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.

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.

[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.

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.

[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.

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.

Accelerated aging of the brain in Werner's syndrome.

We report the electrophysiologic examination of a 55-year-old woman with Werner's syndrome. Needle EMG and peripheral conduction studies were normal. In contrast, EEG was moderately abnormal, the N20 and P25 potentials of SEPs were delayed and enlarged, and the event-related potential, P300, was delayed. These characteristic findings indicated accelerated aging of the brain, as in the other organs, in Werner's syndrome.

Numb chin syndrome secondary to Burkitt's cell acute leukemia.

We describe a case of Burkitt's cell acute lymphoblastic leukemia presenting with the bilateral numb chin syndrome as the initial symptom of the disease. Postmortem study of the trigeminal nerve showed heavy infiltrations of leukemic cells and destruction of axon and myelin by leukemic cells in the mandibular nerve.

Assessment of MRI criteria for MS in Japanese MS and HAM/TSP.

We evaluated the usefulness of the MRI criteria for multiple sclerosis (MS) proposed by Paty et al and Fazekas et al in 36 Japanese MS patients, using HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) as the control. Although 30 of 36 HAM/TSP patients had multiple white matter lesions on T2-weighted cranial MRI, only two fulfilled the MRI criteria for MS. At the same time, 31 of the 36 MS patients fulfilled the primary MRI criterion, yielding 93% specificity and 86% sensitivity for the criterion. MS has disease-specific MRI abnormalities.

In situ demonstration of the HTLV-I genome in the spinal cord of a patient with HTLV-I-associated myelopathy.

Using polymerase chain reaction (PCR) and in situ hybridization, we investigated the HTLV-I genome in the CNS of an HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient with a 20-year disease duration. Neuropathologically, there was severe white matter degeneration throughout the spinal cord, but lymphocytic infiltrates were not evident in any lesion. PCR amplification of the pX region of HTLV-I DNA detected its sequence in the spinal cord and all extra-CNS tissue samples. In situ hybridization using probes complementary to the pX and gag regions detected the HTLV-I genome in the cytoplasm and nucleus of cells in the thoracic cord. The findings indicate a direct involvement of HTLV-I in the neurodegeneration of HAM/TSP.

Clinicopathological analysis of 19 cases of isolated carcinoma in situ of the bronchus.

Nineteen cases of isolated squamous cell carcinoma in situ (CIS) of the bronchus were described clinicopathologically from among 149 male heavy smokers with roentgenographically occult lung cancer discovered mainly by mass screening performed from 1982 to 1991. All 19 patients had positive sputum cytology tests and negative chest x-ray films and underwent lobectomy (except one who had segmentectomy because of poor lung function). Prior to operation, localization was accomplished by one to eight bronchoscopies using repetitive brush cytology and biopsy. Five cases were bronchoscopically invisible. Polypoid protuberance was noted in three cases, micronodular swelling in three, thickening of spur in five, and mucosal granularity in three. Histology by serial block sectioning showed that there was no nodal involvement in any cases; the maximum length or diameter was 12 mm. Thirteen tumors were < or = 4 mm, four of which were confined to the spur where they occurred. Follow-up data showed a favorable prognosis. Segmentectomy or sleeve resection of bronchus without mediastinal lymph node dissection may be adequate for CIS.

Q-wave regression unrelated to patency of infarct-related artery or left ventricular ejection fraction or volume after anterior wall acute myocardial infarction treated with or without reperfusion therapy.

We examined the relation of Q-wave regression to left ventricular (LV) indexes in acute anterior wall myocardial infarction (AMI) in relation to reperfusion therapy. A total of 94 patients with their first anterior wall AMI (segment 6 or 7 occlusion according to the American Heart Association classification) were examined. The follow-up period with 12-lead electrocardiograms ranged from 6 to 60 months (mean 24 +/- 18). An abnormal Q wave was defined as > 40 ms and > 25% of the R-wave amplitude. Q-wave regression was defined as Q-wave disappearance and r-wave regression > 0.1 mV in > or = 1 lead. Contingency tables with the chi-square test and analysis of variance were used for assessment of the relation between Q-wave regression and angiographic and clinical indexes. Q-wave regression in > or = 1 lead was found in 77% of the patients. The incidence of Q-wave regression in patients with patent infarct-related artery (81%) was not significantly different from that in those with an occluded lesion (67%). Q-wave regression appeared within 1 month in 60% of patients with a patent infarct-related artery but in 25% of those with an occluded lesion. No difference in the incidence of Q-wave regression was seen between patients with lesions at segments 6 (81%) and 7 (70%), or between those with (75%) and without (77%) collateral circulation. Q-wave regression did not correlate with LV ejection fraction, LV end-diastolic or end-systolic volumes, or regional wall motion.(ABSTRACT TRUNCATED AT 250 WORDS)