Tomoko Kamimura

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.

Determinants of bronchodilator responsiveness in patients with controlled asthma.

Short-term bronchodilator responsiveness to an inhaled β 2 adrenergic agonist was assessed by changes in forced expiratory volume in 1 second (FEV1) in nonsmoking adults with controlled asthma (mild disease, 20 patients; moderate disease, 20 patients; severe disease, 18 patients). Responsiveness correlated significantly with age and with percent of predicted FEV1 (%FEV1) except in patients with severe asthma, who showed significantly less responsiveness than others. Thus, responsiveness is closely associated with degree of airflow limitation in patients with controlled asthma and is significantly influenced by severity of disease and by aging.

Dengue hemorrhagic fever in a Japanese traveler with pre-existing Japanese encephalitis virus antibody.

An adult Japanese man who had just returned from Thailand developed dengue hemorrhagic fever (DHF). A primary infection of dengue virus (DENV) was confirmed, specifically DENV serotype 2 (DENV-2), on the basis of the detection of the virus genome, a significant increase in the neutralizing antibody and the isolation of DENV-2. DHF is often observed following a secondary infection from another serotype of dengue virus, particularly in children, but this case was a primary infection of DENV. Japan is a non-endemic country for dengue disease. In fact, only Japanese encephalitis (JE) is known to be a member of the endemic flavivirus family. In this study, IgG antibody against Japanese encephalitis virus (JEV) was detected. JEV belongs to the family of dengue virus and prevails in Japan, particularly Kyushu. Among many risk factors for the occurrence of DHF, a plausible candidate could be a cross-reactive antibody-dependent enhancement (ADE) mechanism caused by JEV antibody. This indicates that most Japanese travelers who living in dengue non-endemic areas, particularly Kyushu, should be aware of the occurrence of DHF.

Phase II Study of Irinotecan and Ifosfamide in Patients with Advanced Non-Small Cell Lung Cancer

Objectives: This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Methods: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, 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. Results: Forty-four patients (31 men) with a median age of 65 years (range 43–75) and a median ECOG performance status of 1 (range 0–2) were enrolled. The response rate was 29.5% [95% CI: 16.7–45.2%], with 13 partial responses. The median survival was 12.5 months, the median time to progression was 5.3 months, and the 1 and 2-year survival rates were 52.3 and 11.3%, respectively. Toxicity was generally mild; WHO grade 3–4 neutropenia was recorded in 38.6% of the patients, grade 3 diarrhea in 6.8%, and grade 3–4 nausea/vomiting in 0%. Conclusions: CPT-11 combined with ifosfamide demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of cisplatin-based chemotherapy but with a more favorable toxicity profile.

High Detection Rates of Urine Mycobacterium tuberculosis in Patients with Suspected Miliary Tuberculosis

Objective The utility of detecting Mycobacterium tuberculosis in urine samples from patients with pulmonary tuberculous with diffuse small nodular shadows (suspected miliary tuberculosis (MTB)) is still unclear in Japan. A retrospective cross-sectional study was conducted to investigate the detection rates of M. tuberculosis in urine of patients with suspected MTB. Methods Among 687 hospitalized patients with tuberculosis, 45 with culture-confirmed suspected MTB and the data of culture and polymerase chain reaction (PCR) for M. tuberculosis in urine and sputum samples were investigated. The detection rates of M. tuberculosis in urine using cultures and PCR were calculated. The detection rate of urine was then compared with that of bone marrow aspiration. Results Fourteen patients with suspected MTB were ultimately analyzed. A diagnosis of miliary tuberculosis was suspected in all patients before anti-tuberculosis chemotherapy. Positive results by PCR (11 [78.6%] cases) and culture (8 [57.1%]) were obtained from urine samples. In patients with suspected MTB, there was no significant difference in the detection rates between M. tuberculosis in urine using a combination of PCR and culture (85.6% [12/14 cases]) and bone marrow aspiration (66.7% [8/12 cases]) (p>0.05). Conclusion Using PCR and culture, we demonstrated high detection rates of M. tuberculosis in the urine of patients with suspected MTB. A combination of PCR and culture compared favorably with the detection rates achieved with bone marrow aspiration. We believe that detection of M. tuberculosis from urine and sputum samples may be easy and safe for patients with disseminated tuberculosis infections such as definitive MTB.

Organizing pneumonia associated with Mycoplasma pneumoniae infection

Mycoplasma pneumoniae infection is known to produce infiltrative and/or nodular opacities that are often localized. A patient presented to us with diffuse centrilobular, peribronchovascular, and perilobular opacities after documented Mycoplasma pneumoniae infection. A surgical biopsy proved the lung disease to be organizing pneumonia, which dramatically resolved in response to treatment with corticosteroid. This case represents an unusual radiological manifestation associated with M. pneumoniae infection, thereby stressing the importance of this disease in the differential diagnosis for patients with diffuse opacities of the lungs.

Cat scratch disease presenting with a retroperitoneal abscess in a patient without animal contacts.

Cat scratch disease (CSD) is usually diagnosed in patients presenting with regional lymphadenopathy and pyrexia that follow contacts with animals. We describe here a young adult male patient who presented with marked pyrexia and a retroperitoneal abscess without relevant medical histories, illustrating that CSD can be a diagnostic challenge on selected occasions.

A Hybrid Lesion of Lung Cancer and Aspergillosis

Oxaliplatin plus 5Fluorouracil (5FU) and leucovorin (LV) is the standard treatment of metastatic colorectal cancer (CRC). We describe a rare clinical case of acute renal failure probably oxaliplatin-related at one day from the end of the palliative treatment. A 36 year-old woman developed a stage I CRC. Five months later a liver lesion was detected and treated with FOLFOX4 schedule. Because of progression the patient underwent surgery and she repeated the Oxaliplatin-based therapy for more than one cycle. After many months of therapy, on the second day, the patient noticed urine discoloration. Immediate urinanalysis demonstrated haemoglobinuria. The patient’s complete blood count exhibited signs consistent with acute hemolysis, neutrophilic leucocytosis, thrombocytopenia and acute renal failure. She was treated with blood transfusion and hemodialysis and she was managed conservatively with monitored intravenous hydration and loop diuretics. The patient gradually recovered and the results of successive hematological and biochemical tests confired the improvement of her condition but a cardiologic evaluation showed a iatrogenic depressed systolic function (ejection fraction of 40%).Introduction Pharyngo-laryngeal tumors classified as T3-4, N0-3, M0, are conventionally treated by mutilating surgery (total (pharyngo)-laryngectomy). Neo-adjuvant chemotherapy with 5-FU/platinum salt can be proposed in an attempt to preserve the larynx. The level of the response to chemotherapy ranges from 36 to 54% of cases. Thus, a large number of patients receive chemotherapy that is ineffective and not free from adverse effects. Three main enzymes are involved in the metabolism of 5-FU: thymidylate synthase (TS), thymidylate phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). Several studies suggest that a high level of expression of these three genes correlates with a poor clinical response to 5-FU. The main purpose of our study was to look for a correlation between the levels of expression of the genes for sensitivity to 5-FU (TS, TP, DPD) within the tumor and the clinical response observed after three courses of chemotherapy combining 5-FU/platinum salt in patients presenting with advanced cancer of the pharyngo-larynx. Methods This was a prospective genetic study that had required approval from the Ethics Committee. The main assessment criterion was based on the assessment of the clinical response by an ENT panendoscopy and a cervical CT scan, after three courses of chemotherapy. The expression of the genes was determined by quantitative RT-PCR, using total RNA extracted from tumor biopsies taken during the initial panendoscopy. Results The means calculated, in our study, for the three genes of interest (TS, TP, DPD) were lower in the responder group than those in the non-responder group. Discussion Our preliminary findings reveal trends that confirm the hypothesis that the lower the level of expression of the sensitivity genes, the better the clinical response to chemotherapy. They now form part of a larger study that is currently in progress.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and it is responsible for up to one million deaths annually. Although multiple risk factors for HCC have been identifi ed, and despite preventive measures, the incidence of HCC continues to rise to epidemiologic proportions in the United States. In general, tumor resection and orthotopic liver transplantation are the treatment with the best outcome; however, HCC is generally diagnosed late in its course when patients are not eligible for curative treatment options. HCC is a relatively Chemo-refractory tumor secondary to heterogeneity of the tumor and the high rate of multidrug resistant gene expression. There are no standard treatments for HCC, multiple palliative treatment modalities have been used for patients with unresectable disease. None of these modalities have shown any superiority; and the retrospective nature of these available data has confounded any reasonable conclusions. Different institutions use different treatment schema dependent on the center expertise. Sorafenib, a tyrosine kinase inhibitor, has recently demonstrated a survival advantage in metastatic HCC, and if approved by the FDA, might become the standard of care. In this article we will review the rationale behind the currently available treatment options for HCC.In 125 early breast cancer patients who underwent multiple bone marrow aspirates, there was no significant difference in terms of disease-free and overall survival after a median follow-up of 163 months between the patients with or without micrometastasis at the time of primary surgery. However, when the time-dependent evolution of the bone marrow aspirates was taken into account, some evidence for a longer disease-free and overall survival was found for the patients with negative bone marrowWe present a 20-year-old male patient with localized osteosarcoma arising in osteogenesis imperfecta who underwent high-dose chemotherapy together with autologous peripheral blood stem cell transplantation followed-by a successful extremity sparing surgery.A 74-year-old man presented with gradual wall thickening of a cystic lung lesion. Serologic tests indicated Aspergillus infection, but neither fungal organisms nor evidence of malignant disease were recovered from repeated sputum collections, a bronchoscopic lung biopsy specimen, or bronchial washings. Treatment with antifungal agents did not result in clinical improvement. Surgical resection of the lesion demonstrated both squamous cell carcinoma and aspergillosis. These distinct disorders share common radiologic manifestations that can present a diagnostic challenge, as in the present case.DCIS is a heterogeneous group of non-invasive cancers of the breast characterized by various degrees of differentiation and unpredictable propensity for transformation into invasive carcinoma. We examined the expression and prognostic value of 9 biological markers with a potential role in tumor progression in 133 patients with pure DCIS treated with breast conserving surgery alone, between 1982–2000. Histology was reviewed and immunohistochemical staining was performed. Pearson correlation coefficient was used to determine the associations between markers and histopathological features. Univariate and multivariate analysis examined associations between time to recurrence and clinicopathologic features and biological markers. Median age at diagnosis was 55 years (25–85). With a median follow up of 8.91 years, 41/133 patients recurred (21 as invasive recurrence). In this cohort 13.5% had low, 43% intermediate and 42% high nuclear grade. Comedo necrosis was found in 65% of cases. Expression of ER (62.4%), PR (55.6%), HER2/neu (31.6%), MIB1 (39.8%), p53 (22.6%), p21 (39.8%), Cyclin D1 (95.5%) calgranulin (20.5%), psoriasin (12%), was found in DCIS. HER2/neu was overexpressed in 45% that recurred as DCIS and 42.9% that recurred as invasive cancer, and only in 26.1% in cases that never recurred. On univariate analysis, HER2/neu overexpression was the only marker associated with an increased risk for any recurrence (p = 0.044). The hazard ratio for recurrence for HER2/neu positive DCIS was 1.927 (confidence interval 1.016–3.653) compared to HER2 negative DCIS. On multivariate analysis, HER2/neu overexpression remained the only independent variable significantly associated with any recurrence (p = 0.014) and with invasive recurrence (p = 0.044). This data suggest that HER2/neu testing may become an important parameter in the management of DCIS and the treatment of cases with positive HER2/neu status could be modified accordingly, similar to the current approach for HER2/neu positive invasive disease.