Pleural effusion adenosine deaminase (ADA) level and occult tuberculous pleurisy.

BACKGROUND: We investigated the incidence of tuberculous pleurisy among patients with adenosine deaminase (ADA) levels of 50 IU/L or less in a pleural effusion, and without a previous diagnosis of carcinomatous pleurisy or Mycobacterium tuberculosis. SUBJECTS AND METHODS: Subjects were selected from patients who had undergone pleural biopsy by thoracoscopy at National Hospital Organization Tokyo Hospital from January 1995 to November 2004, and who had ADA levels of less than 50 IU/L in pleural fluid obtained preoperatively by thoracentesis. In all subjects, smear, culture, and polymerase chain reaction for Mycobacterium tuberculosis were negative. RESULTS: Of 138 patients who underwent thoracoscopic pleural biopsy, a total of 50 had effusions with ADA levels of less than 50 IU/L. Six (12%) of these patients were diagnosed with tuberculous pleurisy after biopsy. Three patients with an effusion ADA level of 35 IU/L or less were diagnosed with tuberculous pleurisy. CONCLUSIONS: Occult tuberculous pleurisy is significantly common in patients with pleural effusion ADA levels of 50 IU/L or less and who may otherwise be diagnosed with nonspecific pleurisy.

Phase I/II study of docetaxel and S-1 in patients with previously treated non-small cell lung cancer.

INTRODUCTION: The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. METHODS: In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. RESULTS: The recommended dose of docetaxel was 40 mg/m in combination with S-1 80 mg/m/d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. CONCLUSIONS: This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

Lung cancer in patients with chronic pyothorax.

BACKGROUND AND OBJECTIVE: The aim of this study was to describe the features of lung cancers associated with chronic tuberculous pyothorax. METHODS: Clinicopathological data from patients with coexisting lung cancer and chronic latent pyothorax caused by tuberculosis (TB) were analysed, and cancer tissue samples were investigated for the presence of Epstein-Barr virus. RESULTS: Twelve patients were identified, and all had a history of tuberculous pleuritis or surgical intervention for TB. The interval between the onset of TB and lung cancer was more than 30 years in nine patients and the most frequent symptom was chest pain (six patients). All cancers were in the ipsilateral lung to the pyothorax, and in nine of the 12 patients the cancers were located adjacent to the pyothorax. In situ hybridization analysis for Epstein-Barr virus-encoded small RNA failed to show positive signals in any of the six cancer tissues examined. CONCLUSIONS: Lung cancer associated with chronic pyothorax always developed in the ipsilateral lung to the pyothorax, and there was no evidence for the presence of Epstein-Barr virus in the cancer tissues examined.

Thoracoscopic pleural biopsy for tuberculous pleurisy under local anesthesia.

OBJECTIVE: We directly examined the thoracic cavity by thoracoscopy under local anesthesia, performed pleural biopsy, and made a definitive pathological diagnosis in tuberculous pleurisy. SUBJECTS AND METHODS: We performed a retrospective study of 32 patients who had been bacteriologically and pathologically diagnosed with tuberculous pleurisy by thoracoscopy under local anesthesia in our hospital between January 1995 and November 2004. RESULTS: Bacteriological examination of pleural fluids obtained by thoracentesis before examination showed that one sample was polymerase chain reaction (PCR)-positive, and 5 samples were culture-positive. Bacteriological examination of pleural fluids obtained by thoracoscopy revealed that 2 samples were PCR-positive, and 5 samples culture-positive, including 2 preoperatively positive samples. The adenosine deaminase (ADA) levels ranged from 18.3 to 279.0 U/L, with a mean of 72.9 U/L, including 50 U/L or less in 5 patients and 35 U/L or less in 3 patients. Thirty patients (93.8%) were successfully diagnosed by pleural biopsy with pathological examination, and 21 (65.6%) of them by pathological examination alone. CONCLUSION: In patients with suspected tuberculous pleurisy, thoracoscopic pleural biopsy under local anesthesia should be actively performed, because the technique has a high diagnostic rate, and can be easily and safely performed.

Diagnostic value of thoracoscopic pleural biopsy for pleurisy under local anaesthesia.

BACKGROUND: We find pleural effusion in clinical practice frequently. However, it is difficult to make a diagnosis definitively by thoracocentesis or closed pleural biopsy. We directly examine the thoracic cavity by thoracoscopy under local anaesthesia, carry out pleural biopsy and make a definitive pathological diagnosis in pleurisy. METHOD: A retrospective study of 138 patients who had been diagnosed by thoracoscopy in our hospital was carried out between January 1995 and January 2005. RESULTS: The patients were 114 men and 24 women, ranging in age from 21 to 85 years, with a mean of 59 years. The right side was involved in 83 patients and the left side in 55. The operations took 11-145 min, with a mean of 46 min. Thoracoscopy directly without thoracocenteses was carried out in 28 of 138 patients. Lung cancer with pleural dissemination was diagnosed in 27, malignant pleural mesothelioma in 10, tuberculous pleurisy in 32, non-specific pleurisy in 58, other tumour in 2 and pyothorax in 9 patients. The overall diagnostic efficacy was 97.1% (134/138). The diagnostic efficacy in the cases of carcinoma was 92.6% (25/27), in malignant pleural mesothelioma it was 100% (10/10) and in tuberculosis it was 93.8% (30/32). No major complications occurred during the examination. CONCLUSION: Pleural biopsy by thoracoscopy under local anaesthesia should be actively carried out in patients with pleurisy, because the technique has a high diagnostic rate and can be easily and safely carried out.

Coexistent lung carcinoma and active pulmonary tuberculosis in the same lobe.

We observed a rare case of lung carcinoma accompanied by active pulmonary tuberculosis in the same lobe. The chest x-ray of a 49-year-old man revealed an abnormal shadow in the right upper field and a giant bulla in the left upper field. Chest computed tomography (CT) revealed a nodule with consolidation, which was not continuous in the right S3. Bronchoscopically, epidermoid carcinoma existed in the proximal right upper bronchus. In the sputum specimens, the smear was negative, but the polymerase chain reaction of Mycobacterium tuberculosis and culture was positive. Anti-tuberculosis treatments were administered for approximately 4 weeks, but the chest x-ray remained unchanged. Right upper lobectomy with bronchoplasty (wedge resection of the right upper bronchus) was performed, and the anastomosis was covered with an intercostal muscle flap. Lymphadenectomy of the right hilum and mediastum was also performed. Microscopy revealed epidermoid carcinoma in the proximal tumor (pT3N0M0-stage IIB) and epithelioid granuloma with caseous necrosis, granulomatous pneumonia, exudative lesions, and fibrocaseous nodules in the distal lung. After surgery, anti-tuberculosis treatment was resumed.

Second primary cancers in patients with stage III non-small cell lung cancer successfully treated with chemo-radiotherapy.

BACKGROUND: Patients successfully treated for non-small cell lung cancer (NSCLC) remain at risk for developing second primary cancer (SPC). The purpose of the current study is to assess the incidence of SPC and the impact of smoking status on the SPC in long-term survivors with stage III NSCLC after chemo-radiotherapy. METHODS: Using the database from the Japan National Hospital Lung Cancer Study Group between 1985 and 1995, information was obtained on 62 patients who were more than 3 years disease-free survivors. Details of clinical information and most smoking history were available from the questionnaire. RESULTS: Nine of the 62 patients developed SPC 3.9-12.2 years (median, 6.2 years) after the initiation of the treatment. The site of SPC was 2 lung, 1 esophagus, 2 stomach, 1 colon, 1 breast, 1 skin and 1 leukemia. Among these nine, three cancers occurred inside the radiation field. The relative risk of any SPC was 2.8 [95% confidence interval (CI) 1.3-5.3]. The risk changed with the passage of time and it increased significantly (5.2 times at or beyond 7 years) after the treatment. In univariate analysis, the patients who were male, had more cumulative smoking and continued smoking, had an increased risk of SPC [relative risk (RR) 2.7, CI 1.1-5.3; RR 3.0, CI 1.2-6.2; RR 5.2, CI 1.6-11.7, respectively]. In multivariate analysis, factors including smoking status and histological type had no effect on the development of a SPC. CONCLUSION: The patients with stage III NSCLC successfully treated with chemo-radiotherapy were at risk for developing SPC and this risk increased with time.

[Coexistence of lung cancer and active pulmonary mycobacteriosis].

OBJECTIVES: The aim of this study is to clarify the clinical and pathological anatomical picture of cases in which lung cancer and active pulmonary mycobacteriosis are intermingled in the same lobe of the lung. MATERIALS AND METHODS: We analyzed clinicopathological data on 11 cases in which lung cancer and active pulmonary mycobacteriosis are intermingled in the same lung lobe out of 61 admitted cases of coexisting lung cancer and active pulmonary mycobacteriosis, encountered at National Hospital Organization Tokyo National Hospital during the period from 1991 to 2003. RESULTS: The subjects were 10 men and 1 woman, with a mean age of 68 years. The species of mycobacteriosis were M. tuberculosis in 6 and nontuberculous mycobacteriosis in 5 (M. avium disease and M. abscessus disease in 2 each, and M. kansasii disease in 1). The frequency of the mixture was 13% (6/45) in patients with lung cancer and tuberculosis and was 31% (5/16) in patients with lung cancer and nontuberculous mycobacteriosis. Radiographic findings revealed that both cancer shadows and mycobacteriosis shadows are identified in 8 of the 11 patients, whereas cancer shadows were recognized but mycobacteriosis shadows could not be pointed out in the remaining 3 patients. We divided 7 cases (5 resection scases and 2 autopsy cases) with the mixture of cancer and mycobacteriosis into 2 types from the macroscopic images: (1) type A (4 cases, the foci of lung cancer and tuberculosis, which were separated originally, progressed mutually, and has adjoined), and (2) type B (2 cases, the foci of mycobacteriosis existed within or in the edge of the foci of lung cancer). There were 3 nontuberculous mycobacteriosis cases and 1 tuberculosis case in type A, and 2 tuberculosis cases and 1 nontuberculous mycobacteriosis in type B. In nontuberculous mycobacteriosis cases, cancer and mycobacteriosis had often adjoined under the conditions of preexisting lung disease, such as a lung cyst, whereas in tuberculosis cases, it was characteristically shown that the wall of encapsulated caseous nodules was destroyed by cancer invasion, and that the tuberculous nodules were reactivated. These findings seemed to be related to exogenous infection of nontuberculous mycobacteriosis to the injured lungs and to endogenous reactivation of tuberculosis from inactive tuberculous lesions. CONCLUSION: Lung cancer and active pulmonary mycobacteriosis are often seen intermingled in the same lung lobe, and the mixture pictures of the two diseases are variable. The physicians should carefully note about the mixture of lung cancer and mycobacteriosis, though the findings are not clear on the chest plain radiographs.

[A case of malignant mesothelioma showing rapid progression during one month].

A 57-year-old man with massive right pleural effusion was admitted to our hospital. Thoracoscopy revealed, fine granulations and small nodules scattered on the parietal pleura. Biopsy specimens suggested malignant mesothelioma. We performed thoracoscopy again one month later under general anesthesia to make a definitive diagnosis. At that time, the parietal pleura was covered with a large tumor and malignant mesothelioma was diagnosed by biopsy. We could find early pleural lesions of malignant mesothelioma in thoracoscopy. While we managed to make a definitive diagnosis, the tumor progressed rapidly during one month. If malignant pleural mesothelioma is suspected, it is necessary to make all efforts, including surgical biopsy, to diagnose during the early stage of disease.

Smoking history before surgery and prognosis in patients with stage IA non-small-cell lung cancer--a multicenter study.

The prognosis of lung cancer patients with surgically resected non-small-cell lung cancer (NSCLC) can be predicted generally from age, sex, histologic type, stage at diagnosis, and additional treatment. Nine studies have reported that a history of smoking before diagnosis influences the prognosis of the disease in lung cancer patients. In this study, a total of 3082 patients who underwent surgery and were diagnosed with primary pathological stage IA NSCLC at 36 national hospitals from 1982 to 1997 were analyzed for the effect of smoking on survival. Smoking history and other factors influencing either the overall survival or the disease-specific survival rates of patients were estimated with the Cox proportional hazards model. Multivariate analysis demonstrated significant associations between overall survival and age (P < 0.0001), sex (P = 0.0002), and performance status (PS) (P < 0.0001). Disease-specific survival was associated with age (P = 0.0063), sex (0.00161), and PS (P = 0.0029). In males, disease-specific survival was associated with age (P = 0.0120), PS (P = 0.0022), and pack-years (number of cigarette packs per day, and years of smoking) (P = 0.0463). These results indicate that smoking history (pack-years) is important clinical prognostic factor in estimating disease-specific survival, in male patients with stage IA primary NSCLC that has been surgically resected.

Cytological characteristics of pulmonary large cell neuroendocrine carcinoma.

To establish cytological features of pulmonary large cell neuroendocrine carcinoma (LCNEC), we evaluated the cytological characteristics of LCNEC. Samples from 25 histologically confirmed LCNECs (14 touch imprint (TI) and 11 curettage) were analyzed. The findings were compared with those for seven small cell lung carcinomas. Cytological findings of TIs were as follows: Tumor cells were medium- to large-sized, round or polygonal, and nuclear polymorphism was observed. Some of the tumor cells had clearly identified cytoplasms, but naked nuclei were frequently observed. Nuclei were round, oval, or polygonal, and possessed thin and smooth nuclear membranes. The nuclear chromatin pattern was finely or coarsely granular. One or two nucleoli were observed in the nuclei, but were inconspicuous in some cases. Tumor cells appeared in clusters, and rosette formation was observed, but single cells were frequently observed also. Necrotic background and nuclear streaking were frequently observed. In brush or curettage specimens, the number of cells observed on a glass was small, but the findings were almost the same as those for the TI samples. TI samples have characteristic features, such as a neuroendocrine morphologic pattern, large cell size, abundant cytoplasm, finely or coarsely granular chromatin of the nucleus, and prominent nucleoli, and the diagnosis of LCNEC is possible. In brush or curettage specimen, the LCNEC diagnosis may be possible if a sufficient number of tumor cells are obtained.

A case of invasive thymoma with endobronchial growth.

We report a rare case of invasive thymoma with endobronchial growth in a 69- year-old woman. Chest CT revealed an ill-defined mass with a calcified lesion in the anterior mediastinum and coin lesion in the bilateral lung fields. An endobronchial polypoid tumor in the right B3 bronchus was found by bronchoscopic examination. A biopsy specimen obtained from the polypoid tumor suggested thymoma. After radiotherapy combined with chemotherapy, thymothymectomy combined with right upper lobectomy through median sternotomy was performed. The surgical specimen revealed that the tumor extended nodularly, not only into the pulmonary parenchyma but also into the bronchial lumen. We performed an added chemotherapy for lung metastasis, and partial resection of lung with video-assisted thoracoscopic surgery (VATS) was done. Now she is alive and disease-free.

Impact of large tumor size on survival after resection of pathologically node negative (pN0) non-small cell lung cancer.

BACKGROUND: The current TNM staging system first adopted the tumor size of 3 cm for subdivision of stage I and II disease. The aim of the present study was to evaluate the impact of tumor size on survival in patients with pathologically node negative (pN0) non-small cell lung cancer after complete resection. METHODS: We retrospectively reviewed the records of 603 patients with pN0 non-small cell lung cancer patients (403 men and 200 women) who underwent a complete resection in five national chest hospitals between 1992 and 1996, with follow-up duration of more than 5 years, and analyzed tumor size and survival. Survival rate was estimated by the Kaplan-Meier method, and differences were compared by log-rank test. For the multivariate analysis, the Cox proportional hazard model was used to identify variables that significantly affected survival. RESULTS: There were 355 adenocarcinomas, 208 squamous cell carcinomas, and 40 large cell carcinomas completely resected. No significant prognostic differences were seen among three groups with smaller-sized tumors (< or =2 cm [n = 171], 2.1 to 3 cm [n = 202], and 3.1 to 5 cm [n = 170]); however, patients with a tumor size greater than 5 cm (n = 60) showed a significantly worse prognosis. The 5-year survival rates were 79.6%, 72.7%, 68.1%, and 46.6%, respectively, in these four groups. Multivariate analysis showed the tumor size to be an independent prognostic predictor in patients with pN0 tumors. CONCLUSIONS: We found that a tumor size of greater than 5 cm was an independent prognostic predictor in pN0 disease; therefore, upgrading the T factor of tumor diameter to greater than 5 cm may be necessary in the next reversion of the TNM staging system.

Surgical treatment of tuberculous abscess in the chest wall.

BACKGROUND: We reviewed surgical cases of tuberculous abscess in the chest wall and analyzed the indications and methods of surgery, results, perioperative complications, and postoperative treatment. METHODS: We retrospectively reviewed the records of 13 patients who underwent surgical treatment of tuberculous abscess in the chest wall between January 1994 and December 2003 at National Hospital Organization Tokyo Hospital. RESULTS: There was a past history of tuberculosis in 3 patients, concomitant active pulmonary tuberculosis in 5, concomitant active tuberculosis in the neck lymph node in 1, and no antecedent tuberculosis in 4. The locations of the tuberculous abscesses were right chest wall in 8 patients, left chest wall in 3, and anterior chest wall in 2. All of the patients underwent surgical treatment. In all patients, postoperative antituberculous treatments were administered. The combination regimens consisted of isoniazid (400 mg/d), rifampicin (450 mg/d), ethambutol (750 mg/d), pyrazinamide (1,500 mg/d), or some combination of these, and the duration ranged more than 6 months. Postoperative complications were not seen, and there was no recurrence. CONCLUSIONS: We recommend a complete resection of the abscess with rib resection, and postoperative treatment by tuberculous chemotherapy regimen. We consider that these treatments reduce postoperative recurrence.

[Pulmonary nontuberculous mycobacteriosis in patients with lung cancer].

OBJECTIVES: To clarify the clinical features of the coexisting lung cancer and nontuberculous mycobacteriosis of the lung. MATERIALS AND METHODS: We analyzed clinical data on 11 admitted cases of coexisting lung cancer and pulmonary non-tuberculous mycobacteriosis at National Organization Tokyo Hospital during the period from 1997 to 2002. RESULTS: There were 10 men and 1 woman, with a mean age of 66 years. Five of 11 patients had underlying pulmonary disorders, such as healed tuberculosis and lung cyst. Histological types of lung cancer were squamous cell carcinoma in 4, adenocarcinoma and small cell carcinoma in 3 each, and 8 out of 11 cases were in stages III to IV. We classified the 11 cases into 2 groups: (1) lung cancer concurrently detected with mycobacteriosis (8 cases) and (2) lung cancer sequentially detected during the follow-up of mycobacteriosis (3 cases). Lung cancers in the latter group were in relatively early stages and all patients of this group received resection of the cancer, while most of lung cancers in the concurrent group were in far-advanced, and palliative and/or supportive treatment for lung cancer were frequently selected. The strains of mycobacteria were as follows: M. avium complex (6 cases) and M. kansasii (5 cases). The incidence of lung cancer among patients with nontuberculous mycobacteriosis was 2.5 percent (2 percent of M. avium complex diseases patients and 8.2 percent of M. kansasii disease patients), while the incidence of nontuberculous mycobacteriosis in untreated lung cancer patients was 1.4 percent. Analysis of anatomical relationship between lung cancer and non-tuberculous mycobacteriosis revealed that the two diseases located in the same lung in 8 cases, and also in the same lobe in 4 out of the 8 cases. Outcome of treatment for nontuberculous mycobacteriosis was good especially in patients with M. kansasii disease, and it seemed that coexisting nontuberculous mycobacteriosis did not influence on the prognosis of lung cancer patients. CONCLUSION: In the management of lung cancer, physicians should consider the possibility of coexisting pulmonary non-tuberculous mycobacteriosis, as well as coexisting pulmonary tuberculosis.

[Thoracic malignancies in patients with chronic tuberculous empyema].

OBJECTIVES: To clarify features of thoracic malignancies occurred in patients with chronic tuberculous empyema. MATERIALS AND METHODS: We analyzed clinicopathological data of 15 patients with thoracic malignancies who had chronic tuberculous empyema, encountered at Tokyo National Hospital during the period from 1977 to 2002. RESULTS: There were 13 men and 2 women, with a mean age of 67 years. Most of all (13/15) patients had history of surgery for tuberculosis including artificial pneumothorax (9 cases). Malignancies consisted of pyothorax-associated lymphoma (PAL; 9 cases), lung cancer (4 cases), malignant fibrous histiocytoma (1 case), and angiosarcoma (1 case). There were no differences in background factors between PAL patients and the other patients. Common symptoms were chest pain (10 cases), fever (7 cases), and bloody sputum (4 cases) and it seemed that these symptoms were more evident in patients with PAL than in patients with other diseases. Plain chest X-ray films often failed to detect the tumor, and the diagnosis was often obtained by sputum cytology, bronchofiberscopy, transcutaneous biopsy, and resection with support of CT and/or MRI films. On radiographs, all tumors located in empyema cavities or around empyema walls, and a pulmonary mass adjacent to the empyema wall was characteristic of lung cancer. PAL showed certainly good outcome; 40% 5-year survival rate with resection or chemoradiotherapy. On the other hand, all of lung cancer cases were diagnosed at stage III, and had poor outcome, and the remaining patients with the other malignancies also had poor outcome. CONCLUSION: Clinicians should keep in mind occurrence of several thoracic malignancies during the follow-up of patients with chronic tuberculous empyema.

[Leukopenia due to anti-tuberculous chemotherapy including rifampicin and isoniazid].

OBJECTIVES: To examine the incidence rate by age and gender of leukopenia caused by chemotherapy including rifampicin (RFP) and isoniazid (INH), and to study the relationships between the leukopenia and the hepatic side effect or other haematological disorders such as thrombocytopenia. SUBJECTS: Out of the tuberculosis patients who were admitted to our hospital in 1987-88, 1991-92, and 1996-2000, 1,525 patients (1,153 men, 372 women) were chosen for our study who had the white blood cell counts (WBC) in the peripheral blood more than 3,000/mm3 before chemotherapy, and underwent haematologic examination at least twice within 3 months after starting chemotherapy. METHODS: The definition of leukopenia was as follows: 1) WBC became less than 3,000/mm3 during chemotherapy for patients with pre-treatment WBC more than 4,000/mm3, or 2) WBC decreased more than 1,000/mm3 in patients with pre-treatment WBC between 3,000 and 4,000/mm3. The incidence rates of leukopenia by age, gender, and regimens of chemotherapy were calculated. The case-control study was done between the control and the leukopenia groups excluding patients suffered from agranulocytosis to clarify the hematological and biochemical characteristics of the leukopenia group. The control patients were chosen in the following way. For each patient with leukopenia, a patient with the same admission year, same gender, same regimen of chemotherapy, and the nearest age was chosen as a control patient. The changes in counts of white blood cell, granulocyte, and platelet, in hemoglobin concentration, and in hepatic enzyme levels before and during chemotherapy were compared between the leukopenia and the control groups. Thrombocytopenia was defined as platelet count less than 15 x 10(4)/mm3 and hepatic dysfunction as either asparate aminotransferase (AST) higher than 31 IU/l or alanine aminotransferase (ALT) higher than 34 IU/l. RESULTS: (1) Incidence rate of leukopenia The leukopenia appeared in 36 patients (14 men, 22 women), two (one man, one woman) of whom showed agranulocytosis. The incidence rate was 1.2% (14/1,153) for men and 5.9% (22/372) for women. The incidence rate of women was higher than that of men in the age groups between 20 to 79 y.o., but no difference was seen in the age groups elder than 80 y.o. There were no differences in the incidence rate among groups treated with HRE (E: ethambutol), HRS (S: streptomycin), and HREZ (Z: pyrazinamide). The chemotherapy was continued in 30 patients after the appearance of leukopenia, and the natural recovery from leukopenia was seen in 19 patients, while the leukopenic state lasted during the chemotherapy in the remaining 11 patients. In two patients who exhibited agranulocytosis all drugs were discontinued. In the remaining 4 patients one or more drugs were discontinued. (2) Case-control study between leukopenia (N = 34) and the control (N = 34) groups There were no differences in age, sputum culture positivity on admission, degree of roentgenographic extent of the disease, ratio of cavity formation, and quantity of daily doses between the two groups. There was also no difference between the days until leukopenia appeared after starting chemotherapy (47.6 +/- 29.5 days) in the leukopenia group, and the days until WBC count became minimum within 3 months after starting chemotherapy (41.7 +/- 21.0 days) in the control group. The negativity of tuberculin skin testing was higher in the leukopenia group [7/14 (50%)] than in the control group [1/10 (10%)], however, the difference was statistically not significant due to rather small size of cases. Before the starting chemotherapy, the counts of WBC (7,230 +/- 1,530 vs 5,500 +/- 1,510/mm3, p < 0.001), neutrophil (5,230 +/- 1,450 vs 4,320 +/- 1,620/mm3, p < 0.05), lymphocyte (1,440 +/- 830 vs 830 +/- 440/mm3, p < 0.001) and platelet (34.9 +/- 12.2 vs 24.1 +/- 6.4 x 10(4)/mm3, p < 0.001) in the peripheral blood and the globulin level (3.71 +/- 0.61 vs 3.35 +/- 0.61 g/dl, p < 0.05) in the serum were significantly higher in the control group than in the leukopenia group. The decrements in the counts of WBC and granulocyte during chemotherapy were larger in the leukopenia group than in the control group (delta WBC: 2,880 +/- 1,530 vs 1,910 +/- 1,520/mm3, and delta Neut: 2,840 +/- 1,510 vs 1,820 +/- 1,380/mm3, p = 0.01, respectively), but the counts of lymphocyte were similar in both groups. The platelet counts also decreased in both groups, but to the mid-normal level in the control group, and to the lowest normal level in the leukopenia group, in which 15 out of 34 patients (44%) showed thrombocytopenia. The levels in the serum of hepatic enzymes such as AST, ALT, and gamma-GTP (gamma-glutamyl aminotransferase) increased during chemotherapy in the leukopenia group, while decreased in the control group, and the facts indicate that in the former not only bone marrow cells but also hepatic cells were impaired by anti-tuberculosis drugs. CONSIDERATIONS: Leukopenia may occur in the course of treatment with anti-tuberculosis drugs, but it is not necessary to stop the chemotherapy immediately, because the WBC count recovers spontaneously or remains under stable leukopenic state during chemotherapy in most cases. But when leukopenia appears, the peripheral blood counts must be checked cautiously, and the chemotherapy should be stopped if the WBC count progressively decreases. The patients who showed leukopenia due to anti-tuberculosis drugs may have had weaker natural and acquired (cell-mediated) immunologic response to tuberculosis infection, and more vulnerable bone marrow cells and hepatic cells to anti-tuberculosis drugs than the control.

[Agranulocytosis due to anti-tuberculosis drugs including isoniazid (INH) and rifampicin (RFP)--a report of four cases and review of the literature].

We experienced 4 cases of agranulocytosis due to anti-tuberculosis drugs (rifampicin [RFP], isoniazid [INH], ethambutol [EB], streptomycin [SM] or pyrazinamide [PZA]) among some 6,400 tuberculosis patients who underwent chemotherapy over the past 20 years from 1981 to 2002 in our hospital, and the incidence rate of agranulocytosis was estimated at 0.06%. The 4 cases of agranulocytosis were as follows. CASE 1: A 51-year-old woman with right chest pain and fever was admitted to our hospital on Jan 4, 2001. The white blood cell (WBC) count was 5,200/microliter. The tubercle bacilli were cultured in her sputum. The treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, allopurinol and teprenone was started on Jan 13. Pyrazinamide and allopurinol were stopped because of hyper-uric acidemia on Feb 7. Agranulocytosis and eosinophilia (WBC 1,300 [Neut 1%, Ly 57%, Eos 35%]) developed on Feb 13. All drugs were withdrawn and G-CSF drug nartograstim 100 micrograms was injected subcutaneously for 3 days. The WBC recovered to normal level and she was thereafter treated with INH, EB and Levofloxacin (LVFX) without any further trouble. Agranulocytosis in this case was supposed to be due to RFP. CASE 2: A 66-year-old man who had had nephrotic syndrome and hypothyroidism and has been treated with prednisolone 10 mg/day was admitted to our hospital on Aug 9, 2000 because of miliary tuberculosis. The tubercle bacilli were cultured in his sputum and the treatment with INH 0.3, RFP 0.45, and EB 0.75 g/day were started on Aug 10, but it was withdrawn on Aug 17 because of general skin eruption. After re-starting treatment with EB and INH on Aug 24, RFP was added in small dosage (0.05 g) on Oct 12, but agranulomatosis (WBC 2,300/microliter [Neut 2%]) developed on Nov 21, and all drugs were withdrawn again. The G-CSF drug filgrastim was used once subcutaneously, and WBC recovered immediately. He was thereafter treated with INH, EB, LVFX successfully. Agranulocytosis was supposed to be due to RFP. CASE 3: A 60-year-old woman without symptoms had abnormal chest roentgenograph, and consulted with our hospital on Aug 26, 2002. The broncho-alveolar lavage fluid was smear and culture-negative, but PCR-TB positive, and the case was diagnosed as pulmonary tuberculosis. Treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, alloprinol 300 mg and rebamipide 300 mg/day was started on Sept. 5, 2002. Late in September, she complained of appetite loss. The laboratory data on Oct 3 revealed WBC 900/microliter (Neut 1%, Ly 94%), aspartate aminotransferase (AST) 199 IU/l, and alanine aminotransferase (ALT) 253 IU/l, showing agranulocytosis and drug-induced hepatitis. The chemotherapy was immediately withdrawn and she was admitted to our hospital on the next day. Glycyrrhizin derivative (SNMC) 40 ml was injected for 5 days, and WBC recovered, and AST and ALT also became normal. CASE 4: A 60-year-old man was admitted to our hospital on March 11, 1981 because pulmonary tuberculosis had recurred. He had been treated with SM, PAS and INH in 1973 for pulmonary tuberculosis. On admission examination of blood count and blood chemistry were normal. Treatment with RFP, INH and SM was started on March 11. He stopped out from the hospital on April 17, but in a few days he returned back with sore throat, lower lip swelling and gingival bleeding. Blood cell count on April 24 showed pancytopenia with RBC 226, Hb 7.5, WBC 800 (Ly 96%, Eos 4%) and Plt 10,000/microliter. The bone-marrow showed NCC (nuceated cell count) of 5,500, and megakaryocyte 0. Thereafter ground glass appearance shadows were seen on the whole lung field, and he died May 26. Autopsy showed generalized aspergillosis. It was strongly suspected that either of RFP, INH or SM was responsible for his pancytopenia. We collected another 10 cases of agranulocytosis due to anti-tuberculosis drugs in the world wide literature, and found men/women ratio 5/8 (in one case gender was not known), the duration of chemotherapy before appearance of agranulocytosis 1-3 months, no change in the lymphocyte count of the peripheral blood, and the accompanying of another allergic signs such as skin eruption, blood eosinophilia or drug-induced hepatitis in some cases, and these findings suggest that the mechanism of agranulocytosis due to anti-tuberculosis drugs was allergic in nature.

Large cell carcinoma of the lung with a rhabdoid phenotype.

A variant of large cell carcinoma showing a rhabdoid phenotype, which is rare among primary lung cancers, is presented. A 59-year-old man was admitted to hospital for an operation. Computed tomography scans showed a mass with a smooth border, invading the thoracic wall. A right upper lobe lobectomy was carried out with resection of a part of the thoracic wall. Pathological examination showed that the tumor was mostly composed of cells with prominent eosinophilic cytoplasmic globules and giant cells, which did not adhere to each other. Cytologically, the tumor cells contained nuclei with a reticular chromatin pattern and one to two prominent nucleoli, and hyaline-like and reticular inclusion bodies, which were immunohistochemically positive for vimentin, but not for alpha-smooth muscle actin, myoglobin or pan-actin. Radiological and laboratory examinations did not detect the presence of the tumor in other organs, indicating that the primary lesion was not situated elsewhere. Metastasis to the right adrenal gland was observed 1 year and 4 months after the operation; however, the patient has been free of the disease 3 years and 11 months after the second operation of an adrenalectomy. This case showed a relatively good prognosis, which is rare among rhabdoid tumors of various organs that generally have poor prognoses with rapid, fatal progression.

Prognosis of non-surgically treated, clinical stage I lung cancer patients in Japan.

OBJECTIVE: The optimal management of stage I lung cancer is surgical resection. However, some of these patients are not candidates for surgery because of several medical problems. We analyzed prognosis of non-surgically treated, clinical stage I lung cancer patients. METHODS AND RESULTS: There were 21211 lung cancer patients registered from 1982 to 1991 in the data-base of the Japanese National Chest Hospital Study Group for Lung Cancer, and the number of non-surgically treated, clinical stage I lung cancer patients during the 10 years was 802. The 5- and 10-year survival rates of the 799 patients, exclusive of two carcinoid tumors and one adenid cystic carcinoma which have good prognosis, were 16.6 and 7.4%. We analyzed the 799 patients according to several prognostic factors. Sex, T factor of the tumor, histology, performance status and the method in which lung cancer was detected were prognostic factors, but age and treatment method were not associated with prognosis. Forty-nine patients survived for 5 years or more without surgical resection, but the survival rate continued to decrease even after 5 years, and the 7- and 10- year survival rates were 34.4 and 18.1% in the 49 patients. CONCLUSIONS: It is a fact that there are long-term survivors in non-surgically treated, stage I lung cancer patients. However, the rate is low, and the survival curve continues to decrease even after 5 years. Long-term survivors might suggest the presence of a lung cancer in which the tumor growth is slow.