[Clinical characteristics of near-fatal asthma attack induced by NSAIDs].

Despite advance in the treatment of asthma, asthma-related deaths have not declined. One of the reasons in those cases may be that there is a surprising lack of information on death from asthma since most of asthma deaths take place outside the hospital. Learning about near-fatal asthma attack (NFA) patients is useful to understand the mechanisms of asthma deaths because NFA patients and fatal asthma possess common clinical characteristics. It is well-known that there are two types of severe asthma exacerbation, that is, "sudden onset" and "slow onset attaches", in terms of clinical, functional and blood gas parameters. On the other hand, NSAIDs is one of the factors leading to exacerbation of asthma or asthma-related death. We examined the characteristics of NSAIDs-induced asthma and the pattern of respiratory arrest in the NSAIDs-induced NFA group compared to non-NSAIDs group at a Kyoto National Hospital from 1986 to 1997. A Total of 30 patients (34 cases) with NSAIDs-induced asthma among 265 admissions with asthma attack were reviewed involving 15 women and 15 men, mean age 46 +/- 14 years old. Six patients (8 cases) of NSAIDs group and 13 patients of non-NSAIDs group had intubation for their NFA. NSAIDs group showed more severe respiratory insufficiency with higher arterial CO2 level compared to non-NSAIDs group (91.5 +/- 16.3 vs 76.3 +/- 17.0 Torr) and significant lower pH level (7.02 +/- 0.14 vs 7.18 +/- 0.07, p < 0.05). But, NSAIDs group showed significantly more short weaning time than that of non-NSAIDs group (p < 0.01). We suggest that many sporadic cases of rapid onset severe asthma attacks may result from the ingestion of NSAIDs.

Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression.

This investigation studied the general conditions and prognostic factors of pulmonary epithelioid haemangioendothelioma (PEH), which is a rare disease. Twenty-one patients were collected throughout Asia by a questionnaire. Age at the detection or onset of symptoms of PEH was 14-64 yrs (mean 44 yrs). Males were more likely to be detected by symptoms (4/8, 50%) than were females (1/13, 8%). Fifteen showed bilateral multiple nodular opacities. Partial spontaneous regression occurred in three asymptomatic patients (one male and two females, all with bilateral multiple nodular opacities) 5, 13 and 15 yrs after detection. Two of the three patients with pleural effusion died within 1 yr, while the 16 patients with no effusion were alive more than 1 yr later (p<0.05). Histologically, two patients with fibrinofibrous pleuritis and extrapleural proliferation of tumour cells died within 2 yrs, while only one of 14 patients lacking such manifestations died within the same period (p<0.05). All three patients without spindle tumour cells survived for 12 yrs after the diagnosis, while all four patients with such cells died during the same period (p<0.05). In conclusion, 21 patients with pulmonary epithelioid haemangioendothelioma were reported, of whom three demonstrated partial spontaneous regression, and adverse prognostic features were identified.

Cisplatin plus oral etoposide in the treatment of patients with advanced small cell lung cancer. Japan Clinical Oncology Group.

BACKGROUND: Etoposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC). METHODS: Fifty-seven patients with SCLC with extensive disease (ED) or limited disease (LD) with pleural effusion registered in the 21 institutions of the Japan Clinical Oncology Group were treated with oral etoposide 40 mg/m2/d for 21 days and cisplatin 80 mg/m2 on day 1 of every 28-period day. The entry period was between February 1992 and August 1995. The actual percentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively. RESULTS: Nine patients (15.8%) achieved a complete response resulting in an overall response rate of 82.5% (95% confidence interval, 70.1-91.3%). Leukopenia and thrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1%) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia. The mean survival time was 47.0 weeks. CONCLUSIONS: This dose and schedule of administration of etoposide in combination with cisplatin are considered to be clinically active. However, prolonged gastrointestinal toxicity of oral etoposide was a problem in comparison with the standard etoposide platinum regimen given by intravenous administration.

[Comparative study of sustained-release in theophylline (Slobid, Theolong, Theodur) by pharmacokinetics].

We made a comparative study of three kinds of sustained-release of theophylline compounds by means of analysis of plasma concentrations. The drugs were Slobid (SB) (Up-john) 11 patients (10 men, 1 women), Theolong (TL) (Eisai) 22 (10 men, 12 women), Theodur (TD) (Nikken chemicals) 34 (18 men, 16 women), who were hospitalized from January 1989 to November 1994. Theses patients were given oral theophylline, bid at 9:00 and 21:00, plasma concentration of theophylline was determined at 9:00, 12:00, 15:00, 18:00 and 21:00, after plasma concentration reached a plateau. There were no significant differences as to the zero absorption rate, clearance, the moment absorption rate, but there were significant differences to Cmax-Cmin of SB (3.34 micrograms) < TL (4.22) < TD (5.22) (P = 0.0150), the zero half life time (T1/2) of SB (18.9 hr) > TL (13.5) > TD (10.1) (P = 0.0061), the apparent distribution volume (V) of SB (0.811/ kg) > TL (0.78) > TD (0.55) (P = 0.0309), mean residence time (MRT) of SB (21.3 hr) > TL (16.7) > TD (15.2) (P = 0.0034), the moment half life time (Tm1/2) of SB (13.7 hr) > TL (10.6) > TD (9.55) (P = 0.009), by measurements analysis of variance. These results suggest that these sustained-release drugs have different pharmacokinetics judging from the important indices including Cmax-Cmin, T1/2, V, MRT and Tm1/2, and that the best one is the SB, the second is the TL, and the third is the TD for RTC therapy.

Intracranial tuberculosis: report of two unusual cases.

Neurotuberculosis is uncommon in the industrialized countries of the world. Consequently, when such cases occur, they are overlooked and not treated adequately. Two cases of interest are described to remind clinicians of the entity of central nervous system tuberculosis.

[Pulmonary eosinophilic granuloma--clinical analysis of 17 patients].

We studied the clinical features of 17 Japanese patients with pulmonary eosinophilic granuloma. Fourteen of the patients were men and three were women; they ranged in age from 19 to 64 years, with a mean of 34 years at the time of the first examination. Pathologic diagnosis in all patients was based on histologic findings of specimens obtained by open lung biopsy. Major symptoms were dry or productive cough, chest pain, dyspnea, and fever; 23.3% of the patients were asymptomatic. Five patients had pneumothorax. Most patients did not have abnormal physical signs. All 17 patients had histories of smoking, and 14 had started to smoke cigaretts before the age of 20 years. Ten patients (58.8%) first presented with cough or dyspnea, and in the other patients (41.2%) the first abnormalities detected were pulmonary infiltrates on chest radiographs during health examinations. Chest roentgenograms usually showed bilateral abnormalities. These abnormalities were distributed over all lung fields in 9 cases (52.9%), in the upper and middle lung fields in 4 cases (23.5%) in the upper lung fields in 3 cases (17.7%), and in the middle lung fields in 1 case (5.9%). Micronodular, reticular, cystic or linear shadows were evident in most cases, and were mixed in various proportions. Eleven patients (65%) had abnormalities of pulmonary function. Low %VC and %FEV1 and high RV/TLC ratios were observed in 20-40% of the patients. Low DLCOs (%DLCO < 70%) were observed in 53% of the patients. Arterial blood gases were normal in 11 of 15 patients. The extent of shadows in the chest roentgenogram was related to the frequency of dyspnea, to the total number of cells in bronchoalveolar lavage fluid, and to the abnormally low %FVC and %FEV1, but not to the %DLCO. Data from bronchoalveolor lavage fluid were non-specific in this disease, but further studies will be needed. Follow-up data were collected on 16 patients. The mean time from the histologic diagnosis after open lung biopsy to the last observation was 81.8 +/- 45.1 months (range, 2 months to 15 years). One patient died of pulmonary eosinophilic granuloma. The usefulness of steroid therapy remains uncertain.

[Primary pulmonary alveolar proteinosis--clinical observation of 68 patients in Japan].

The clinical features of 68 Japanese patients (53 men and 15 women; mean age 44 years) with primary pulmonary alveolar proteinosis were reviewed. Pulmonary alveolar proteinosis was diagnosed from histologic findings after open lung biopsy (n = 7) or transbronchial lung biopsy (n = 61). Major symptoms were a dry cough (24.2%) and dyspnea or shortness of breath on exertion (51.5%), but one third of the patients were asymptomatic. Crackles were audible in 30% of the patients, but clubbing (6%) and cyanosis (4%) were rare. Ten patients had been occupationally exposed to dust. Slightly less than half (46%) of the patients first presented with symptoms, and the remainder (54%) first presented with abnormal pulmonary infiltrates seen on chest roentgenograms taken during general health examinations. Many patients had abnormally high levels of LDH and CEA in serum (62% and 63%, respectively). Restrictive pulmonary dysfunction (%VC < 80%) was seen in 31% of the patients, an abnormally low DLco (%DLco < 70%) was seen in 62%,m and hypoxemia (PaO2 < 80 mmHg) was seen in 67%. Arterial blood gas tension was closely correlated with the severity of disease in these patients. Chest roentgenograms usually showed bilateral symmetric alveolar infiltrates, mainly distributed from hilar areas toward the pleura, but on CT scans many of the shadows were mixed with alveolar and interstitial infiltrates of various extent along the pulmonary arteries and bronchi. There was no apparent relation between chest roentgenographic findings and chest CT findings in these patients. Neither the extension nor other characteristics of shadows in the chest roentgenograms and chest CT scans were closely related to symptoms, laboratory data, or pulmonary function in these patients. Symptoms were alleviated and chest roentgenographic findings improved in 82% of the 51 patients who underwent therapeutic bronchoalveolar lavage, and in 94% of the 17 patients who did not undergo that procedure. In patients who underwent therapeutic bronchoalveolar lavage and also in those who recovered spontaneously, both diffusing capacity and blood gas values improved significantly. When compared to the patients who did not undergo therapeutic bronchoalveolar lavage, significantly more of those who did undergo that procedure has initial PaO2 values below 60 mmHg, and fewer of them had values greater than 80 mmHg. Thus, a PaO2 below 60 mmHg may be an indication for therapeutic bronchoalveolar lavage in patients with this disease. During the follow-up period (mean 5 years, range 2 months to 23 years), four patients had pneumothorax and none died of pulmonary alveolar proteinosis.

[A randomized comparative study of 254-S plus vindesine (VDS) vs. cisplatin (CDDP) plus VDS in patients with advanced non-small cell lung cancer (NSCLC)].

It has been shown in phase II studies that 254-S, a new anticancer platinum complex, is effective in the treatment of various cancers. In order to more objectively evaluate the clinical usefulness of this compound, a randomized comparative study of 254-S plus VDS vs. CDDP plus VDS was conducted in patients with advanced NSCLC. 254-S or CDDP was intravenously administered at 90 mg/m2, at least 2 times at 4-week intervals. VDS was intravenously administered at 3 mg/m2 on Days 1 and 8 of each treatment of 254-S or CDDP. Of 136 patients registered, 121 (64 of the 254-S/VDS group and 57 of the CDDP/VDS group) were evaluable for tumor response (complete cases). There was no significant intergroup difference in the tumor response rate (254-S/VDS group: 12.5% [8/64], CDDP/VDS group: 15.8% [9/57]), nor by cancer staging, histological type or survival. As for toxic effects, leukopenia was significantly less frequent in the 254-S/VDS group while thrombocytopenia was significantly less frequent in the CDDP/VDS group. Nephrotoxicity such as an elevation of BUN and a decrease in serum creatinine was significantly less frequent in the 254-S/VDS group in spite of the lower volume hydration performed. In addition, nausea and vomiting as well as anorexia were observed with significantly lower incidences in the 254-S/VDS group despite the less frequent anti-emetic treatment. Based on these results, it was concluded that combination treatment with 254-S and VDS is a safe and useful regimen for treatment of NSCLC, generating antitumor effects equivalent to the CDDP/VDS regimen.

[The efficacy and side effects of chemotherapy for primary lung cancer with cisplatin and etoposide].

We treated 34 primary lung cancer patients with chemotherapy of cisplatin and etoposide. There were 2 cases of CR (15%) and 8 cases of PR (61%) out of 13 cases of small cell lung cancer. No case of CR and one case of PR (5%) were obtained out of 21 cases of non-small cell cancer. Side effects were leukopenia, increase of BUN and creatinine, angina pectoris, supraventricular premature contraction, and renal failure. WBC reached nadir on day 15 on average. When we repeated this regimen, we encountered 3 cases of acute myocardial infarction, and it was useful for small cell lung cancer.

[Acute myocardial infarction induced by lung cancer chemotherapy with cisplatin and etoposide].

From June of 1986 to May of 1989, we encountered 78 cases of lung cancer and administered CDDP and etoposide, orally and intravenously. We found 3 cases of acute myocardial infarction (AMI) onset after this chemotherapy regimen. It is important to detect AMI onset as soon as possible. We must take prophylactic procedures for patients with coronary risk factors who have had radiation therapy previously.

Centrilobular lesions of the lung: demonstration by high-resolution CT and pathologic correlation.

To determine the value of high-resolution computed tomography (HRCT) in the diagnosis of diffuse pulmonary diseases, a direct HRCT-pathologic correlative study was performed using four inflated and fixed lungs from autopsy. In normal lungs, the smallest pulmonary artery resolved by HRCT was 200 microns in diameter; the artery was accompanied by the terminal bronchiole and the first-order respiratory bronchiole. The distance from the vessel to the corresponding lobular border ranged from 3 to 5 mm. These results suggest that the centrilobular area or the area around the terminal or respiratory bronchioles can be recognized with HRCT. In addition, the authors confirmed that centrilobular emphysema and centrilobular tuberculous nodules can be diagnosed with HRCT. Thus, HRCT can demonstrate the location of pathologic changes within a lobule and may be helpful in the differential diagnosis of diffuse pulmonary diseases.

Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation.

An animal model [the nonobese diabetic (NOD) mouse] for type I diabetes features a striking infiltration of T cells into the pancreatic islets. This infiltration selectively destroys beta cells. Most of the T cells are Lyt-1+, but some are Lyt-2+,3+. Transfer experiments using parabiosis revealed that insulitis can be transferred within 2 weeks after parabiosis to immunoincompetent thymectomized mice. When NOD mice (6 mo old) were irradiated and reconstituted with bone marrow cells from young BALB/c nu/nu mice (less than 2 mo old), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in mesangial areas of the glomeruli disappeared within 3 mo after bone marrow transplantation in such irradiated allogeneic bone marrow reconstituted mice. Assays for immunological functions, including mitogen response and mixed lymphocyte reaction, revealed that both T- and B-cell functions were increased in NOD mice with overt diabetes. NOD mice reconstituted with BALB/c nu/nu bone marrow cells displayed normal T- and B-cell functions. The newly developed T cells in the allogeneic bone marrow recipients are tolerant to cells with both donor- and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation may ultimately be developed as a component of a strategy to be employed for treatment of type I diabetes in humans.

[CDDP-containing combination chemotherapy for advanced lung cancer].

The effect and toxicities of Cis-containing combination chemotherapy were tested in 28 patients with primary lung cancer. All patients were treated with 80 mg/m2 Cisplatinum on the first day and 750 mg ftorafur p.o. every day. In addition to these drugs, patients with squamous cell cancer were treated with continuous subcutaneous infusion of 4 mg/m2 Peplomycin for 5 days and one shot i.v. of 4 mg MMC. Patients with adeno- and large cell cancer were treated with 30 mg/m2 Adriamycin and 4 mg MMC, while patients with small cell cancer were given 150 mg/m2 VP-16 p.o. for 5 days. The following results were obtained. Of 22 evaluable patients, overall response rate was 50%. In each histologic type, response rate was 50% (5/10) for squamous cell carcinoma 50% (4/8) for adenocarcinoma 33% (1/3) for large cell carcinoma and 100% (1/1) for small cell carcinoma. No CR was obtained in this series. Main side effects due to Cisplatinum were nausea, vomiting, loss of appetite, mild leukopenia and thrombocytopenia, mild elevation of serum creatinine and BUN and alopecia, all of which were transient. Interstitial pneumonitis was observed in 40% of patients with squamous cell cancer. Two patients with adenocarcinoma died within 3 weeks after treatment due to embolism of the abdominal aorta and myocardial infarction probably caused by treatment with Adriamycin.