Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma.

BACKGROUND: Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. OBJECTIVE: We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. METHODS: In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. RESULTS: High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. CONCLUSION AND CLINICAL RELEVANCE: IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

[Surgically repaired bilateral giant bullae after long-time follow-up; report of a case].

A 44-year-old male was admitted to our hospital owing to severe dyspnea of sudden onset. Chest X-ray disclosed bilateral giant bullae. His pulmonary function was severely depressed. VC (%) was 2.61 l (66.3%) and FEV1% (%) was 1.47 l (64.5%). Indication of surgical repair of giant bullae are; space occupying lesion more than 25-50% in 1 thorax, progressive dyspnea, enlargement over time irrespective of symptoms, and expectation that re-expand the normal lung. He was conducted two-staged bullectomy using video-assisted thoracoscopic surgery (VATS) with small incisions. First operation was performed to left lung. Pulmonary function improved. VC (%) increased 3.02 l (76.8%) and FEV1% (%) 2.36 l (76.6%). After second operation, which was performed to right lung, VC (%) was 2.40 l (60.5%) and FEV1% (%) was 2.21 l (92.1%). Hugh-Jones grade improved class IV to class I. Postoperative course was uneventful and he was discharged 15 days after second operation. Two-staged bullectomy was appropriate in this case, because he might have suffered from re-expansion pulmonary edema after first surgery. The extent of recovery of pulmonary function was unpredictable. And performing right lung bullectomy just after the left bullectomy may be dangerous, because the patient have to receive anesthesia with his resected left lung. There is some possibility that patient who has bilateral giant bullae shows severe dyspnea during the progress, care should be taken to conduct operation as soon as possible.

A case-control study for evaluating the efficacy of mass screening program for lung cancer in Miyagi Prefecture, Japan.

BACKGROUND: In Miyagi Prefecture, Japan, a mass screening program for lung cancer has been conducted since 1982 (miniature chest X-ray for all screenees and sputum cytology for those with a smoking index > or = 600) [smoking index 600 = 30 pack years, the average number of cigarettes smoked per day multiplied by the number of years of regular smoking]. Over 1500 lung carcinomas, including 250 roentgenographically occult lung tumors, were detected and treated up to 1999. In the current study, a nested case-control study was conducted in the population that was screened in 1989 to evaluate the efficacy of the screening program for lung cancer. METHODS: To reduce self-selection bias, the source population was defined as screenees with negative results in 1989 (284,226 individuals). In the population, 474 individuals died of lung carcinoma during 1992-1994. After exclusion, 328 patients who died of primary lung carcinoma at between ages 40 years and 79 years were defined as the cases. Six controls were supposed to be selected in the source population for each case and matched by gender, year of birth, municipality, and smoking habits. Controls who had died or moved before the matched case was diagnosed were excluded. Finally, 328 cases and 1886 controls were selected. Screening histories were compared, and odds ratios were calculated using conditional logistic regression analysis. RESULTS: Within the 12 months before diagnosis, 241 of 328 cases (73.5%) had attended the screening compared with 1557 of 1886 controls (82.6%). The smoking-adjusted odds ratio was 0.54 (95% confidence interval, 0.41-0.73). CONCLUSIONS: The mass screening program for lung cancer in Miyagi Prefecture was capable of reducing by 46% the risk of death from carcinoma of the lung.

Diagnostic results before and after introduction of autofluorescence bronchoscopy in patients suspected of having lung cancer detected by sputum cytology in lung cancer mass screening.

For the purpose of early detection, we have conducted population-based mass screening for lung cancer by sputum cytology since 1982. Although detection of lung cancer in its early stage is important for a good prognosis, it is often difficult to localize lesions in roentgenographically occult cancer. To clarify the role of autofluorescence bronchoscopy in localizing tumors in patients with roentgenographically occult cancer, we analyzed our diagnostic results. Fifty patients who had been detected by sputum cytology were screened by the light-induced fluorescence endoscope (LIFE)-Lung System from November 1997 to April 1999. We compared the results according to the screening methods: conventional bronchoscopy alone versus LIFE with conventional white-light bronchoscopy (November 1997 to April 1999). Twenty-eight cancerous lesions and 39 borderline lesions were detected by LIFE. Of the 39 borderline lesions, nine were detected only by LIFE. Multicentric lesions including cancer or dysplasia were also detected in 21 of the 50 patients by LIFE. The sensitivity by white-light bronchoscopy alone was 85.3%, whereas that of the LIFE-Lung System with white-light bronchoscopy was 94.1% (P=0.078). There were no cancerous lesions in the area observed as normal by LIFE. We also compared the diagnostic results of two localization methods: brushing of all bronchi (September 1986 to December 1990) and the LIFE-Lung System (November 1997 to April 1999). Although this was a historical comparison, the number of detected borderline lesions increased, which led to a high detection rate in patients with suspected-positive sputum (P=0.0006) by the LIFE-Lung System. In conclusion, the LIFE-Lung System is a safe and non-invasive system for detecting small intraepithelial lesions of the tracheobronchial tree. Autofluorescence bronchoscopy is more efficacious for localizing intraepithelial lesions and places fewer burdens on the patient than brushing of all bronchi.

Experience with fatal interstitial pneumonia after operation for lung cancer.

BACKGROUND: The number of patients with lung cancer is increasing. This study was undertaken to realize the probability, fate and management of acute fatal postoperative complications. Since interstitial pneumonia was one of the most fatal postoperative complications, to know its incidence and fate is very important. METHODS: A total of 2667 patients who underwent thoracotomy caused by malignant tumors during the past 17 years were reviewed and studied. We performed investigations on medical records, chest X-rays, whole-body CT films, operative records and pathological specimens for all inpatients. RESULTS: Nineteen patients died in hospital 30 days after thoracotomy (operative death). Nine patients died in hospital more than 31 days after thoracotomy (hospital death). Eight cases out of 28 patients (operative and hospital deaths) developed and finally died by interstitial pneumonia. Each case was treated with steroids, neutrophil-elastase inhibitor, and/or immunosuppressive agents. These patients could not be selected by any preoperative laboratory examination, such as preoperative pulmonary function tests, serum biochemistry tests, and chest X-ray or CT films. Interstitial pneumonia as a complication of postoperative stage, was fatal and once developed, it was very difficult to save their lives. CONCLUSIONS: Since we reported the cases who died from acute postoperative complications, especially interstitial pneumonia, we could not present effective management. However, in this report, several therapeutic trials that may solve the problems of acute postoperative interstitial pneumonia were proposed.

Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia.

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.

[Reconstruction of chest wall using myocutaneous flap].

Reconstruction of chest wall using myocutaneous flap has been performed in 2 cases. A 72-year-old female referred to our hospital for locally recurrent left breast cancer without any distant metastases. The other patient was a 77-year-old female, having locally recurrent liposarcoma of the left lateral chest wall. Chest wall was resected with wide margin of normal tissue, and myocutaneous flaps of latissimus dorsi were used for reconstruction of skin defect (13 x 8 cm and 14 x 10 cm) in both cases. Although additional split-thickness skin graft was required for one of them, myocutaneous flaps were useful for the reconstruction of widely defected chest wall. By using this technique, wider margin can be obtained, which could decrease the risk for local recurrence of malignant tumor.

[The application of poly (L-lactide) sternal coaptation pins for median sternotomy].

Poly (L-lactide) sternal coaptation pin has been developed as an assistant material for the fixation of sternum. We used the novel material to a patient who underwent median sternotomy. A 21-year-old male was suspected to have invasive thymoma in the anterior mediastinum. The median sternotomy was indicated as an approach for the resection of tumor. Tumor was completely resected and there was no invasion to sternum. For the fixation of sternum, three poly (L-lactide) sternal coaptation pins were inserted in the bone marrow of sternum and five stainless steel wires were used as conventional procedure. Sternum was adapted without slippage and no complication from the material was observed in the post-surgical period. The application of poly (L-lactide) sternal coaptation pin is a good option for ensuring the fixation of sternum.

[Successful treatment for descending necrotizing mediastinitis: a case report].

A 21-year-old female was admitted to our hospital because of high fever, neck swelling, and dyspnea. She was diagnosed as descending necrotizing mediastinitis (DNM) extended from odontogenic infection. On the day of admission, she underwent cervical drainage. Next day, the CT scan showed an abscess below the tracheal bifurcation and bilateral pleural effusion. Mediastinal drainage was performed through a right thoracotomy, and a left thoracic tube was inserted. Anaerobic Peptostreptococcus was found with bacteriological culture. After the mediastinal drainage, bilateral thoracic irrigation was performed through the thoracic tubes. Left thoracic tube was removed on the 8th day and right one was removed on the 20th day after the thoracotomy. She was discharged on the 42nd day. DNM is relatively rare, but it is lethal disease with high mortality. Immediate and sufficient mediastinal drainage is indispensable for the disease.

MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer.

Although MDM2, p21/WAF1, and p53 are considered as regulating each other based on in vitro studies, the relation in human lung cancer is not fully understood. The expressions of these proteins were examined immunohistochemically in 112 resected non-small cell lung cancer specimens and the correlation between them were analyzed. MDM2 was expressed in 45% of all lung cancers. In advanced stage, MDM2-positive cases were observed more frequently than in early stage, showing significant difference. No significant difference was observed in the prognosis of the patients regardless of the expression of any protein. Although no correlation was observed between MDM2 expression and p53 expression, or between p21/WAF1 expression and p53 expression, MDM2 expression was strongly related with p21/WAF1 expression. Therefore, MDM2 expression may relate to the progress of the stage of lung cancer, and MDM2 expression and p21/WAF1 expression may be associated not through the p53-related pathway.

Endothelial signal transduction system enhances neutrophil-induced pulmonary vascular permeability.

The mechanism by which stimulated polymorphonuclear leukocytes and neutrophils (PMNs) damage pulmonary vascular endothelium was investigated. The authors assessed the ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability, measured as the pulmonary filtration coefficient (K) and haemodynamics. PMNs were stimulated by gentle agitation in a glass vial for 10 s. Perfusing lungs with the stimulated PMNs (n=6) resulted in significant accumulation of PMNs within the lungs, assessed by myeloperoxidase levels, and elicited a 4-fold increase in K and a 2-fold increase in pulmonary vascular resistance as compared to lungs perfused with unstimulated cells (n=6). The increases in K were completely blocked by GF109203X, a protein kinase C inhibitor (n=6); however, GF109203X only partially attenuated the increase in vascular resistance and had little effect on the accumulation of stimulated PMNs. An agonist of protein kinase C, phorbol myristate acetate, elicited dose dependent increases in both K and pulmonary vascular resistance even in the absence of PMNs (n=6). These findings indicate that the increases in pulmonary filtration coefficient and pulmonary vascular resistance induced by polymorphonuclear neutrophils result from endothelial cell injury mediated by activation of protein kinase C within the endothelial cells themselves.

Superoxide possibly produced in endothelial cells mediates the neutrophil-induced lung injury.

BACKGROUND: The mechanism by which stimulated neutrophils (polymorphonuclear leukocytes [PMNs]) damage pulmonary vascular endothelium was investigated. METHODS: The ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability was tested. Each series was conducted on 6 rats. To stimulate PMNs, they were agitated gently in a glass vial for 10 seconds. RESULTS: Perfusing lungs with the stimulated PMNs elicited a fivefold increase in permeability compared with lungs perfused with the unstimulated cells. This increase in permeability was blocked completely by preincubation of stimulated PMNs with CD18 monoclonal antibody. This increase in permeability was also blocked completely by superoxide dismutase (SOD) or the xanthine oxidase (XO) inhibitor allopurinol. Pulmonary vascular hemodynamics were unaffected by any treatment protocol. The accumulation of stimulated PMNs within the lungs was not inhibited by SOD but was partially blocked by allopurinol. CONCLUSIONS: These findings suggest that stimulated PMN-induced increases in pulmonary vascular filtration resulted from endothelial cell injury caused by superoxide anion possibly generated by XO, exclusively present in the endothelial cells.

[Assessment of systematic nodal dissection by VATS lobectomy for lung cancer].

The feasibility of the complete systematic nodal dissection by the video-assisted thoracic surgery was prospectively assessed in 22 cases of clinical stage I lung cancer (16 right, 6 left cases). Resection of the designated lobe with the mediastinal lymph node dissection was carried out by the small thoracotomy with the aid of the thoracoscope, followed by the standard surgery to verify the completeness of systematic nodal dissection. Although residual lymph nodes were found in 14 of 22 cases, the residual rate was 2.9% and 2.7% by the number and 2.3% and 2.1% by the weight in right and left cases, respectively. Average time and hemorrhage for performing the procedure were 196 minutes, 216.7 minutes and 157.5 g, 145 g in right and left cases, respectively. As a consequence, sufficient systematic nodal dissection in lung cancer was suggested to be feasible by VATS lobectomy.

A therapeutic approach to roentgenographically occult squamous cell carcinoma of the lung.

BACKGROUND: The significance of limited resections, including wedge resection and segmentectomy, remains controversial because of their curability rates. In the current study, the objective was to determine a strategy for the treatment of patients with roentgenographically occult bronchogenic squamous cell carcinoma (ROSCC) based on the pathologic findings from 184 patients with ROSCC who underwent resection. METHODS: In Miyagi Prefecture, 1422 patients with lung carcinoma were diagnosed during a mass screening program between 1982 and 1995. Among them, 236 patients had ROSCC, and 184 patients with ROSCC underwent pulmonary resection followed by systemic lymph node dissection. RESULTS: Pathologically, only 0.9% of the ROSCCs that were within the range of endoscopic visibility were revealed to have lymph node involvement, whereas 13% of patients with extracartilage invasion had lymph node involvement. Early ROSCC, which means ROSCC that is limited within the cartilaginous layer and is without lymph node involvement, comprised 90% of ROSCCs that measured <10 mm in longitudinal extension, comprised 77% of ROSCCs that measured 10-29 mm in longitudinal extension, and comprised 33% of ROSCCs that measured >30 mm in longitudinal extension. Eighty-nine percent of the tumors with lymph node involvement had extracartilaginous invasion. The 3-year survival rate of patients after undergoing photodynamic therapy was 100% when their tumor was regarded as early ROSCC (i.e., within 10 mm in longitudinal extension and within the range of endoscopic visibility). To date, 18 patients with ROSCC underwent segmentectomy, and all of these patients are alive without tumor recurrence. The incidence rate of multiple lung carcinomas, including synchronous and metachronous tumors, in patients with ROSCC was 22%. CONCLUSIONS: The authors concluded the following: 1) Patients with lesions that are within the range of endoscopic visibility and that measure <10 mm in longitudinal extension are candidates for photodynamic therapy. 2) Patients with lesions that are beyond the range of endoscopic visibility or that measure >10 mm in longitudinal extension are candidates for segmentectomy as long as intraoperative examination shows a tumor free bronchial stump and negative lymph nodes 11-13. 3) Patients with lesions that show bronchial obstruction or extrabronchial invasion should undergo standard resection.

[Present condition of lung transplantation candidates in eastern Japan].

We investigated the present condition of lung transplant candidates and the familiarity of doctors in eastern Japan by questionnaire. We shipped questionnaires to 614 hospitals in the Hokkaido district, the Tohoku district, the Kanto district and Niigata Prefecture, a received responses from 216 departments (200 hospitals). The percentage of respondents was 32.6%. There were 191 lung transplant candidates, 97 men and 94 women, in the past two years. Moreover, there were 45 patients with primary pulmonary hypertension (PPH), 38 with idiopathic pulmonary fibrosis, 23 with pulmonary emphysema, 20 with pulmonary lymphangiomyomatosis, among others. Currently, however, there are 88 patients who are lung transplant candidates, a large number, in eastern Japan. On the other hand, only 38 of 68 departments had informed their patients about lung transplantation. It was a lamentable result for transplant surgeons, and points urgently to the importance of giving information about lung transplantation.

A randomized trial of postoperative CDDP-based chemotherapy/chemoradiotherapy vs short-term immunochemotherapy in lung cancer.

BACKGROUND: Although a few reports indicated some benefit to survival, the effect of adjuvant therapy for the patients with resected lung cancer was still controversial. The aim of our study was to evaluate survival advantage of CDDP-based adjuvant therapy compared with short-term immunochemotherapy. EXPERIMENTAL DESIGN: prospective randomized trial. PATIENTS: from 1990 through 1994, 94 patients were registered. Forty-seven patients were randomly assigned to each group, i.e., CDDP-based therapy group (CB Group, CDDP+VDS+tegafur+OK-432 or CDDP+OK-432+mediastinal irradiation) or immunochemotherapy group (IC Group, tegafur+OK-432). PATIENTS in both groups were followed at 4-month intervals with the routine follow-up program of our department. RESULTS: No significant difference was observed between the patients' characteristics of two groups. Compliance of the regimen in each group was 79% in CB Group and 85% in IC Group. No treatment-related death was observed. Five-year survival rates of CB Group and IC Group were 49% and 51%, and 5-year disease-free survival rates were 46% and 44%, respectively. There were no statistical differences between the two groups. Furthermore, no survival differences could be found between CB Group and IC Group in any subgroup of patients. CONCLUSIONS: Both of these regimens were feasible. However, we have not observed any survival benefit in the CB Group in any subgroup, so far. Induction therapy, new chemotherapeutic agents, or anti-angiogenetic a agents may improve the survival of surgically treated lung cancer patients.

[The pattern of mediastinal nodal involvement in lung cancer according to tumor-located lobe].

To clarify the pathway of the metastases from each pulmonary lobe to mediastinal nodes, we examined the pattern of mediastinal nodal involvement in 462 resected pN2 non-small cell lung cancer. Carcinomas of the right upper lobe frequently involved #3 (78/133) and #4 (70/133) nodes, whereas those of the right middle or lower lobe frequently metastasized to #7 nodes (18/23 and 86/113, respectively). On the other hand, carcinoma of left upper lobe frequently involved #5 nodes (81/118), whereas those of the left lower lobe most frequently metastasized to #7 nodes (50/75). Of 462 pN2 patients, 95 (20.6%) had skip metastases to the mediastinal nodes. Skip metastasis was observed more frequently in carcinomas of right upper and middle lobe. One of the reasons of skip metastasis may be the direct lymph drainage through subpleural space to mediastinum.