Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the effects of irinotecan (CPT-11) given in combination with etoposide (VP-16) in metastatic non-small-cell lung cancer (NSCLC), to evaluate response and survival rates, and to determine the qualitative and quantitative toxicities of the combination chemotherapy. PATIENTS AND METHODS: Sixty-one metastatic NSCLC patients received concurrent administration of CPT-11 and VP-16 for 3 days with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support. RESULTS: Fifty-nine patients were assessable for response and all 61 patients were assessable for toxicity and survival. Fifty-six patients were treated with two or more courses of chemotherapy. Thirteen patients achieved a partial response (PR), 36 showed no change (NC), and 10 showed progressive disease (PD). The overall response rate was 21.3% (95% confidence interval, 12.9% to 33.1%). The median duration of PRs was 141 days (range, 62 to 299). Of the hematologic toxicities, 14 (23%) and 24 (39%) patients experienced grade 3 or 4 leukopenia and neutropenia, respectively. The toxicities were feasible. Treatment-related death occurred in one patient who suffered hypovolemic shock induced by hematemesis. The median survival time was 10.0 months and the 1-year survival rate was 36.1%. CONCLUSION: Combination chemotherapy with concurrent administration of CPT-11 and VP-16 with rhG-CSF support was only modestly effective against metastatic NSCLC, with feasible toxicities of moderate diarrhea and pulmonary toxicity. The results were equivalent to those expected with either cisplatin-based chemotherapy or with CPT-11 alone.

Enhanced expression of heparin-binding EGF-like growth factor and its receptor in hypertrophied left ventricle of spontaneously hypertensive rats.

OBJECTIVES: Although heparin-binding epidermal growth factor-like growth factor (HB-EGF) is thought to produce hypertrophy in isolated cardiomyocytes via an autocrine mechanism, the pathophysiological role of HB-EGF, in myocardial hypertrophy in vivo, is not yet known. To investigate the involvement of HB-EGF in cardiac remodeling associated with hypertension in vivo, we assayed the expression of HB-EGF mRNA and protein in the left ventricle (LV) during the development of left ventricular hypertrophy in spontaneously hypertensive rats (SHR). METHODS: Prior to sacrifice and assay of HB-EGF and EGF-receptor (EGF-R) mRNA, morphologic and hemodynamic variables were measured in SHR and in age-matched Wistar Kyoto rats (WKY). At 5, 9 and 12 weeks of age, rats were killed, their hearts were removed, and the expression of HB-EGF and EGF-R mRNA and protein were measured. In addition, SHR and WKY were treated with enalapril, atenolol, or both for 4 weeks. RESULTS: In untreated SHR, double products (i.e. systolic blood pressure (sBP) multiplied by heart rate (HR), an index of mechanical load, peaked at 9 weeks. Expression of HB-EGF mRNA was also observed to peak in these animals at 9 weeks, while expression of EGF-R mRNA increased from 5 to 9 weeks, but remained constant thereafter. In untreated WKY, double products and EGF-R mRNA expression did not change over time, whereas the level of HB-EGF message increased gradually. Antibody to HB-EGF reacted primarily with myocyte membranes in SHR, whereas antibody to EGF-R reacted mainly with interstitial cells in these animals. The angiotensin-converting enzyme inhibitor, enalapril, markedly decreased sBP in SHR, whereas the beta 1-adrenoreceptor antagonist, atenolol, significantly decreased HR. While neither alone affected the expression of HB-EGF mRNA, their combination significantly reduced the expression of HB-EGF mRNA, as well as double products, in these rats, but had no effect on expression of EGF-R mRNA. CONCLUSIONS: The enhanced expression of HB-EGF mRNA and protein in LV of SHR suggest that this growth factor may play an important role during the early development of LV hypertrophy and cardiac fibrosis in SHR. The association between double products and HB-EGF expression suggest that the latter may be induced by increased mechanical load and may contribute, in turn, to cardiac remodeling.

Absence of antioxidant effects of nifedipine and diltiazem on myocardial membrane lipid peroxidation in contrast with those of nisoldipine and propranolol.

Both the production of active oxygen species and cellular damage due to concurrent lipid peroxidation are believed to be important factors in the pathogenesis of cardiovascular diseases and the ageing process. Since cardiovascular drugs are often administered over a long term, it might be advantageous if they reduced lipid peroxidation. There have been conflicting reports concerning the antiperoxidant effect of nifedipine. Therefore, we investigated whether nifedipine could inhibit lipid peroxidation in a nonenzymatic active oxygen-generating system, utilizing rat crude myocardial membranes, and compared its effect with those of propranolol, nisoldipine, and diltiazem. Nifedipine and diltiazem had no inhibitory effects on the lipid peroxidation of myocardial membranes. In contrast, nisoldipine and propranolol had a concentration-dependent antiperoxidant effect, with IC50 values of 28.2 and 50.1 microM, respectively. In addition, nisoldipine appeared to possess dual antiperoxidant mechanisms, involving both preventive and chain-breaking properties.

Transforming growth factor-beta 1 proliferated vascular smooth muscle cells from spontaneously hypertensive rats.

To clarify whether the growth inhibitors, transforming growth factor-beta 1 (TGF-beta 1), heparin, and interferon-gamma (IFN-gamma) contribute to the development of vascular hypertrophy in spontaneously hypertensive rats (SHR), the growth of vascular smooth muscle cells (VSMC) was evaluated both for cell numbers over a period of 4 days, and [3H]thymidine incorporation over 24 h. Heparin and IFN-gamma inhibited the proliferation of VSMC from SHR and Wistar-Kyoto (WKY) rats. TGF-beta 1 enhanced SHR-VSMC proliferation by 16.6 +/- 8.9%; in contrast TGF-beta 1 inhibited WKY-VSMC proliferation by 60.5 +/- 7.4%. There was no difference in affinity, number of binding sites, or subtype expression of TGF-beta 1 receptor between SHR-VSMC and WKY-VSMC. This evidence suggests that the signal transduction system of TGF-beta 1 either the receptor itself or downstream signaling molecules, may be altered in SHR-VSMC versus WKY-VSMC. This abnormal responsiveness to TGF-beta 1 is involved in the proliferative characteristics of SHR-VSMC. Therefore, TGF-beta 1 could contribute to the development of hypertension or vascular hypertrophy in SHR.

Antioxidant effects of calcium antagonists on rat myocardial membrane lipid peroxidation.

We studied the antioxidant effects of nine calcium antagonists (nisoldipine, benidipine, nilvadipine, felodipine, nicardipine, nitrendipine, nifedipine, verapamil, and diltiazem) by means of rat myocardial membrane lipid peroxidation with a nonenzymatic active oxygen-generating system (DHF/FeCl3-ADP). The order of antioxidant potency of these agents was nilvadipine > nisoldipine > felodipine > nicardipine > verapamil > benidipine. Their IC50 values (microM) were 25.1, 28.2, 42.0, 150.0, 266.1, and 420.0, respectively. In contrast, nitrendipine, nifedipine, and diltiazem had little inhibitory effect on lipid peroxidation. These six calcium antagonists could be divided into four types on the basis of their antioxidant mechanisms. Nilvadipine, nisoldipine, and verapamil, which showed antioxidant effects both before and after the addition of active oxygen, and reduced the dihydroxyfumarate (DHF) auto-oxidation rate, were chain-breaking and preventive antioxidants. Felodipine, which showed antioxidant effects both before and after exposure to active oxygen and increased the DHF auto-oxidation rate, was only a chain-breaking antioxidant. Nicardipine, which showed an antioxidant effect only before exposure to active oxygen and reduced the DHF auto-oxidation rate, was mainly a preventive antioxidant. Benidipine, which showed an antioxidant effect only before exposure to active oxygen and had no appreciable effect on the DHF auto-oxidation rate, could interrupt the chain reaction of lipid peroxidation at the initial step alone. Although these results suggest that the antioxidant properties of some calcium antagonists may be beneficial clinically in protecting against cellular damage caused by lipid peroxidation, further studies are required to establish the antioxidant effects of these agents in vivo.

Mechanism of endothelium-dependent vasorelaxation evoked by lysophosphatidylcholine.

Vasorelaxation induced by lysophosphatidylcholine (LPC) and platelet activating factor (PAF) was examined in rings isolated from rat aorta and mesenteric artery. LPC caused dose-dependent vasodilatation, which was sensitive to CV-6209, a PAF antagonist, and NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, but insensitive to indomethacin. PAF (10(-7)M) caused a tachyphylactic effect in mesenteric artery, but no tachyphylactic effect was demonstrated with LPC. Vasorelaxation patterns with LPC differed from those with PAF in the rat mesenteric artery. These results suggest that LPC-induced vasorelaxation may involve increased nitric oxide production mediated by the PAF receptor pathway, another receptor pathway possibly blocked by CV-6209, or PAF itself produced in endothelial cells in response to LPC.

Prolonged period of global ischemia causes no change in the GTP-binding proteins in the isolated perfused rat heart.

The response of the beta-adrenoceptor transduction system to global ischemia for 40 min was investigated in isolated working heart of rat. The enhancement of beta-adrenoceptors was not observed in the ischemic myocardium. A depression of forskolin-stimulated adenylate cyclase enzyme occurred with global ischemia, but no change in Gs or Gi2 was detected. Thus, the present in vitro ischemic heart model may not necessarily reflect the identical milieu induced by the in vivo myocardial ischemia.

Exertional rhabdomyolysis as a result of strenuous military training.

We reviewed biochemical data from 19 soldiers who marched intermittently over 4 weeks, carrying about 45 kg of kit, with a limited intake of food and water. The mean serum creatine kinase activity was higher after the march (p < 0.01), although the subjects did not develop symptomatic rhabdomyolysis. The mean serum potassium level (p < 0.005) and the mean serum sodium level (p < 0.05) were lower after the march. The level of serum osmolality showed no significant changes. Subclinical rhabdomyolysis was not rare among the soldiers. We also report a case of the soldier with exertional clinical rhabdomyolysis.

Transient pulsus alternans induced by isosorbide dinitrate: echocardiographic and hemodynamic evidence of reduced venous return--a case report.

Transient pulsus alternans was induced by isosorbide dinitrate (ISDN) in a patient with postmyocarditis congestive heart failure under diuretic therapy. The severity and duration of pulsus alternans depended on the dose of ISDN. According to the echocardiographic and hemodynamic examinations, the superimposed preload reduction caused by ISDN combined with decreased blood volume owing to diuretic therapy most likely contributed to the development of pulsus alternans.

Bronchial brushing cytology features of primary malignant fibrous histiocytoma of the lung. A case report.

BACKGROUND: Malignant fibrous histiocytoma (MFH) of the lung is rare. Early diagnosis is very important because of its poor prognosis. Long-term survivors of pulmonary MFH are patients who had surgical resection. When the patient can undergo surgery after a prompt diagnosis, the prognosis improves more than with other therapy. However, it is not easy to establish the diagnosis of thoracic MFH. In general, the small fragments from bronchial or percutaneous transthoracic fine needle aspiration (FNA) biopsies are inadequate for cytologic or pathologic analysis. Bronchial brushing cytology is greatly superior to FNA cytology because one can obtain a large amount of cells. Therefore, bronchial brushing cytology may play a useful role in diagnosis when endobronchial involvement is found. CASE: A 65-year-old female was admitted with a cough, yellow sputum and exertional dyspnea. A chest roentgenogram showed a 12 x 12-cm mass in the left lung field. Bronchial brushing cytology revealed many fibroblastlike, histiocytelike, bizarre and multinucleated giant cells in a background of necrosis. Atypical mitotic figures were also found. The cytologic findings strongly suggested MFH. Although the pathologic findings from FNA biopsy showed storiform clusters structured by pleomorphic, fibroblastlike cells with bizarre nuclei and mitotic figures, the material was too small to diagnose it definitively. Six months later the patient died. An autopsy confirmed the diagnosis of MFH: the typical storiform clusters were composed of many fibroblastlike and histiocytelike cells that were positive for CD68 (PGM1) antibody. CONCLUSION: Bronchial brushing cytology may be a useful method for early, definitive diagnosis of MFH. The presence of pleomorphic, spindle-shaped fibroblastlike and histiocytelike cells with the clusters showing a storiform pattern may permit the diagnosis of MFH.

[A case of rhabdomyolysis complicated with myocardial injury].

A 22-year-old man developed transient unconsciousness during running. He developed fever, nausea, vomiting, diarrhea and general fatigue. Next day, he was admitted to National Hospital Nayoro because of high serum CK level of 13,610U/l. Biochemical analyses revealed elevated serum myoglobin, increased CK-MM isozyme, aldolase and lactate dehydrogenase, increased serum osmolality, increased uric acid, and decreased serum potassium levels. Therefore, he was diagnosed as having rhabdomyolysis. In addition, serum CK-MB isozyme, cardiac myosin light chain I and troponin T were increased, suggesting the damage of cardiac muscle. Electrocardiogram showed elevated ST segment and inverted T on V2-4, which were not observed previously. He had no preceding infectious disease, drug ingestion or an underlying metabolic disorder. The rhabdomyolysis may be precipitated by the superimposition of dehydration and loss of potassium due to diarrhea and vomiting. The myocardial injury, probably produced by transient myocardial ischemia, should be paid attention in case of rhabdomyolysis.

[A case of Nothnagel syndrome].

A 72-year-old woman developed a sudden onset of bilateral ptosis, diplopia and gait disturbance. Neurological examination revealed bilateral oculomotor palsies, truncal ataxia, and transient slight weakness in the right upper extremity. She was diagnosed to have Nothnagel syndrome. T2-weighted MRI disclosed a high signal intensity lesion at the left paracentral portion of the upper midbrain in addition to the bilateral medial thalamic lesions, while brain CT showed only the thalamic lesions. Brain MRI was useful for detecting the small midbrain lesion.

[A case of pulmonary tuberculosis complicated with multiple bone and joint tuberculosis].

A 29-year-old male complaining of fever and general fatigue was admitted to our hospital. On admission chest X-ray showed infiltrative shadows with cavities in the bilateral lung apical areas, and sputum examination for acid fast bacilli was smear positive, Gaffky 1. He was treated as pulmonary tuberculosis (TB), and chest X-ray findings and sputum examination improved after a few months of treatment with antituberculous chemotherapy (INH, RFP, EB, PZA). However, tuberculous cold abscess appeared in retropharyngeal area, subcutaneous tissue of thoracic cage and retroperitoneal space, and shortly later, bone and joint TB were recognized in shoulder and wrist joints and vertebrae. The findings of vertebral foci were not recognized by a simple X-ray picture of vertebrae. at that time, but MRI of vertebrae showed low intensity areas with ring enhancement in the cervical, thoracic and lumbar vertebrae. Despite treatment with antituberculous agents, new bone and joint TB had developed in many tissues and had accompanied with cold abscess in adjacent tissue, whereas pulmonary TB had improved after the initial transient worsening. The appearance of bone and joint TB was most probably caused by the initial transient worsening of hidden bone and joint TB as a part of the initial systemic transient worsening of tuberculosis. After treatment for 4 months, pulmonary TB as well as bone and joints TB had improved. Tuberculous cold abscess in retropharyngeal may be secondary to cervical vertebral TB but is now rarely seen. In this case, involvement in many tissues such as retropharyngeal area, subcutaneous tissue of thoracic cage and retroperitoneal space were seen, and these findings are now uncommon and usually represents involvement secondary to contiguous infection.

[Pulmonary infection caused by Mycobacterium gordonae in immunocompetent patient].

We report a case of 67-year-old female immunocompetent patient admitted to our hospital because of hemoptysis. Computed tomography (CT) of the lung showed bronchiectasis in the right S5 and small nodules in the right S6 and left S5. The cultures of sputum and bronchial washing specimen repeatedly revealed acid-fast bacilli identified as Mycobacterium gordonae (M. gordonae) by DNA-DNA hybridization (DDH) method. Thus, she was diagnosed to be infected with M. gordonae. She was treated with isoniazid, rifampicin, ethambutol and streptomycin. After treatment, the cultures of sputum and bronchial washing specimen converted to negative, and the chest CT showed improvement of small nodules. M. gordonae is a nontuberculous mycobacterium of very low pathogenic potency. Recently there have been a few reports of infection by M. gordonae not only in immunocompromised patients but also in immunocompetent patients. These cases were considered to be sensitive to initial standard antimycobacterial therapy, therefore, it is important to examine for M. gordonae in cases suspected of nontuberculous mycobacterial infection.

[Technetium-99m-pyrophosphate myocardial scintigraphy in polymyositis--a case report].

A patient with polymyositis who had cardiac involvement underwent myocardial scan with technetium-99m-pyrophosphate. We used Activity Index for evaluating myocardial uptake of technetium-99m-pyrophosphate, which correlated with the degree of serum creatine phosphokinase elevation. Our findings indicate that these examinations may be helpful for identifying patients who have cardiac involvement and evaluating their response to the treatment with corticosteroids or immunosuppressants.

[A case of malignant lymphoma showing a stratum of lymphoma cells].

A 74-year man suffered an artificial pneumothorax of the right lung because of pulmonary tuberculosis 41 years before. He was admitted, and enlargement of chronic pyothorax was noted in chest radiography in 1998. A 67Ga scintigram revealed uptake at the site of the chronic pyothorax. Cytological findings of the pleural effusion included many atypical lymphocytes. We suspected the presence of a malignant lymphoma and performed a biopsy under thoracoscopy, but could not arrive at a diagnosis. Therefore, resection of the chronic empyema was performed. Histological examination demonstrated the layer of lymphoma cells covering the wall of empyema between the layers of necrotic and connective tissue. Lymphoma cells were stained with L 26, which is known as a B cell marker. We diagnosed diffuse large cell lymphoma (B cell type). No case like this case has ever been published of malignant lymphoma bearing a layer of lymphoma cells. This case is thought to show early-phase malignant lymphoma complicated with chronic pyothorax after artificial pneumothorax. Malignant lymphoma should be suspected when chronic pyothorax undergoes enlargement, even if CT scanning or MRI does not show typical findings.

[Three cases of Mycobacterium avium lung disease in an iron foundry].

We report three cases of M. avium lung disease, all occurring in the same iron foundry over a 5-year period. Case 1: A 38-year-old man was admitted to our hospital because of abnormal chest x-ray shadows observed during a routine checkup. M. avium complex was isolated from the sputum and a CT scan showed multiple nodular shadows with cavities. Case 2: A 63-year-old man presented with dyspnea. Chest CT showed nodular shadows in both upper lobes. M. avium complex was isolated from his sputum. Case 3: A 62-year-old man was hospitalized for treatment of diabetes mellitus. A nodular cavitary shadow* OK?* in the right upper lobe was observed in the radiograph. CT scanning demonstrated a nodular shadow with thick pleural indentation. M. avium was isolated from the sputum and gastric juices. There were similarities in the radiographic findings in all cases: nodular shadows with cavities in the upper lung fields. These findings differed from those in another M. avium infection in the lung which occurred in a middle-aged woman. We suspected inhalation of an aerosol contaminated by M. avium complex. There have hitherto been no reports of group infections in healthy persons. We suspected the same environmental source for the infection.

[Results of surgery in Mycobacterium avium complex pulmonary disease].

Recently, several studies have revealed the usefulness of surgical therapy for nontuberculous mycobacterial (NTM) disease. We have encountered and taken many opportunities for surgical therapy in Mycobacterium avium complex (MAC) disease. From April 1995 through March 1999, 14 patients with MAC disease underwent 16 pulmonary resections. NTM was diagnosed at our hospital in all subjects according to the criteria of the American Thoracic Society. There were 8 women and 6 men, with a mean age of 54 years. The most common indications for surgery were localized lesion (7 cases), severe symptoms (5 cases) and progressive disease (2 cases). Twelve patients were receiving multidrug chemotherapy, 10 of whom were also receiving clarithromycin. The mean period of preoperative chemotherapy was 17 months. Ten patients had a variety of symptoms, with some combination of cough, sputum, hemosputum, dyspnea, fever and anorexia. About 30% of the symptoms were improved after preoperative chemotherapy. The symptoms disappeared in all except one patient, who underwent pneumonectomy. After surgery, all patients attained a sputum-negative status. Nine patients underwent 11 partial resections, comprising 3 thoracotomies and 8 video-assisted thoracic surgeries (VATS). There was no operative mortality. Re-operation was performed in a patient with bronchopleural fistula after initial surgery. Currently, 2 months after the last operation, we have encountered no other severe complication and no relapse. Surgery may play an important role in treatment of MAC disease. We recommend partial resection with VATS for localized MAC disease.

[Two cases of acute eosinophilic pneumonia--analyses of cytokines in BALF before and after treatment].

Acute eosinophilic pneumonia (AEP) has been well recognized as sudden onset respiratory failure characterized by an increased eosinophilic cell count in the bronchoalveolar lavage fluid (BALF). Although several lines of research have demonstrated that the Th2 cytokine network is likely to play a pivotal role in the development of AEP, that mechanism has not been clearly understood yet. Previous reports published in Japan demonstrated that the BALF CD4/CD8 ratio in patients with AEP ranged between 1.1 and 5.8. In this report, we describe 2 cases of AEP in which the CD4/CD8 ratios were 0.3 and 7.8 when present. We measured IL-4, IL-5, IL-10 and IFN gamma in the BALF before and after treatment in these patients. IL-5 decreased drastically after the treatment phase, while the other cytokines did not change much. We concluded that the IL-5 concentration in the BALF is probably related to the development of AEP. In addition, we also speculated that the CD4/CD8 ratio in BALF from patients with AEP may be affected whether a patient has an atopic background or not.

[Changes in atrial natriuretic peptide and pulmonary hemodynamics induced by exercise in patients with chronic pulmonary emphysema].

We studied the changes in pulmonary hemodynamics induced by arm-stretching exercise in 12 patients with chronic pulmonary emphysema (CPE) and 9 control subjects (Controls). Both patients and control subjects underwent right heart catheterization with inspired gas analysis at rest and during exercise for the 6 minute-exercise test. Mean pulmonary arterial pressure (mPAP) in patients with CPE significantly increased from 18.5 +/- 3.9 mmHg at rest to 25.7 +/- 5.1 mmHg during exercise without decreased oxygen tension of the arterial blood. Both mPAP and total pulmonary resistance increased in proportion to the increases in cardiac output. Mixed venous plasma atrial natriuretic peptide (ANP) was significantly evaluated during exercise in patients with CPE, but did not in Controls. There were a significantly positive relationships between ANP and mPAP, and a significantly negative relationships between ANP and PvO2 during exercise. These results suggest that pulmonary hypertension during light exercise in cases of CPE may be caused by deterioration of the pulmonary capillary bed, and that ANP may be a useful indicator for evaluating pulmonary hypertension in patients with CPE.