcoidosis. In these cases granulomatous involvement was observed at all levels from large elastic pulmonary arteries to venules, and venous involvement was more prominent than arterial involvement. The extent of granulomatous vascular involvement was related to that of parenchymal granuloma. No significant difference was found between upper and lower lobes in the incidence of granulomatous vascular involvement. The distribution of granulomata in the blood vessels was segmental and adventitial, and medial involvement was prominent in the larger vessels. Healed lesions of granulomatous vascular involvement also were observed at various levels in blood vessels. Prominent granulomatous involvement was found in the lymphatic capillaries and collecting lymphatic vessels in lungs with sarcoidosis. Serial sections of the lungs demonstrated interstitial granuloma directly connecting the lymphatic capillaries around small blood vessels. Granulomatous involvement in vasa vasorum and lymphatic capillaries is likely to be an important factor in the pathogenesis of granulomatous vascular involvement in lungs with sarcoidosis. The present study suggests that granulomatous vascular involvement and its sequelae may contribute to the development of pulmonary sarcoidosis.

[Proposal of a new classification of adult bronchial asthma--child onset asthma, adult onset asthma and adult relapse asthma. Project Team for Research into Adult Bronchial Asthma in Japan].

The first nationwide research into adult bronchial asthma in Japan proposed a new classification of adult asthma. Adult asthma was categorized into child onset asthma, adult onset asthma and adult relapse asthma. The frequency of child onset asthma, adult onset asthma and adult relapse asthma in adult asthma was 11.2%, 77.3% and 3.7%, respectively. The frequency of child onset asthma decreased markedly in the older age group. On the other hand, the frequency of adult onset asthma increased, and reached more than 90%, in the older age group. The frequency of the following factors: atopic asthma, complications with other atopic diseases, mild asthma, male patients, experience of mechanical ventilation, visits to night clinics and oxygen therapy on acute attack, was significantly higher in the child onset asthma group than in the adult onset asthma group. The frequency of infectious type, aspirin intolerance, steroid dependent asthma, severe asthma and regular medication was significantly higher in the adult onset asthma group. Adult relapse asthma seemed to fall between these two groups. Based on the above observations, we proposed a new classification of adult asthma which includes child onset asthma, adult onset asthma and adult relapse asthma.

[Clinical criteria for definition of idiopathic interstitial pneumonia (IIP)].

Clinical criteria for definition of IIP proposed in 1991 by the Project Team for Diffuse Lung Diseases Organized by Japanese Ministry of Health and Welfare are reviewed. After the clinical roentgenological, and pathological researches of 92 IIP patients, we concluded that IIP patients were grouped into two clinical types, acute and chronic, by their clinical courses and characteristic pathological findings. The latter is, moreover, grouped into two types, typical and atypical, by their morphological characteristics. The acute type are represented by alveolitis with marked edema and cell infiltration of alveolar wall, and by hyaline membrane formation. "Typical" of chronic types only have typical pathologic changes of interstitial pneumonia and/or fibrosis represented by honeycombing. "Atypical" have both those interstitial changes and intra-alveolar scar formation and fibrosis due to organized pneumonia and secondarily occurred emphysema such as bulla as well. The continuity in clinical courses between acute and chronic types are still obscure.