The N-ERC index is a novel monitoring and prognostic marker for advanced malignant pleural mesothelioma.

BACKGROUND: Although N-ERC/mesothelin (N-ERC) is an attractive diagnostic and treatment monitoring biomarker for malignant pleural mesothelioma (MPM), its clinical utility for predicting the prognosis has not yet been clarified. The aim of this study is to investigate whether the serum N-ERC level can accurately predict the outcome in patients with MPM. METHODS: Twenty-six patients with MPM were enrolled. Serum N-ERC level was measured before and after chemotherapy. The N-ERC index was determined by the logarithm of the division of the N-ERC level after two courses of chemotherapy by the prior level. RESULTS: The median N-ERC index in the partial response (PR) group was significantly lower than that in patients with the stable disease (SD) plus the progressive disease (PD) group. The overall survival in the group whose median N-ERC index was lower than its median value was significantly longer than the group whose median N-ERC index was higher than its median value. CONCLUSIONS: The N-ERC index is therefore considered to be a useful biomarker for predicting not only the chemotherapeutic response, but also the prognosis in patients with advanced MPM.

A feasibility study of zoledronic acid combined with carboplatin/nedaplatin plus paclitaxel in patients with non-small cell lung cancer with bone metastases.

AIMS AND BACKGROUND: Although zoledronic acid (ZOL) has been reported to inhibit bone metastasis from lung cancer, the optimum chemotherapy regimen in combination with ZOL has not yet been determined. METHODS AND STUDY DESIGN: Eighteen patients having non-small cell lung cancer (NSCLC) with bone metastasis who received carboplatin/nedaplatin plus paclitaxel combined with ZOL (4 mg every 28 days) were enrolled to investigate the feasibility of this treatment. The efficacy was evaluated by the percentage of patients at 9 months who were receiving radiation therapy, the time to first radiation treatment, and quality of life. Adverse effects were also evaluated. RESULTS: Only 3 among 18 patients received radiation therapy for bone metastases during the 9 months of the study. ZOL seems to prolong the median time to the first radiation treatment and maintain the quality of life regarding pain and activity status. No patients discontinued the treatment, although grade 3 or 4 treatment-related adverse effects occurred in 8 patients. CONCLUSIONS: ZOL combined with carboplatin/nedaplatin plus paclitaxel is an effective and tolerable treatment for NSCLC with bone metastases.

Chronic myelogenous leukemia with mild basophilia as the predominant manifestation at presentation.

Chronic myelogenous leukemia (CML) is a clonal hematological malignancy typically presenting with basophilia and massive proliferation of differentiating myeloid cells. We report an atypical case of CML in which mild basophilia was the sole manifestation at presentation, and the condition persisted for 27 months with no sign of progression. This case reconfirms the importance of basophilia as a clinical manifestation of CML, and BCR-ABL FISH analysis should always be applied to cases of basophilia, even when the basophilia is modest and no other features of CML are present.

[Twelve cases of advanced thymic carcinoma: a clinical review].

Thymic carcinoma is comparatively rare and no standard treatment has been established for advanced stage cases. We reviewed our therapeutic experience in 12 cases of thymic carcinoma. They consisted of 9 men and 3 women, ranging from 38 to 69 years of age, with a mean age of 56.5. According to Masaoka's classification, 5 cases were stage III and 7 were preoperative stage IVb. Nine cases were squamous cell carcinoma and 3 were adenocarcinoma. Four cases of preoperative clinical stage III underwent extended thymectomy, but none were completely resected and were classified as stage IV postoperatively. Chemotherapy combined with radiation therapy was given in 1 case, chemotherapy (monotherapy) was given in 4 cases, radiation therapy was given in 1 case, and 2 cases received best supportive care. The median survival time (MST) of patients who had undergone combined modality treatments including surgery was 1971 days, which was longer than the MST of 567 days of patients who were not able to undergo surgery. The prognosis outcome of advanced thymic carcinoma is poor, but combined modality therapies such as surgery, chemotherapy and radiation can be effective for some advanced thymic carcinoma cases.

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer.

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.

[Efficacy of gefitinib according to smoking status in non-small cell lung cancer patients].

Gefitinib is a molecular targeting agent and more effective in patients with characteristics of oriental ethnicity, female gender, adenocarcinoma and non-smokers. It is sometimes effective in smokers, but few papers have focused on the association between efficacy and smoking history. The aim of this study is to evaluate the association between efficacy of gefitinib and patients' characteristics, especially smoking history. Between July 2002 and September 2006, 89 patients were diagnosed as non-small cell lung cancer and administered gefitinib. Eighty of them were assessable for efficacy and toxicity of gefitinib. Response rate was 16.2% and 39.6%(p=0.031)in smokers and non-smokers. Survival was statistically greater in non-smokers. In smokers, there are more cases which showed response to gefitinib with a lower smoking index and longer duration after smoking cessation. Smoking index and duration after smoking cessation should be considered when gefitinib is administered or EGFR mutation analysis is conducted in patients with non-small cell lung cancer.

ERC/mesothelin as a marker for chemotherapeutic response in patients with mesothelioma.

BACKGROUND: It has been recently reported that soluble mesothelin-related protein (SMRP), serum mesothelin, and osteopontin (OPN) are considered as relevant biomarkers for the diagnosis of mesothelioma. The aim of this study was to investigate whether serum N-ERC/mesothelin, an NH3-terminal fragment of mesothelin, and plasma OPN reflect chemotherapeutic effect in patients with mesothelioma. MATERIALS AND METHODS: Serum N-ERC/mesothelin and plasma osteopontin were determined with a sandwich enzyme-linked immunosorbent assay (ELISA) system. RESULTS: The average N-ERC ratio, determined by dividing the N-ERC levels following chemotherapy by those prior to chemotherapy, in the partial response (PR) group was significantly lower than that of the stable disease (SD)/progressive disease (PD) group. In contrast, the average OPN ratio, determined by dividing the OPN levels following chemotherapy by those prior to chemotherapy, in the PR group was not statistically different from that of the SD/PD group. CONCLUSION: N-ERC/mesothelin is considered as relevant in monitoring chemotherapeutic response in patients with mesothelioma.

Lymphangioleiomyomatosis diagnosed by immunocytochemical and genetic analysis of lymphangioleiomyomatosis cell clusters found in chylous pleural effusion.

A 37-year-old woman presented with a cough and discomfort in the chest. Computed tomography revealed the right pleural effusion and a number of cysts in the lungs. Thoracentesis revealed LAM cell clusters (LCC) in chylous pleural effusion, confirmed by immunocytochemical examinations showing that the cells at the center of cluster were LAM cells positive for alpha-smooth muscle actin and HMB45 and the outer layer was lymphatic endothelium cells. When LCC were cultured in vitro, the loss of heterozygosity of TSC2 markers was detected. This case illustrates that LAM can be diagnosed by the identification of LCC without an invasive biopsy if complicated with chylous effusion.

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.

[Usefulness of support during treatment by alignment with health centers and DOT during hospitalization].

OBJECTIVES: To evaluate the effectiveness of patient support by alignment with public health centers and DOT during hospitalization, on treatment completion of tuberculosis patients. SUBJECTS: Four hundred seventy-seven patients (male 344, female 133) newly admitted from July 1, 2002 to June 30, 2003 to our hospital were enrolled in the study. METHOD: The patients were divided into two groups: one comprised of the patients who were discussed in the conference held by the hospital staffs and the regional public health center staffs about the necessity of support for continuing treatment regularly after discharge from our hospital (Conference (+) group; N=306), and the other who were not discussed in the conference (Conference (-) group; N=171). The Conference (+) group was further divided into two groups: One comprised of the patients who were regarded to need support after discharge (Support (+) group; N=106), and the other no need of support after discharge (Support (-) group; N=200). The patients' characteristics and backgrounds were compared between the Conference (+) and the Conference (-) groups, and between the Support (+) and the Support (-) groups. The rate of treatment completion and of default were compared between the Conference (+) and the Conference (-) group, and between the Support (+) and the Support (-) group. They were also compared between the patients with and without DOT for a month during hospitalization, and between the patients who were treated for the first time (new case) and those who had been treated previously (retreated case) or who had been treated when they were admitted to our hospital and continued treatment after admission (continuous cases). RESULTS: There is no significant differences in patients' characteristics and backgrounds between the Conference (+) and Conference (-) groups, but the ratios of male, sputum-culture positivity, far advanced lesions on chest X-ray, hypoalbuminemia, and disemployment were higher in Support (+) group than in Support (-) group. The overall (N=477) treatment outcomes were as follows: cured (defined by sputum-culture negativity at completion of chemotherapy) 300 (62.9%), completed (defined by no sputum data at completion of chemotherapy) 90 (18.9%), failed 5 (1.0%), defaulted 6 (1.3%), transfer out 6 (1.3%) and death 70 (14.7%). Therefore, the ratio of treatment success (defined by cured+completed) was 390/477 (81.8%). Because of more died cases in Conference (-) groups, treatment success rate was significantly higher in the Conference (+) groups than in the Conference (-) groups. There were no significant differences in the rate of treatment success and of default between the Support (+) and the Support (-) groups, but no defaulter case was seen in the Support (+) group. There were no differences in the rate of treatment success and of default between the groups with and without DOT for a month during hospitalization. There were no differences in the rate of treatment success and of default between the groups with the retreated and continuously treated cases and the new cases. CONSIDERATIONS: Treatment success rate was excellent in our study. DOT for a month during hospitalization didn't affect the improvement of treatment success after discharge, partly because the education on tuberculosis treatment was sufficiently done for most patients during hospitalization and a nurse made a telephone call to the patient who didn't attend the outpatient department of the hospital. CONCLUSIONS: To hold conference with regional public health center is effective for completion of tuberculosis treatment.

[A case of primary squamous cell carcinoma of the lung with a metastatic thyroid tumor improved following chemotherapy].

Metastatic thyroid tumor is rarely diagnosed clinically. We report here a case of a 59-year-old male of a primary squamous cell carcinoma of the lung with metastatic thyroid tumor diagnosed by an ultrasonography-guided aspiration cytology. A squamous cell carcinoma of the lung (c-T4N3M1 stage IV) was diagnosed in March 2001, and so chemotherapy using carboplatin and paclitaxel was tried initially. A partial response was obtained. Then, he was re-admitted to our hospital because his thyroid gland was swollen. Ultrasonography-guided aspiration cytology of the thyroid tumor was performed and revealed a metastatic squamous cell carcinoma from the lung cancer. The patient was given chemotherapy using gemcitabine and docetaxel as second line chemotherapy. This reduced the thyroid tumor size and improved the symptoms.

Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth.

Angiogenesis, which is essential for tumor growth, is regulated by various angiogenic factors. Osteopontin (OPN) is expressed in various human tumors and is postulated to be involved in tumor progression. We have recently reported that culture medium with murine neuroblastoma C1300 cells transfected with OPN gene significantly stimulates human umbilical vein endothelial cell migration and induces neovascularization in mice by dorsal air sac assay. However, the effect of OPN on tumorigenesis as an angiogenic factor remains to be clarified. In this study, we injected the OPN-transfected C1300 cells and control cells into the nude mice subcutaneously. OPN-overexpressing C1300 cells significantly formed rapidly growing tumor as compared to the control cells in mice, although in vitro and in vivo cell growth rates were similar. In vivo tumorigenecity of these cells correlated with the amount of secreted OPN protein. In addition, neovascularization of OPN-transfected tumor was significantly increased in comparison with those of control cells by immunohistochemistry for CD31. In vitro chemoinvasiveness and gene expression of proteases including uPA, MMP2, 9, MT1-MMP, and cathepsin B, D, L, were not different between OPN-transfected and control cells determined with matrigel invasion assay and cDNA expression macroarray, respectively. Conclusively, these results strongly imply that OPN plays an important role in tumor growth through the enhancement of angiogenesis in vivo.

Restoration of CD44S in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity.

CD44 is a cell surface receptor for osteopontin (OPN) and hyaluronate. Transformation of normal tissue to a variety of cancers has been demonstrated to be associated with alterations of CD44 isoform expression. However, few reports have paid attention on differences in CD44S expression between non-small cell lung cancer (NSCLC) and adjacent normal lung tissue. In this study, we demonstrate that CD44S expression is down-regulated in NSCLC tissue when compared with paired normal lung tissue. To investigate the role of CD44S down-regulation in NSCLC cells, we reintroduced the CD44S back into the NSCLC cell line, H322 cells, which originally lack CD44S expression. The cytotoxicity by activated macrophage (RAW264.7 cells stimulated with lipopolysaccharide and interferon-gamma) against the H322 cells transfected with the CD44S gene (H322DeltaS) is more prominent than that against the H322 control transfectants (H322Deltaneo). The enhanced susceptibility of H322DeltaS cells to the activated macrophage cytotoxicity appears to be mediated by the interaction between CD44S expression on H322DeltaS cells and OPN produced by activated macrophages since it is completely blocked by either anti-OPN or anti-CD44 antibody. Moreover, H322DeltaS cells are attracted toward OPN produced by activated RAW264.7 cells to a much greater extent than H322Deltaneo cells. These findings suggest that CD44S down-regulation in NSCLC cells may confer a protective advantage of allowing escape from tumoricidal effector cells including activated macrophages of the host.