Toru Rikimaru

Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma

Background: The 72 kDa matrix metalloproteinase 2 (MMP-2) and the 92 kDa matrix metalloproteinase 9 (MMP-9) are type IV collagenases implicated in various aspects of inflammation including accumulation of inflammatory cells, tissue injury, and development of remodelling. The role of these enzymes in the pathogenesis of asthma exacerbations is unknown. Methods: Circulating levels of MMP-2 and MMP-9 proteins and the expression of their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP-1), were measured in 21 patients experiencing an asthma exacerbation and 21 age matched patients with stable asthma. Circulating gelatinolytic activity was compared during the asthma exacerbation and during subsequent convalescence by gelatin zymography in the same individuals. In addition, MMP-9 specific activity was quantified with a colorimetric assay which uses an artificial proenzyme containing a specific domain recognised by MMP-9 in the same paired samples. Results: A significant increase in the circulating level of MMP-9 was seen in patients with an asthma exacerbation compared with patients with stable asthma (202.9 (22.0) v 107.7 (9.9) ng/ml, p=0.0003). There were no significant differences in the circulating levels of MMP-2 or TIMP-1. Gelatin zymography identified two major circulating gelatinolytic activities corresponding to MMP-2 and MMP-9, and showed that asthma exacerbations are characterised by markedly increased MMP-9 activity with no significant change in MMP-2 activity compared with the activities during convalescence in the same individuals. Direct measurement showed that MMP-9 specific activity is significantly increased during asthma exacerbations compared with subsequent convalescence (269.6 (31.7) v 170.4 (12.6) ng/ml, p=0.0099). Conclusions: Asthma exacerbations are characterised by increased circulating MMP-9 activity. This increased activity may be related to exaggerated airway inflammation and airway remodelling.

Phase 1 clinical study of cyclophilin B peptide vaccine for patients with lung cancer.

Cyclophilin B (CypB) possesses two antigenic epitopes (CypB84–92 and CypB91–99) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). To determine the safety of CypB-derived peptides and its ability to generate antitumor immune responses, patients with advanced lung cancer received subcutaneous vaccinations of these peptides or their modified peptides. All 16 patients were vaccinated with CypB91–99 or its modified peptide, whereas only two patients were vaccinated with the modified CypB84–92, as immediate-type hypersensitivity to CypB84–92 or its modified peptide was observed in the remaining patients. No severe adverse events were associated with the vaccination. No significant increase in cellular responses to either peptides or tumor cells was observed in the postvaccination PBMCs by the conventional CTL assays in any patients tested. These results suggest that the vaccination of CypB91–99 peptide was safe, but failed to induce objective immune responses at this regimen.

Combination Chemotherapy with Irinotecan and Ifosfamide as Second-Line Treatment of Refractory or Sensitive Relapsed Small Cell Lung Cancer: A Phase II Study

This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as second-line chemotherapy for relapsed small cell lung cancer (SCLC). Eligibility criteria included histologically or cytologically confirmed SCLC, prior chemotherapy including platinum + etoposide, and measurable or evaluable disease. CPT-11 (80 mg/m2) was administered intravenously on days 1, 8 and 15, while ifosfamide (1.5 g/m2) was given on days 1 through 3 every 4 weeks. Thirty-four patients (29 men) with a median age of 69 years (range 42–77) and a median Eastern Cooperative Oncology Group (ECOG) performance status of 1 (range 0–2) were enrolled. The response rate was 52.9% (95% confidence interval: 29.8–64.9%) with 2 complete responses and 16 partial responses. Our analyses of prognostic factors showed risk factors assessed before receiving second-line chemotherapy, which were the number of metastatic sites, performance status and the type of relapse. WHO grade 3–4 neutropenia was recorded in 52.9% of the patients, grade 3 diarrhea in 5.9%. The combination of CPT-11 and ifosfamide demonstrated clinical efficacy in relapsed SCLC with a favorable toxicity profile, particularly for performance status 0–1 and sensitive cases with only one metastatic site.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer.

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer (LD-SCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Four chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated every 28 days. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle with 20 Gy administered from the first to the third cycles (a total of 60 Gy). 17 patients were enrolled at three dose levels (CPT-11/cisplatin: 40/60, 50/60 and 60/60 mg/m(2)), and 16 were evaluable for toxicity and outcome. 2 of 4 patients at 60/60 mg/m(2) refused continuation of therapy because of general fatigue, and the relative dose intensity of CPT-11 at 50/60 mg/m(2) was approximately 50%. These levels were considered as the MTD. Tumour responses included four complete responses (CR), 11 partial responses (PR) and one no change (NC), and the overall response rate was 93.8% (95% confidence interval: (CI) 71.7-98.9%). This combined modality is tolerable, and CPT-11/cisplatin of 40/60 mg/m(2) in this modality is recommended for phase II study.

Chronic pulmonary scedosporiosis simulating aspergillosis

Abstract:  Scedosporium apiospermum, a ubiquitously distributed saprophyte, is emerging as an important pathogen in immunocompromised patients. We describe a 72‐year‐old patient with chronic S. apiospermum infection of the lung simulating aspergilloma. His medical history was unremarkable except that he had undergone partial lung resection as a treatment for pulmonary tuberculosis several decades previously. He had no underlying immunosuppressive conditions. This patient illustrates that pulmonary scedosporiosis is not confined to immunocompromised patients and that the clinical presentation may be indistinguishable from that of aspergilloma.

Therapeutic management of endobronchial tuberculosis

Endobronchial tuberculosis (EBTB) is defined as tuberculous infection of the tracheobronchial tree. Common symptoms are cough, haemoptysis, sputum production, wheezing, chest pain and fever in active disease and dyspnoea and wheezing in the fibrous stage. This form of tuberculosis is difficult to diagnose because the lesion is not evident in the chest radiograph, frequently delaying treatment. Computed tomography is very useful in evaluating bronchial lesions such as stenosis or obstruction. The most important goal of treatment in active EBTB is eradication of tubercle bacilli. The second most important goal is prevention of bronchial stenosis. Corticosteroid therapy for the prevention of bronchial stenosis in EBTB remains controversial. However, the healing time of ulcerous lesions was shorter and bronchial stenosis was less severe, in patients treated with aerosol therapy, consisting of streptomycin 100 mg, a corticosteroid (dexamethasone 0.5 mg) and naphazoline 0.1 mg administered twice-daily along with conventional oral therapy. In inactive disease, treatment to restore full patency is appropriate. As steroids or other medications are unable to reverse stenosis from fibrous disease, airway patency must be restored mechanically by surgery or endobronchial intervention. Effectiveness and complications remain important issues with the mechanical techniques as use and evaluation continue. Corticosteroid therapy for prevention of bronchial stenosis in EBTB remains controversial. Our observations suggest that progression of bronchial stenosis can be prevented in patients who are treated with aerosol therapy with corticosteroids.

Chronic eosinophilic pneumonia associated with Schizophyllum commune

Abstract:  We describe the first known Japanese patient with chronic eosinophilic pneumonia caused by Schizophyllum commune. The patient presented to Social Insurance Tagawa Hospital, Fukuoka, Japan with cough, wheezing, dyspnoea, and fever. Computed tomograms of the chest showed bilateral areas of consolidation with air bronchograms as well as interstitial infiltrates in the upper lobe, without ectasia of proximal bronchi. Fibreoptic bronchoscopy revealed no impacted mucus in the bronchi. BAL fluid from the right upper lobe yielded an increased total cell count with a high percentage of eosinophils. A transbronchial lung biopsy specimen showed a bronchoalveolar chronic inflammatory infiltrate composed of eosinophils, lymphocytes and plasma cells, associated with fibrosis of the alveolar walls. S. commune was identified in lavage fluid. Antibodies to this organism were present in the serum, confirming that S. commune was the cause of chronic eosinophilic pneumonia. Inhaled corticosteroids without accompanying oral corticosteroids or antifungal agents decreased the respiratory symptoms, and the infiltrates disappeared from the chest radiograph within a few days.

Fatal idiopathic acute eosinophilic pneumonia with acute lung injury

A fatal case of idiopathic eosinophilic pneumonia with acute lung injury is described. The patient required treatment with mechanical ventilation and intravenous corticosteroids, however, she died on the third hospital day. At autopsy, both exudative and proliferative phases of diffuse alveolar damage were observed bilaterally. Marked eosinophilic infiltrate was noted in the alveolar wall and within the alveolar cavities with occasional abscess‐like features. To our knowledge, this is the first report of fatal acute eosinophilic pneumonia, and provides important information for the management of this condition.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in unresectable and locally advanced non-small cell lung cancer

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in locally advanced stage III non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Two chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated with a 28-day interval. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 24 Gy and 36 Gy administered for the first and second cycle, respectively. 24 eligible patients were enrolled at five dose levels (CPT-11/cisplatin: 40/60, 50/60, 60/60, 60/70 and 60/80 mg/m(2)), and 23 patients were evaluated for toxicity and clinical outcome. Only 1 patient experienced a DLT with neutropenia and diarrhoea at 60/60 mg/m(2). Dose escalation was limited to 60/80 mg/m(2) which was the recommended dose for CPT-11/cisplatin alone in NSCLC. Tumour responses included one complete response (CR), 15 partial response (PR), and 7 no change (NC), and the overall response rate was 69.6% (95% confidence interval (CI) 47.1-86.8%). This combined modality is tolerable, and CPT-11/cisplatin of 60/80 mg/m(2) in this modality is recommended for phase II study.

Relationship between cancer cell proliferation and thallium-201 uptake in lung cancer

Although thallium-201 (201Tl) uptake is related to perfusion in many normal tissues, the biologic rationale for201Tl uptake in tumors is uncertain. To determine if tumor uptake is related to cell proliferation, we correlated the relative retention of201Tl in lung tumors with expression of Ki-67, an indicator of cell proliferation.Methods: Sixty patients with lung tumors, included small cell carcinoma (n=8) and non-small cell carcinoma (n=52), underwent201Tl single photon emission computed tomography (SPECT) imaging. The201Tl lesion uptake was determined on early and delayed images and the radiotracer retention index (RI) was calculated. Tumor specimens were obtained at surgery or bronchoscopy. The cell proliferation ratio was estimated with MIB-1, a monoclonal antibody that recognized the nuclear antigen Ki-67.Results: The average201Tl index was 2.13±0.61 (early) and 2.46±0.83 (delayed). The average RI was 17.44±35.01. Overall, the201Tl index (delayed) and the cancer cell proliferation were correlated (r=0.70, p<0.0001). Of interest, there was a significant correlation (r=0.872, p<0.0005) between the201Tl index on delayed images and the cell proliferation ratio in patients with small cell but not non-small cell lung carcinoma. The201Tl index (delayed) was significantly higher (p<0.0001) in patients with small cell lung carcinoma than in patients with non-small cell lung carcinoma.Conclusion:201Tl imaging appears to be useful for evaluating patients with small cell lung carcinoma but not non-small lung carcinoma, and is correlated with the monoclonal antibody MIB-1, a marker of cell proliferation.