[S-1 monotherapy in patients with pretreated advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of S-1 monotherapy in patients with pretreated advanced non-small cell lung cancer(NSCLC). METHODS: We prospectively analyzed patients previously treated with a platinum-containing regimen or monotherapy with a third-generation chemotherapeutic drug. S-1 was orally administered at approximately 80 mg/m / 2day for 28 days followed by a 2-week rest period. We evaluated the efficacy and toxicities. RESULTS: A total of 15 patients received S-1 monotherapy. Three partial responses were observed among them with an overall response rate of 20%. Toxicities of grade 3 or higher included anemia(13%), thrombocytopenia( 6%), fatigue(6%), anorexia(13%), diarrhea(13%), interstitialpneumonitis(6%)and infection(6%). The ratio of outpatient treatment period was 73.5%. The median time to progression, median survivaltime and 1-year survival rate were 4.2 months, 7.8 months and 27.8% respectively. CONCLUSIONS: S-1 monotherapy was suggested to be effective and tolerable in patients with pretreated advanced NSCLC.

Prognostic significance of thin-section CT scan findings in small-sized lung adenocarcinoma.

OBJECTIVES: The purpose of this study is to evaluate the prognostic importance of thin-section (TS) CT scan findings in small-sized lung adenocarcinomas. PATIENTS AND METHODS: We reviewed TS-CT scan findings and pathologic specimens from 359 consecutive patients who underwent surgical resection for peripheral lung adenocarcinomas

Amplification of plasmids containing a mammalian replication initiation region is mediated by controllable conflict between replication and transcription.

We previously showed that plasmids containing both a mammalian replication initiation region and a matrix attachment region were efficiently amplified in human cancer cells and that they were either integrated into preexisting extrachromosomal double minutes (DMs) or induced the generation of a chromosomal homogeneously staining region (HSR). In this article, we elucidated the mechanism by which such plasmids mimic gene amplification. Hybridization experiments using chromatin fiber, metaphase spread, and genomic Southern blot analysis suggested that a circular molecule comprising a plasmid direct repeat was generated initially. Recombination between this molecule and the preexisting DMs led to the apparent stabilization of the plasmid repeat. If the plasmid repeat was integrated into the chromosome, it initiated the breakage-fusion-bridge cycle, which generated HSR. Importantly, we found that HSR formation was blocked by inserting a poly(A) signal or the orientation-specific replication fork barrier downstream of the drug-resistance gene, where the transcription would meet head to head with the supposed replication fork from the initiation region. The matrix attachment region enhanced HSR formation if it was inserted at the same site. These data suggested that strand breakage generated by the conflict between replication and transcription might trigger the breakage-fusion-bridge cycle. This is the first study suggesting that such a conflict leads to genomic instability in higher eukaryotes.

[Gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We analyzed 19 patients with advanced NSCLC retrospectively, who were treated with gefitinib as a first-line therapy. These patients were not considered for systemic chemotherapy secondary to co-morbid conditions, poor performance status (PS) or refusal of chemotherapy. RESULTS: Median age 68 years, male/female 10/9, stage III/IV 7/12, smoker/non-smoker 12/7, adenocarcinoma/non-adeno 13/6, PS 0/1/2/3/4 0/4/7/5/3. Four patients had a partial response and the overall response rate was 21.0%. The median survival time was 6.8 months and 1-year survival was 27%. Overall toxicities were mild. Grade (G) 3 diarrhea was observed in one patient and G1 interstitial pneumonia in one. CONCLUSIONS: These results demonstrate that gefitinib is active as a first-line therapy in patients with advanced NSCLC.

[Effectiveness of pneumococcal polysaccharide vaccine in older patients with chronic respiratory diseases].

To evaluate effectiveness of pneumococcal polysaccharide vaccine, we recommended 1378 outpatients aged over 60 with chronic respiratory diseases to be vaccinated from August to October 2002, and 647 patients were vaccinated from August to November 2002. In the 1229 patients without respiratory failure, the incidence of antimicrobial treatment for bacterial respiratory infections in 547 vaccinated patients significantly decreased from 7.9% in the 2001/02 winter season to 5.7% in the 2002/03 winter season, although that in the 682 unvaccinated patients increased from 3.8% to 5.7%. The incidence of antimicrobial treatment for bacterial respiratory infections in 229 vaccinated patients with pneumococcal and influenza vaccines together significantly decreased from 10.5% in the 2001/02 winter season to 5.2% in 2002/03 winter season although that in 110 subjects vaccinated with influenza vaccine only increased from 2.7% to 7.2%. These findings suggest the effectiveness of the pneumococcal polysaccharide vaccine for the prevention of bacterial respiratory infections and the additive effectiveness of pneumococcal and influenza vaccines together.

[Combination chemotherapy with carboplatin and weekly Paclitaxel in patients with advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of carboplatin plus weekly paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-nine patients were analyzed retrospectively. Every 4 weeks patients received 70 mg/m(2)paclitaxel on days 1, 8, and 15, and AUC 5-6 carboplatin on day 1. RESULTS: A median of four cycles (range, 1-7) was administered. Twenty-four patients had a partial response, and the overall response rate was 48.9%. The median survival time was 12.8 months and the 1-year survival was 50.7%. Overall toxicities were mild. The most common toxicity was neutropenia, grade 3/4 in 32% of the patients. Grade 3/4 hematologic toxicities included anemia (16%) and thrombocytopenia (8%). Grade 3/4 non-hematologic toxicities included febrile neutropenia (2%), pneumonia (10%) and interstitial pneumonia (2%). Grade 2 peripheral neuropathy was seen in one patient (2%). CONCLUSIONS: These results demonstrate that this regimen is an active and tolerable treatment for patients with advanced NSCLC. It is suggested that this weekly regimen should be considered as one of the standard therapies for future chemotherapy in advanced NSCLC.

[Eighty cases of chronic respiratory failure treated with home noninvasive positive pressure ventilation].

We studied the clinical features and efficacy of home noninvasive positive pressure ventilation (NPPV) therapy in 80 patients to ascertain its indications and problems. The causes of chronic respiratory failure were restrictive thoracic diseases of post-tuberculosis sequelae (40 cases) and kyphoscoliosis (9 cases), COPD (8 cases), bronchiectasis (7 cases), and interstitial pneumonia (4 cases). One year survival rate of the patients with post-tuberculosis sequelae was 76% and most of the patients who started NPPV at their acute exacerbation died within several months. About half of the patients of COPD improved their quality of life (QOL) through NPPV. However, their survival rate 3 months later was only 69%. More than half of the patients with bronchiectasis felt that their QOL was improved by NPPV. Most of the patients with interstitial pneumonia died within 3 months indicating that NPPV is less useful for improving QOL of interstitial pneumonia PaCO2, after home NPPV, decreased significantly in the responder group (70.0 +/- 15.4 vs. 57.6 +/- 10.7[SD]Torr, p < 0.05), while PaCO2 in the non-responder group was unchanged (65.4 +/- 12.1 vs. 64.2 - 10.4 [SD] Torr). Body Mass Index (BMI) in the responder group tended to be higher than in the non-responder group. In conclusion, the restrictive thoracic diseases with post-tuberculosis sequelae and kyphoscoliosis are a good indication for NPPV and the therapy is also useful for patients with bronchiectasis who can dispose of their sputum by themselves. Home NPPV is suitable for patients whose PaCO2 decreases through NPPV and whose BMI is relatively high. QOL of interstitial pneumonia barely improves through NPPV, because interstitial pneumonia with hypercapnia is at the terminal stage.

Good's syndrome and pernicious anemia.

In a rare case of Good's syndrome with pernicious anemia, one year after thymectomy, recurrent respiratory infections developed. Both panhypoglobulinemia and pernicious anemia were disclosed. An immunological analysis revealed the absence of circulating B cells, but T cell numbers and mitogenic responses were normal. Regular gammaglobulin and vitamin B12 injections were successful in keeping the patient symptom free.

Pulmonary alveolar proteinosis successfully treated with ambroxol.

A 79-year-old woman was admitted to hospital due to a four-month history of a cough and dyspnea on exertion. Chest CT scans revealed ground glass opacity with thickened interlobular septa in both lungs. Bronchoalveolar lavage fluid (BALF) had milky appearance and revealed large acellular eosinophilic amorphous bodies positively stained with periodic acid-Schiff (PAS). Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) were present in sera and BALF from the patient. Ambroxol was started in a daily dose of 45 mg orally. Her oxygen saturation improved and abnormal shadows in CT scan disappeared 6 months after beginning the therapy.

[Complete remission of locally advanced squamous cell lung cancer induced by chemotherapy with cisplatin and docetaxel].

The patient was a 70-year-old man with c-T2N3M0 stage IIIB squamous cell lung cancer in the upper lobe of his left lung. Two cycles of chemotherapy of docetaxel with cisplatin induced complete response. Sequential radiotherapy was performed for the mediastinum. One year after treatment, he underwent a lung resection for a second lung cancer, poorly differentiated adenocarcinoma, in the upper lobe of his right lung. Resected mediastinal lymph nodes showed no cancer cells of the first lung cancer. Now, more than 3 years after the first examination, he maintains complete remission without evidence of recurrence.

[Assessment of the inhalation technique using diskhaler in adult patients with asthma].

This study evaluated the proper use of Diskhaler in 104 adult outpatients with asthma. Logistic regression analysis was performed to determine whether age, gender, the experience with metered dose inhaler (MDI), and the disease period were predictive of incorrect use of the Diskhaler. Frequencies of correct performance of "all actions" (10 items) and "all essential actions" (2 items) were 47% and 69% of patients respectively. The most frequent errors were "not holding breath for five seconds" (37%) and "not inhaling forcefully and deeply" (31%). Relative risks of incorrect inhaler use were as follows: age 1.000, female gender 1.341, no experience with MDI 1.707, and disease period 0.991, all of which were statistically insignificant. We should instruct patients especially to breathe in forcefully and deeply, and to hold breath for five seconds.

[A case of miliary tuberculosis complicated by acute respiratory failure after bronchofiberscopy].

A 79-year-old man presented with persistent nonproductive cough and high fever. The chest radiograph showed bilateral miliary shadows. We performed bronchoalveolar lavage and transbronchial lung biopsy to assist diagnosis. Severe dyspnea developed after the bronchofiberscopy, when the chest radiograph revealed bilateral ground-glass shadows and the oxygen saturation in the room air fell to 60%. It was suspected that the patient had acute respiratory distress syndrome, so that methylprednisolone was given intravenously at a dose of 250 mg daily for 3 days, which resulted in a reduction in ground glass shadows and an improvement in oxygen saturation. We diagnosed miliary tuberculosis because the transbronchial lung biopsy specimen showed caseous granuloma and the PCR test for Mycobacterium tuberculosis in the bronchoalveolar lavage fluid was positive. The patient was cured with antituberculosis chemotherapy.

[Interstitial pneumonia associated with chronic thyroiditis].

A 56-year-old woman was initially seen in March 1998 with a complaint of back pain. Her thyroid gland was swollen and the level of TSH was elevated at 10 microU/ml. Chronic thyroiditis with hypothyroidism was diagnosed. Negative reactions were obtained for both anti-thyroglobulin and anti-thyroid peroxidase antibodies. Daily treatment with thyroxine 50 mg was started. A cough developed in August 1998, and her chest radiographs revealed multiple bilateral consolidation shadows. A transbronchial lung biopsy specimen demonstrated mononuclear cells infiltration in the alveolar septa with fibrosis, consistent with nonspecific interstitial pneumonia (NSIP). There were no findings clinically or serologically suggestive of collagen-vascular diseases. Ultimately interstitial pneumonia compatible with the NSIP pattern in association with chronic thyroiditis was diagnosed. Oral prednisolone (30 mg/day) and azathioprine (50 mg/day) administration was initiated. The cough and the shadows on the chest radiographs improved. However, one year after completion of the treatment, interstitial pneumonia recurred. Retreatment with prednisolone and azathioprine has resulted in its improvement.

Dissection of mammalian replicators by a novel plasmid stability assay.

A plasmid, bearing a mammalian replication initiation region (IR) and a matrix attachment region (MAR) was previously shown to be efficiently amplified to high copy number in mammalian cells and to generate chromosomal homogeneously staining regions (HSRs). The amplification mechanism was suggested to entail a head-on collision at the MAR between the transcription machinery and the hypothetical replication fork arriving from the IR, leading to double strand breakage (DSB) that triggered HSR formation. The experiments described here show that such plasmids are stabilized if collisions involving not only promoter-driven transcription but also promoter-independent transcription are avoided, and stable plasmids appeared to persist as submicroscopic episomes. These findings suggest that the IR sequence that promotes HSR generation may correspond to the sequence that supports replication initiation (replicator). Thus, we developed a "plasmid stability assay" that sensitively detects the activity of HSR generation in a test sequence. The assay was used to dissect two replicator regions, derived from the c-myc and DHFR ori-beta loci. Consequently, minimum sequences that efficiently promoted HSR generation were identified. They included several sequence elements, most of which coincided with reported replicator elements. These data and this assay will benefit studies of replication initiation and applications that depend on plasmid amplification.

When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation.

Amplified genes are frequently localized on extrachromosomal double minutes (DMs) or in chromosomal homogeneously staining regions (HSRs). We previously showed that a plasmid bearing a mammalian replication initiation region could efficiently generate DMs and HSRs after transfection into human tumor cell lines. The Breakage-Fusion-Bridge (BFB) cycle model, a classical model that explains how HSRs form, could also be used to explain how the transfected plasmids generate HSRs. The BFB cycle model involves anaphase bridge formation due to the presence of dicentric chromosomes, followed by the breakage of the bridge. In this study, we used our plasmid-based model system to analyze how anaphase bridges break during mitosis. Dual-color fluorescence in situ hybridization analyses revealed that anaphase bridges were most frequently severed in their middle irrespective of their lengths, which suggests that a structurally fragile site exists in the middle of the anaphase bridge. Breakage of the chromosomal bridges occurred prior to nuclear membrane reformation and the completion of cytokinesis, which indicates that mechanical tension rather than cytokinesis is primarily responsible for severing anaphase bridges. Time-lapse observation of living cells revealed that the bridges rapidly shrink after being severed. If HSR length was extended too far, the bridge could no longer be resolved and became tangled depending on the tension. The unbroken bridge appeared to inhibit the completion of cytokinesis. These observations strongly suggest that anaphase bridges are highly elastic and that the length of the spindle axis determines the maximal HSR length.

Pyothorax-associated T-cell lymphoma: a case report.

We present a case of pyothorax-associated T-cell lymphoma in which Epstein-Barr virus (EBV) genome is not detected in the tumor cells. An 80-year-old male came to our hospital because of a left chest pain. Chest computed tomography (CT) showed a mass at the lower-dorsal part of the pyothorax wall, which involved the adjacent chest wall. The surgical biopsy specimen showed a predominant infiltration of atypical lymphocytes. Results of immunohistochemical analysis were as follows: CD3+, CD4-, CD8+, CD20-, CD30-, CD45RO+ and CD79a-. We diagnosed this case as a type of peripheral T-cell lymphoma. In situ hybridization using EBV-encoded RNA-1 (EBER-1) did not reveal the positive signals in the nucleus of tumor cells. Polymerase chain reaction (PCR) analysis yielded a negative result for human herpesvirus 8 (HHV8). Radiation therapy at 54 Gy reduced the tumor size by 90%. Visual and hearing disturbances of unknown etiology developed just before the completion of radiotherapy. The symptoms progressively worsened and the patient became bedridden. He died of pneumonia 2 months after the completion of radiotherapy. Autopsy did not reveal abnormalities to which the neurological disturbances were attributable.