Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials.

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240.

Evaluation of a Quantitative Serological Assay for Diagnosing Chronic Pulmonary Aspergillosis.

The purpose of this study was to evaluate the clinical utility of a quantitative Aspergillus IgG assay for diagnosing chronic pulmonary aspergillosis. We examined Aspergillus-specific IgG levels in patients who met the following criteria: (i) chronic (duration of >3 months) pulmonary or systemic symptoms, (ii) radiological evidence of a progressive (over months or years) pulmonary lesion with surrounding inflammation, and (iii) no major discernible immunocompromising factors. Anti-Aspergillus IgG serum levels were retrospectively analyzed according to defined classifications. Mean Aspergillus IgG levels were significantly higher in the proven group than those in the possible and control groups (P < 0.01). Receiver operating characteristic curve analysis revealed that the Aspergillus IgG cutoff value for diagnosing proven cases was 50 mg of antigen-specific antibodies/liter (area under the curve, 0.94; sensitivity, 0.98; specificity, 0.84). The sensitivity and specificity for diagnosing proven cases using this cutoff were 0.77 and 0.78, respectively. The positive rates of Aspergillus IgG in the proven and possible groups were 97.9% and 39.2%, respectively, whereas that of the control group was 6.6%. The quantitative Aspergillus IgG assay offers reliable sensitivity and specificity for diagnosing chronic pulmonary aspergillosis and may be an alternative to the conventional precipitin test.

[Outpatient care of tuberculosis].

The outpatient care is important still more in the treatment of tuberculosis (TB). The community DOTS is required, to accomplish the treatment of the TB patients those have various risks of treatment discontinuation. In this symposium, the several points are reported. The number of TB hospitals are decreasing and are maldistributed. And even in TB hospitals, the person/time for the education of patient and the risk assessment of drug compliance, are not sufficient. In general hospitals, the knowledge/experiences of TB treatment are not sufficient. It is important to share the information of the TB patient, between the persons concerned. It is also important to notify and succeed the knowledge/experience regarding TB treatment. For outpatient care of TB, collaborating work in the area is necessary. As practical means, it is important to promote the liaison critical path in the area. The TB hospital and the health center should play a big role.

[Evaluation of galactomannan antigen and beta-D-glucan value for diagnosis of chronic necrotizing pulmomary aspergillosis].

In order to establish the reliable cut-off value of galactomannan (GM) antigen as well as that for beta-D-glucan for CNPA diagnosis, we conducted the following study. From 2001 to 2008, in a total of 1511 patients we measured GM and anti-aspergillus antibody simultaneously. These patients had chronic pulmonary disease including old tuberculosis, nontuberculous mycobacteriosis, COPD, and had bullous lung, interstitial lung disease or were suspected to have suspected to have interstitial lung disease. We designated cases as probable CNPA when the sample represented a positive anti-aspergillus antibody. We then analyzed the sensitivity and specificity according to various GM antigen values. When using the GM antigen cut-off value at 0.5, the sensitivity and specificity for CNPA were 63.4% and 68.6% respectively. Using 1.0 for cut-off value resulted in the better specificity for CNPA diagnosis. Similar analysis was performed on beta-D-glucan for CNPA diagnosis. When using D-glucan cut-off value as 20 pg/ml, the sensitivity and specificity for CNPA. These results indicate that the cut-off value of serological examination for infectious disease should be considered by the type of disease.

[Analysis of chronic necrotizing pulmonary aspergillosis (CNPA) cases complicated with non-tuberculous mycobacteriosis (NTM)].

OBJECTIVE: To clarify the clinical feature of chronic necrotizing pulmonary aspergillosis (CNPA) complicated with non-tuberculous mycobacteriosis (NTM). SUBJECTS AND METHODS: Forty-one CNPA cases underlying NTM were analyzed according to their clinical backgrounds. RESULTS: Concerning the radiological type of prior NTM, CNPA cases were classified into two groups; 1) resembling pulmonary tuberculosis that usually shows cavitary lesion and 2) micronodule and bronchiectasis pattern, and more than half of cases (61.0%) were classified as the latter type. Average duration between prior NTM and CNPA was 1354 days. Isolation of Aspergillus spp. from sputum was 15 out of 41 (36.6%). Positive rates for Aspergillus galactomannan antigen and anti-aspergillus antibody were 58.5%, 46.3% respectively. With regard to subspecies of mycobacteria, M. avium was most frequent (82.9%). Since 6.8% of NTM cases develop CNPA within 10 years, careful observation of CNPA was required for the management of NTM.

[Primary lung cancer with myocardial metastasis mimicking acute myocardial infarction].

A 78-year-old man was admitted to our hospital because of chest and back pain. Fourteen months previously his chest X-ray showed a tumor shadow with cavitation in the left middle field. On admission cardiomegaly was found. Chest CT without contrast enhancement did not detect an intra-myocardial tumor. The electrocardiogram and serological examination suggested acute onset of myocardial infarction. However, emergency coronary angiography detected neither significant stenosis nor occlusion. Thereafter, chest CT with contrast medium demonstrated an intra-myocardial tumor. There wes no pericardial effusion. We clinically diagnosed a myocardial tumor metastatic from lung cancer. He received symptomatic treatment, but died on the 31st hospital day. Autopsy revealed that most of the myocardium had been replaced by lung cancer cells. They did not invading the pericardium directly. These findings supported the clinical diagnosis that myocardial tumor was hematogenous metastasis from lung cancer.

Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection.

OBJECTIVE: Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection. METHODOLOGY: The serum VEGF levels in 46 patients with pulmonary MAC infection were compared with those in 16 normal control subjects. Pulmonary lesions were evaluated using chest CT. In 20 patients, after treatment, serum VEGF levels were measured and chest CT performed again to evaluate pulmonary response to treatment. RESULTS: Infected patients had higher serum VEGF levels than controls (435.2 +/- 29.1 vs. 167.0 +/- 10.6 pg/mL, P < 0.0001), and serum VEGF level correlated with the extent of disease. The serum VEGF levels in 14 patients who underwent treatment and exhibited an improvement in their pulmonary lesions decreased significantly compared with the results pretreatment (509.0 +/- 60.7 vs. 303.6 +/- 65.3 pg/mL, P = 0.0092). In infected patients, alveolar macrophages, epithelioid cells and multinucleated giant cells exhibited VEGF overexpression on immunohistochemical staining. CONCLUSIONS: This study suggests that VEGF may be associated with the pathogenesis of pulmonary MAC infection. Additionally, serum VEGF levels may be a useful surrogate marker for evaluating the extent of disease and of the response to treatment.

[The improvement of the enforcement rate of the standard regimen (A) of tuberculosis chemotherapy by the introduction of common database system for tuberculosis].

OBJECTIVE: The purpose of this study was to improve the enforcement rate of the standard regimen (A) of tuberculosis chemotherapy. SUBJECTIVE AND METHODS: We introduced the common database system for tuberculosis in three national hospitals in Hokkaido. From January 2002 to December 2003, we collected the anonymous informations of the patients with tuberculosis at the start of treatment, at the discharge and at the end of treatment. Then, we reported the enforcement rate of the standard regimen (A) as a clinical indicator periodically to three hospitals. RESULTS: Four hundred and twenty-nine patients were registered. In patients below 80 years old, the enforcement rate of the standard regimen (A) was 48.5% in 2002. The enforcement rate rose significantly to 62.7% (p = 0.0126) in 2003. In elder smear-positive patients (> or =75) and in elder smear-negative patients (> or =70), the enforcement rate was low (29.1% and 25.0%, respectively). Furthermore in young smear-negative patients (< or =29), the enforcement rate was low (28.0%). As the extent of their disease was minimal, they were treated with other regimens. In patients treated with the standard regimen (A), there were no significant differences in the frequency of adverse effects between elder patients ( 70) and other patients (< or =69). There were also no significant differences in the frequency of changing the regimen between them. Median admission period of 2002 was 114 days. In 2003, it was shortened significantly to 110 days (p = 0.0487). CONCLUSION: By the introduction of the common database system for tuberculosis, the enforcement rate of the standard regimen (A) was improved. Low enforcement rate in young smear-negative patients in an important problem to be improved in the future. The clinical indicator based on the common database system between hospitals, is useful to clarify the problems, and then to improve the quality of medical performance.

[Clinical analyses of Aspergillus infections in patients with underlying pulmonary disease].

To elucidate the clinical features of Aspergillus infections with underlying pulmonary disease, we analyzed 79 cases with positive results for anti-aspergillus antibody. The patients were 69 men and 10 women. Mean age at diagnosis was 68.0. Positive rates for isolation of Aspergillus spp. from the airways, and of galactomannan antigen and 1, 3-beta-D glucan in the serum were 44.3, 21.8, 26.5%, respectively. These findings did not show any differences according to underlying pulmonary disease. Twenty-nine patients died of the disease. Body mass indices, serum albumin levels and red blood cell counts were significantly lower in the patients who died. Extension of the lesion to the lower lobes or to 3 or more lobes was correlated significantly with poor survival. A specific diagnostic tool was required for early detection of the disease.

[Validity of measuring time to detect growth of M. tbc by BACTEC MGIT960 system for quantitation and prediction of mycobacterial growth].

STUDY DESIGN: Time to detect growth of M. tbc by BACTEC MGIT960 system was examined in sputum specimens collected from 114 patients with active pulmonary tuberculosis before and during antituberculosis therapy. By measuring TTD under chemotherapy, we tried to quantify mycobacterial growth and determine the sensitivity of MGIT system. RESULTS: The mean TTD significantly decreased in response to an increment in the range of the quantitation scale for solid media. Moreover, the TTD negatively correlated with colony counts (rho = - 0.636, P < 0.01). When automated monitoring continued until Day 28 after incubation, MGIT system had been capable of detecting 98% of Ogawa-positive specimens. The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity in MGIT system, indicating the sensitivity of 98.3% corresponding cutoff level for TTD of Day 28. CONCLUSION: Measuring TTD in MGIT system could allow estimating the mycobacterial growth in similarly quantitative manner. The appropriate endpoint of monitoring could be decided as 4 weeks, accurately reflecting an outcome of cultivation with solid media.

[Two cases of pulmonary Mycobacterium xenopi infection].

We report on two patients diagnosed as having Mycobacterium xenopi infections. Case 1 occurred in a 40-year-old man. His chest radiograph revealed a cavitary lesion with a granular shadow in the right upper lung field. His sputum and bronchial lavage were negative for acid-fast bacilli and malignant cells. For a definitive diagnosis, lung resection was performed by video-assisted thoracoscopy. Case 2 was in a 45-year-old man. His chest radiograph showed a cavitary lesion with infiltration in the right upper lung field. Acid-fast bacilli were seen in his sputum specimens and M. xenopi was identified by culture. Despite medication with isoniazide, rifampicin and ethambutol, the infiltrative shadow in his radiograph increased in size. In this case, right upper lobectomy was performed. In recent years, 8 cases of pulmonary Mycobacterium xenopi infection have been reported in Japan. In the future, the number of such case reports may increase as a result of diagnosis by molecular biological methods. It is necessary to consider carefully whether surgical resection is required when chemotherapy is refused by the patient or is likely to be unsuccessful.

The diagnostic and prognostic relevance of human telomerase reverse transcriptase mRNA expression detected in situ in patients with nonsmall cell lung carcinoma.

BACKGROUND: The objectives of this study were to evaluate the diagnostic and prognostic relevance of human telomerase reverse transcriptase (hTERT) detected in situ in patients with nonsmall cell lung carcinoma (NSCLC) and to investigate the possible correlations between hTERT mRNA in NSCLC and the patients' clinicopathologic features, including survival. METHODS: hTERT mRNA was detected by in situ hybridization in 146 samples from patients with NSCLC. The signal intensity of hTERT mRNA expression was evaluated by two independent observers. The expression level was defined subjectively as strong, moderate, or weak. RESULTS: hTERT mRNA was detected mainly in the cytoplasm of tumor cells. It was detected in the cytoplasm of 100% of samples from patients with NSCLC but was not detected in normal lung tissue, except in activated lymphocytes. There was a significant correlation between hTERT mRNA expression and pathologic tumor status, pathologic disease stage (pStage), and Ki-67 labeling index. There was no significant correlation between hTERT mRNA expression and age, gender, pathologic lymph node status (pN), histology, or tumor differentiation. The 5-year survival rates for patients with strong and moderate hTERT mRNA expression levels were 46.9% and 77.9%, respectively; the difference was statistically significant (P = 0.0001). A multivariate analysis of survival using a stepwise procedure revealed that hTERT mRNA expression, pN status, pStage, and age were statistically significant prognostic factors (P = 0.0029, P = 0.0012, P = 0.0237, and P = 0.0496, respectively). CONCLUSIONS: The findings suggested that hTERT mRNA expression may be useful for the diagnosis of NSCLC and also may be an independent prognostic factor for patients with NSCLC.

[An adult case of tuberculous meningitis].

A 36-year-old man was referred to our hospital with complaints of high fever and headache. A diagnosis of miliary tuberculosis with tuberculous meningitis was made. He was treated with isoniazid (400 mg/day), rifampicin (300 mg/day), ethambutol (750 mg/day), pyrazinamide (1.0 g/day) and prednisolone (60 mg/day). However, he lost consciousness because of hydrocephalus on the second day of hospitalization. Emergency cerebrospinal fluid drainage improved his neurological symptoms. After two months, he again complained of headache with nausea and double vision. Numerous tuberculomas were found not only in the cerebrum but also in the liver, the spleen and the retina. Recurrent hydrocephalus was treated with a V-P shunt, and combination therapy with four antituberculous agents was maintained for 18 months. He was discharged in a healthy condition, although a mild left facial palsy remained. In addition, we examined the inflammatory cytokine levels in both the CSF and the serum over the period of the patient's hospitalization. We concluded that the cytokine levels in the CSF may be associated with the progress and the prognosis of tuberculous meningitis.

Analysis of chest CT in patients with Mycobacterium avium complex pulmonary disease.

BACKGROUND: The radiographic changes of Mycobacterium avium complex (MAC) pulmonary disease during therapy have not been studied well. OBJECTIVE: To assess the efficacy of antituberculous drug therapy against MAC pulmonary disease using computed tomography (CT). METHOD: We analyzed chest CT scans before and after antituberculous therapy in 30 patients (21 women, 9 men) with MAC pulmonary disease. To evaluate radiographic changes during therapy, we defined a 'degree of improvement' (DI) that is calculated according to the CT appearance. RESULTS: DI was better (1.35 +/- 0.21) in patients who had converted sputum culture than in those who had not (0.44 +/- 0.25) (p < 0.05). In patients who were diagnosed by bronchial washing, DI was better (1.60 +/- 0.22) than in patients who were diagnosed by sputum (0.67 +/- 0.20) (p < 0.01). We categorized the CT appearance into 6 types: small nodules, cavities, bronchial wall thickening, infiltration, pleural thickening and atelectasis. Patients who showed pleural thickening had a significantly worse DI (0.12 +/- 0.40) than those who did not (1.23 +/- 0.18) (p < 0.01). Most of the lesions that disappeared after therapy were small nodules. CONCLUSION: These results indicate that chest CT might be a useful tool for the prediction or assessment of drug therapy for MAC pulmonary disease.

[A case of pulmonary cryptococcosis with multiple nodular shadows under treatment of bronchiolitis obliterans with organizing pneumonia (BOOP)].

A 66 year-old man was introduced to our hospital because of multiple infiltrative pulmonary shadows on February, 2001. We diagnosed bronchiolitis obliterans with organizing pneumonia (BOOP) from the clinical and bronchoalveolar lavage fluid (BALF) findings, and initiated oral steroid therapy. Since the abnormal chest shadows disappeared, the dose of steroid was decreased and maintained at 10 mg/day. In August 2001, multiple infiltrative shadows returned, and we therefore increased the steroid dose to 30 mg/day. The expanding infiltrative shadows were then joined by new multiple nodular shadows. The bronchioalveolar lavage fluid revealed small bodies of cryptococcus species. A positive result for anti-cryptococcus antigen was also obtained from the serum. We then diagnosed pulmonary cryptococcosis without meningitis. Therapy was started with anti-mycotic agents including amphotericin-B, flucytosine and fluconazole, which proved successful. This case of opportunistic cryptococcus infection in an immunocompromized patient, which responded to anti-mycotic therapy, is reported.