A randomized phase III trial of postoperative adjuvant therapy for completely resected stage IA-IIIA lung cancer using an anti­angiogenetic agent: irsogladine maleate.

AIM: Although angiogenesis plays an important role in the invasion and metastasis of solid tumors, very few anti-angiogenetic drugs have been developed. Reexamining the anti-angiogenetic effects of existing drugs such as Thalidomide is another possible strategy for drug discovery. Irsogladine maleate (IM) is a drug invented to treat gastric ulcers; however, several reports have shown that IM also exerts anti-angiogenetic effects in vitro, in vivo and in humans. In order to elucidate whether treatment with IM would improve the prognoses of patients with resected lung cancer, we conducted a randomized trial. METHODS: In the control group, uracil-tegafur (250 mg/m2/day) was administered for two years to patients with resected stage IB - IIIA lung cancer, and no adjuvant therapy was administered to those with stage IA disease. In the study group, IM (4 mg/body/day) was additionally administered for two years. RESULTS: No significant differences were observed in the major prognostic factors among 305 eligible patients between the study and control groups. Adverse effects were minimal. The overall survival of the patients in the study and control groups were not statistically different. When the analysis was stratified by regimen, among the patients with resected stage IA disease, disease-specific survival in the study group was slightly higher than that in the control group; however, the difference was not significant (p=0.07). CONCLUSION: Although it could not be proven that IM improves the prognoses of resected lung cancer patients, IM might have some effect on resected stage IA disease, and another trial should be conducted.

Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity. METHODS: We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases. RESULTS: In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3). CONCLUSION: CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.

[Emergency anterior approach for decortication with right pneumonectomy in a patient with chronic expanding hematoma].

The patient was a 68 year-old woman who had a history of treatment of pulmonary tuberculosis 35 years ago. She has experienced dyspnea and hemosputa since several years ago and has been followed up as having chronic empyema. She was admitted to our hospital due to recent exacerbation of symptoms. X-ray films and computed tomography scans of the chest showed the right thoracic cavity to be totally filled with a mass and the shift of mediastinum to the left side. After several days from admission, she needed mechanical ventilation support due to dyspnea exacerbation. Emergency decortication with right pneumonectomy through median sternotomy with anterolateral incision was performed. Postoperative course was uneventful. Pathlogical diagnosis was chronic expanding hematoma.

[Management of surgical approach for intractable secondary spontaneous pneumothorax].

Secondary spontaneous pneumothorax (SSP) such as lymphangioleiomyomatosis (LAM), bronchiolitis obliterans (BO) is intractable or repeated the recurrence of pneumothorax. The most effective chemical pleurodesis for intractable pneumothorax is talc poudrage and so on that is associated with a reduction in the rate of pneumothorax recurrence. However, severe and broad pleural adhesion due to the pleural interventional procedures sometimes cause serious bleeding when the patients undergo lung transplantation. We must be considered for new approaches to these intractable secondary pneumothoraces which replaced traditional conservative and surgical approaches. We had proposed new 2 approaches of total pleural covering (TPC) and awake surgical intervention (ASI) for intractable pneumothorax. We applied the TPC modified with coverage of air leak points with polyglycolic acid (PGA) sheet to 5 patients with intractable bilateral pneumothorax to reduce the risk of excessive bleeding by chemical pleurodesis in lung transplantation. The bilateral pneumothorax was well controlled, and no recurrence has been observed. TPC is reliable procedure for management intractable bilateral SSP. For 12 high-risk patients with other underling pulmonary diseases on general poor conditions, a surgical intervention was performed in awake condition. The air leaks were stopped in 11 cases except for 1 case. The recurrence of pneumothorax after surgery was 2 cases. ASI for intractable secondary pneumothorax can be applicable to selected patients with deteriorated general condition.

Prediction of clinical CYP3A4 induction using cryopreserved human hepatocytes.

The purpose of this study was to construct a method to predict CYP3A4 induction in the clinical setting from in vitro data using cryopreserved human hepatocytes. We recently developed an approach with in vitro assays of HepaRG cell lines for predicting CYP3A4 induction by using a novel value, termed the relative factor (RF), determined from the ratio of the concentration of an inducer to the reference standard. In this study, the applicability of the RF approach was expanded to cryopreserved human hepatocytes. Induction assays were performed in vitro using hepatocytes from four individual donors and eight typical inducers. The obtained RF values were related to the free plasma concentration of each inducer (expressed as Css,u/RF). A good relationship between the Css,u/RF values and the in vivo induction response was found for all donors. Inducers were classified by the Css,u/RF values into three categories for CYP3A4 induction risk (high, medium and low potency), and thereby the degree of CYP3A4 induction in vivo in humans could be predicted from the Css,u/RF values. The RF approach is applicable to human cryopreserved hepatocytes. Thus, a method to predict the potency of CYP3A4 inducers was constructed using cryopreserved human hepatocytes.

[Surgical approaches for superior sulcus tumor].

Surgical approach is one of the most crucial aspects in the treatment of superior sulcus tumor (SST). Posterior approach as described by Paulson and coworkers is appropriate for the resection of SST invading posterior part of the 1st rib and the vertebrae, whereas anterior approaches as described by Masaoka, Dartevelle, Grunenwald, or Rusca are suitable for resection of SST involving subclavian vessels. We present 2 cases of SST who underwent complete resection through the posterior approach and a modified hemi-clamshell approach, respectively. We also discuss the surgical approaches for SST with referring to literatures.

[Experience of postoperative adjuvant chemotherapy of lung cancer at outpatient department].

In late years the cancer adjuvant chemotherapy shifts from an inpatient care to an outpatient treatment. For operated lung cancer patients, outpatient chemotherapy center has been working since October 2005 in our hospital. Chemotherapy regimens were carboplatin (CBDCA) + paclitaxel (PTX), CBDCA + gemcitabine (GEM), docetaxel (DTX) + tegaful-gimeracil-oteracil potassium (S-1), and GEM + vinorel bine (VRE). CBDCA was chosen instead of cisplatin (CDDP) and non-platinum doublets are also used because of less toxicity and more time saving. Adjuvant chemotherapy has been performed for a total of 25 outpatients. Twenty-two out of 25 completed chemotherapy. Neutrophilopenia was the most common toxicity and grade 3 or 4 neutrophilopenia was seen in 6 patients. Adjuvant chemotherapy of outpatients can be completed safely by the choice of a safe regimen, supportive therapy for the toxicity, and cooperation with the community medicine organization. Our chemotherapy regimen are thought to be feasible for postoperative lung cancer outpatients.

[Clinical analysis of bronchoplastic surgery for lung cancer after 2000].

We investigated surgical complications and prognosis of bronchoplasty and bronchoplasty with pulmonary angioplasty (broncho-angioplasty) for lung cancer. Between October 2000 and October 2007, 37 bronchoplastic procedures were done in 572 patients who underwent lung resections for lung cancer. Eleven (29.7%) bronchoplasties were done with pulmonary angioplasty. There was no operative mortality and 1 hospital mortality (2.7%) causing by myocardial infarction. Six of 11 postoperative complications were bronchial complications and 2 additional lung resections were needed. The 5-year survival for all patients was 55.2% and for bronchoplasty was 57.8%. Though the 5-year survival of broncho-angioplasty was not able to calculate at present, the 3-year survival of which was 72.9%. There was no death of patients with adenocarcinoma after introduction of pre-operative assessment by FDG-PET for lymph node metastasis. These data suggest that bronchoplasty and broncho-angioplasty are safe operative procedures and could provide acceptable intermediate survivals with modern multimodality diagnostic and therapeutic tools.

Factors affecting the digestibility of raw and gelatinized potato starches.

The enzymatic digestibilities of raw and gelatinized starches in various potato starches, as well as sweet potato, cassava, and yam starches, were estimated, along with other starch properties, such as the phosphorus content, median granule size, and rapid visco analyzer (RVA) pasting properties. Furthermore, correlation coefficients were calculated between the hydrolysis rates (HR) by amylase and other starch quality parameters. A larger granule size was closely associated with a lower HR in raw starch, while the HR in gelatinized starch did not correlate with the median granule size. An increase in phosphorus content resulted in a definitely lower HR in raw starch and tended to decrease the HR in gelatinized starch for the composite of potato and other starches. In contrast, no correlation coefficients of the phosphorus content with the HRs in raw and gelatinized starches were observed within potato starches. Starches with higher peak viscosity and breakdown showed a lower HR in raw starch, while few or no effects of these RVA parameters on the HR in gelatinized starch were observed for the composite of potato and other starches or among potato starches, respectively.

[Problems in donor lung evaluation for transplantation with regard to airway infection].

The shortage of donor organs has been 1 of the major obstacles to solid organ transplantation. Typical lung donor criteria include clear lung field on chest radiograph, adequate oxygenation, acceptable lung compliance, and satisfactory bronchoscopic findings. To extend usage of available donors, liberalization of donor lung selection criteria has been facilitated, however, marginal donor lungs must be used with discretion, because donor lung injury, especially that related to infection, has a potential leading to early post-operative death of the recipient. From March 2000 to December 2006, we evaluated 15 braindead donors and at least 1 of the lungs from 9 donors was judged suitable for transplantation. One of 9 recipients developed severe pneumonia cased by carbapenems-resistant Pseudomonas aeruginosa possibly originating from the donor lungs, eventually leading to death. The chest radiograph and oxygenation of the donor had been satisfactory, however, a moderate amount of mucopurulent secretions was observed by bronchoscopic inspection and the donor had been given a cefozopran for 9 days before the procurement operation. Remaining 8 recipients were free from air-way infection in the early postoperative period. We discuss the status and problems of donor lung evaluation for transplantation with regard to donor lung infection.

[Bronchoplasty without lung resection for the complete transection of the left main bronchus due to blunt trauma].

Blunt bronchial injury is rare but crucial injury. A 17-year-old female was admitted due to traumatic injury. She was diagnosed with bilateral lung contusion, multiple rib fractures, spleen damage and the suspicion about the complete transection of the left main bronchus on X-ray and computed tomography (CT). She was brought to our hospital at 30 hours later from injury. Bronchoscopy revealed the complete transection and the edema of the left main bronchus. She underwent a resection of the disrupted portion and end-to-end anastomosis of left main bronchus without lung resection. We should be an immediate and accurate diagnosis of tracheobronchial disruption by X-ray, CT and bronchoscopy whenever we evaluate patients with blunt chest trauma.

Genome-wide profiling of promoter methylation in human.

DNA methylation in the promoter region of a gene is associated with a loss of that gene's expression and plays an important role in gene silencing. The inactivation of tumor-suppressor genes by aberrant methylation in the promoter region is well recognized in carcinogenesis. However, there has been little study in this area when it comes to genome-wide profiling of the promoter methylation. Here, we developed a genome-wide profiling method called Microarray-based Integrated Analysis of Methylation by Isoschizomers to analyse the DNA methylation of promoter regions of 8091 human genes. With this method, resistance to both the methylation-sensitive restriction enzyme HpaII and the methylation-insensitive isoschizomer MspI was compared between samples by using a microarray with promoter regions of the 8091 genes. The reliability of the difference in HpaII resistance was judged using the difference in MspI resistance. We demonstrated the utility of this method by finding epigenetic mutations in cancer. Aberrant hypermethylation is known to inactivate tumour suppressor genes. Using this method, we found that frequency of the aberrant promoter hypermethylation in cancer is higher than previously hypothesized. Aberrant hypomethylation is known to induce activation of oncogenes in cancer. Genome-wide analysis of hypomethylated promoter sequences in cancer demonstrated low CG/GC ratio of these sequences, suggesting that CpG-poor genes are sensitive to demethylation activity in cancer.

Unrelated donor bone marrow transplantation for 100 pediatric patients: a single institute's experience.

In all, 100 unrelated donor bone marrow transplantations (UD-BMT) were performed in our institute between October 1993 and January 2003. Of 93 evaluable patients, 73 patients had hematological malignancy, 13 had nonmalignancy and seven had lymphoproliferative disease. The estimated 9-year event-free survival (EFS) rate was 57.1+/-5.5% in all patients. In the following analyses of the patients with hematological malignancy, the standard group had significantly better EFS than the high-risk group (61.5+/-7.0 vs 35.6+/-9.7%, P=0.02), and the EFS rate of the tacrolimus (FK-506)+methotrexate (MTX)+/-methylprednisolone prophylactic group for graft-versus-host disease was superior to that of the FK-506 without MTX group (75.7+/-8.0 vs 55.8+/-7.6%, P=0.02). When we compared the EFS rates of the FK506+MTX+/-methylprednisolone (mPSL) group and the HLA-matched related donor BMT group in our institute, these were almost similar (75.7+/-8.1 vs 68.4+/-9.3%). Therefore, UD-BMT using FK-506+MTX+/-mPSL is a safe and useful method for children with hematological malignancy who require allogeneic BMT.

Study design considerations in clinical outcome research of lung cancer using microarray analysis.

BACKGROUND: Prognosis following a diagnosis of primary lung cancer is very poor and varies significantly even after adjusting for known predictors. Inherent and acquired gene alterations could cause failure in lung cancer treatment and patient survival. To search for potential molecular markers with significant and independent predictive value in lung cancer survival, we applied oligo-nucleotide microarray analysis, along with patients' phenotypic profile, in a case-control study. The focus of this report is on the methodology used in the identification of potential genes as prognostic factors. METHODS: Selected from 304 patients at Mayo Clinic, 18 stage I squamous cell lung cancer patients who died within 2 years (high-aggressive) or lived beyond 5 years (low-aggressive) were included in this study. Both a one-to-one matched design (paired) and a two-group design (grouped) were utilized. Matching variables were age, gender, tumor size and grade, smoking status, and treatment. Two-GeneChip-array sets from Affymetrix (HG-U133) were used. We applied multiple analytic approaches including Dchip (Harvard University), SAM (Stanford University), ArrayTools (US National Cancer Institute), and MAS5 (Affymetrix); and integrated multiple results to generate the final candidate genes for further investigation. We evaluated the consistency across the methods and the effects of matched versus grouped design on the results. RESULTS: Using the same pre-processed data under the same criteria for type I error and fold-change in expression intensity, results are 94-100% concordant in the list of significant genes by Dchip and by ArrayTools, and 53% concordant between the paired and the grouped analysis. If using differently pre-processed data, the concordance rate is under 6% even by the same analytic tool. Combining results from all analyses, we found 23 potentially important genes that may distinguish the high- versus low-aggressive squamous cell tumors of the lung. CONCLUSION: Given the generally low consistency of results across analytic algorithms and study design, poor agreement is expected from different investigators reporting candidate genes for the same endpoint. A well-designed study with a carefully planned analytic strategy is critical. We are in the process of validating the 23 preliminary candidate genes found from this study among independent yet comparable cases.

[New surgical technique of pulmonary segmentectomy by ultrasonic scalpel and absorbable sealing materials].

We developed new surgical technique of pulmonary segmentectomy by ultrasonic scalpel to sever intersegmental pulmonary tissue and absorbable sealing materials to cover the cut surface of lung. This method is expected to preserve more anatomical lung volume than the segmentectomy with surgical stapler. Two cases of post surgical recurrent lung cancer, 3 cases of pulmonary metastasis and 4 cases of primary lung cancer were applied this technique to preserve function. Among 3 materials examined, best result was obtained with polyglycolic acid felt (PGAF:Neoveil). PGAF is a very soft and thin (0.15 mm depth) new absorbable material that is able to closely adhere to irregular sections of the lung with fibrin glue and effectively seals air leakage. Mean chest drainage period after surgery in 6 cases with PGAF was 3.3 days. Excellent lung expansion was obtained immediately after the surgery and PGAF was disappeared completely on chest CT within 1 year. Although the possible superiority of this method is suggested in the present study, further comparative study is necessary to clarify the advantage of this new technique.

[Assessment of mode of recurrence after surgical treatment for thymic carcinoma].

In order to establish an appropriate treatment for thymic carcinoma, clinical courses of 15 patients with type C thymoma of WHO classification were reviewed. Five-years survival rate in all patients was 37.6%. In cases underwent complete resection, survival was 48.5%. The induction chemotherapy was done in 7 cases, and complete resection was possible in all these cases, suggested the possibility of improving the survival by the induction therapy. Upper mediastinal lymph node dissection each performed in 9 cases, and they showed significantly better survival than those without lymph node dissection. In conclusion, we have found that induction chemoradiotherapy and complete tumor resection with lymphnode dissection would contribute to improvement of the results in treatment for thymic carcinoma.

[Reevaluation of bronchoplasty for central-type lung cancer].

The outcome, anastomotic complications, and recurrence rate after bronchoplasty carried out in 198 patients with bronchogenic carcinoma in our institutions were evaluated retrospectively. The outcome of bronchoplasty was reasonable (5-year survival rate of 58%), but that of patients with adenocarcinoma was poor (5-year survival rate of 13%) because of their advanced stage and less complete resection. The complications of anastomosis occurred in 8.2% after bronchoplasty. Postoperative pneumonia significantly increased the risk of complications. There was no difference in the incidence of complications between patients who received end-to-end and telescope-type anastomosis. Local recurrence at the anastomosis occurred in 4.9% who underwent bronchoplasty, but in 28% who underwent carinal resection. Lymph node metastasis was a risk factor for local recurrence. Twenty patients with early superficial squamous cell carcinoma in the central bronchus were treated with photodynamic therapy without local recurrence. This new modality may be of benefit to selected patients.

[Recurrence of febrile convulsions after the first diphtheria-pertussis-tetanus vaccination and measles vaccination in children with febrile convulsions: a questionnaire survey in Takamatsu City].

A questionnaire about convulsions and other adverse events after vaccination was sent to doctors who administered a diphtheria-pertussis-tetanus (DPT) vaccine (the first dose) or a measles vaccine between April 1, 1995 and December 31, 1997 in Takamatsu City to children with convulsions. DPT and measles vaccines were administered to 300 and 339 such children, respectively. Many of them had febrile seizures, the last of which had occurred before more than 1 year. Among them, 175 cases were administered with DPT and 180 with measles vaccine. There were recurrences of febrile convulsions after immunization in 2 (1.1%) of the cases given DPT and 3 (1.7%) of those given measles vaccination. According to the data of the Monitoring System for Adverse Events Following Immunization (the Ministry of Health and Welfare of Japan), the incidence of convulsion after immunization in healthy children between April 1, 1996 and September 30, 1997 was 0.4% after the first dose of DPT vaccination and 0.3% after measles vaccination. In comparison, the incidence was higher in children who had had febrile convulsions before more than one year. Especially, the rate of convulsions after measles vaccinations was significantly higher (p < 0.05) in children with febrile convulsions. These results suggest that the measles vaccination should be administered with caution to the children with previous febrile convulsions.

[A case of pneumonectomy for lung cancer associated with scleroderma].

A 60-year-old female, diagnosed as scleroderma, was referred to our hospital because of symptoms of common cold and abnormal findings on a chest X-ray. The chest X-ray and CT scan revealed a mass in the left upper field, suspected to invade left anterior chest wall. Moreover, fibrotic changes were observed in the lung field. Cytology by bronchofiberscopy showed squamous cell carcinoma. Evaluation of pulmonary function, including unilateral pulmonary artery occlusion test (UPAO), revealed possibility of lung resection. Subsequently, pneumonectomy with combined resection of left 1st rib was performed. Postoperative course was uneventful and she was discharged. She was admitted again four months after the operation with appetite loss and body weight loss. Further examinations revealed arrhythmia, renal failure, pancreatitis and liver metastasis. Her general conditions grew worse and she died five months after the operation. In conclusion, UPAO was a useful method to determine the functional lung resectability for the case with scleroderma. However, effects of surgical stress for the development of scleroderma remain to be elucidated.