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Biomedical subjects

Harubumi Kato

Publications and source records attributed to Harubumi Kato.

At least 19 recordsLinked to original sources
PubMed2006

Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy.

BACKGROUND: Eg5 is a microtubule motor protein that functions in bipolar spindle assembly. We investigated the relationship between Eg5 expression and the response to chemotherapy of patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eg5 expression was investigated immunohistochemically in 122 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. We also investigated cyclin B1 expression, which is involved in the G2/M transition. All patients received antimitotic agents combined with platinum chemotherapy. The response to chemotherapy was compared in relation to Eg5 and cyclin B1 expression and in relation to clinicopathological factors. RESULTS: The response rate to chemotherapy of patients with Eg5-positive tumors was 37%, as opposed to 10% for patients with Eg5-negative tumors, and Eg5 expression was significantly associated with the response to chemotherapy (P=0.002). The response rate of patients with cyclin B1-positive tumors (53%) was higher than that of patients with cyclin B1-negative tumors (23%) (P=0.009), and Eg5 expression was significantly correlated with cyclin B1 expression (P=0.005). A multivariate analysis confirmed Eg5 status to be an independent variable related to response to chemotherapy (P=0.008). CONCLUSIONS: Eg5 expression can predict a response to antimitotic agents combined with platinum chemotherapy among patients with advanced NSCLC.

Adult↗
PubMed2006

Systemic antitumor effect of intratumoral injection of dendritic cells in combination with local photodynamic therapy.

PURPOSE: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of naïve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC-treated tumors. EXPERIMENTAL DESIGN: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated. RESULTS: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-gamma-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected naïve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases. CONCLUSIONS: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.

Animals↗
PubMed2006

Coexpression of actin-related protein 2 and Wiskott-Aldrich syndrome family verproline-homologous protein 2 in adenocarcinoma of the lung.

PURPOSE: Highly invasive and metastatic cancer cells, such as adenocarcinoma of the lung cells, form irregular protrusions by assembling a branched network of actin filaments. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2). In this study, colocalization of Arp2 and WAVE2 in adenocarcinoma of the lung was investigated to elucidate its prognostic value. EXPERIMENTAL DESIGN: Immunohistochemical staining of Arp2 and WAVE2 was done on mirror sections of 115 adenocarcinomas of the lung from pathologic stage IA to IIIA classes. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of the coexpression of Arp2 and WAVE2. RESULTS: Immunoreactivity for both Arp2 and WAVE2 was detected in the same cancer cells in 78 (67.8%) of the 115 lung cancer specimens. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with lymph-node metastasis (P = 0.0046), and significantly lower in bronchioloalveolar carcinomas (P < 0.0001). The patients whose cancer cells coexpressed them had a shorter disease-free survival time (P < 0.0001) and overall survival time (P < 0.0001). Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent risk factor for tumor recurrence. CONCLUSIONS: Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome, and may be involved in the mechanism of cancer metastasis.

Actin-Related Protein 2↗
PubMed2006

Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS: Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION: Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Aged↗
PubMed2006

Early detection of bronchial lesions using newly developed videoendoscopy-based autofluorescence bronchoscopy.

The combination of white light and autofluorescence bronchoscopy has been reported to show better sensitivity in detecting dysplasia and cancer of the bronchus than white light alone. However, fiberoptic bronchoscopy has been replaced by videoendoscopy at most leading facilities for over a decade. To avoid interruption of the videoendoscopy examination to perform fiberscopy-based autofluorescence examination as well as enhancing the sensitivity of intraepithelial lesions, autofluorescence diagnosis system integrated into a videoendoscope (SAFE 3000, Pentax, Tokyo) was created. A total of 154 consecutive patients were studied using this system, containing 83 known or suspected lung cancer cases, 46 of the cases with abnormal sputum cytology findings, 10 follow up cases following lung cancer operations, and 15 heavy smokers with respiratory symptoms. Abnormal findings were recognized by white light and/or SAFE 3000 at 166 sites and biopsies were taken to evaluate the relationship between endoscopic findings and pathology results. The sensitivity of the system for CIS+dysplasia was 65% in white light and 90% in SAFE. This videoendoscopy-based autofluorescence system had significantly higher sensitivity for intraepithelial lesions than white light videoendoscopy alone.

Adult↗
PubMed2006

Plasma proteomics of lung cancer by a linkage of multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis.

To investigate aberrant plasma proteins in lung cancer, we compared the proteomic profiles of serum from five lung cancer patients and from four healthy volunteers. Immuno-affinity chromatography was used to deplete highly abundant plasma proteins, and the resulting plasma samples were separated into eight fractions by anion-exchange chromatography. Quantitative protein profiles of the fractionated samples were generated by two-dimensional difference gel electrophoresis, in which the experimental samples and the internal control samples were labeled with different dyes and co-separated by two-dimensional polyacrylamide gel electrophoresis. This approach succeeded in resolving 3890 protein spots. For 364 of the protein spots, the expression level in lung cancer was more than twofold different from that in the healthy volunteers. These differences were statistically significant (Student's t-test, p-value less than 0.05). Mass spectrometric protein identification revealed that the 364 protein spots corresponded to 58 gene products, including the classical plasma proteins and the tissue-leakage proteins catalase, clusterin, ficolin, gelsolin, lumican, tetranectin, triosephosphate isomerase and vitronectin. The combination of multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis provides a valuable tool for serum proteomics in lung cancer.

Blotting, Western↗
PubMed2006

Large cell neuroendocrine carcinoma of the lung with a cystic appearance on computed tomography.

Almost all reported cases of large cell neuroendocrine carcinoma (LCNEC) of the lung are solid-type tumors. We encountered a rare case of LCNEC displaying a cystic shape. An abnormal cystic shadow was revealed on chest computed tomography in a 71-year-old man who underwent total gastrectomy due to gastric cancer 5 years earlier. The cystic lesion enlarged from 7 mm to 16 mm over 7 months, so surgery was performed for definitive diagnosis and therapy. Microscopy revealed rosette patterns, a high mitotic rate and a large area of necrosis. Neuroendocrine differentiation was confirmed on immunohistochemical examinations using chromogranin, synaptophysin and NCAM (CD56). Given these findings, LCNEC was diagnosed. This is the first report of LCNEC with a cystic shape. This case challenges preconceptions regarding the radiographic appearance of LCNEC.

Aged↗
PubMed2006

Omental transposition for lymphedema after a breast cancer resection: report of a case.

Lymphedema of the arm and hand is one of the major complications after a breast cancer resection. Conservative treatment for the treatment of lymphedema, such as compression garments and centripetal massage, is very important for these cases. However, if the lymphedema is difficult to control with conservative treatment and the patient's quality of life (QOL) is compromised due to swelling of the arms, surgical treatment should be considered. We used omental transposition to improve the status of lymphedema in the present patient whose left arm and hand had been swollen for 5 years, which thus prevented her from being able to lift her arm. After the operation, she was able to lift her left arm herself and perform tasks with her left hand, thereby obtaining a better QOL than before the operation regarding her left arm movement.

Aged↗
PubMed2006

Immunohistochemical differential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel.

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Biomarkers, Tumor↗
PubMed2006

Hypereosinophilia in a patient with invasive thymoma with clonal T-lymphocyte expansion expressing CD4, CD8, and CD25 antigens.

We report the case of a patient with hypereosinophilia and invasive thymoma harboring probable clonal proliferation of CD4+, CD8+, and CD25+ T-lymphocytes. A 64-year-old woman had eosinophilia (14.1 x 10(9)/L) and an anterior mediastinal tumor with elevated levels of serum immunoglobulin E (609.8 mg/dL) and interleukin 5 (239 pg/mL). Bone marrow aspirate showed marked infiltration by morphologically normal eosinophils with a normal karyotype but no FIP1L1-PDGFRA fusion gene. Flow cytometric analysis revealed an increasing number of CD3+/CD25+ lymphocytes in the peripheral blood, and the resected thymoma had infiltrated lymphocytes with CD4/CD8/CD25 antigens. Moreover, the thymoma had T-cell receptor rearrangements with a cytogenetically clonal nature, ie, t(2;4)(p22;q26). Although the number of patients with thymoma showing hypereosinophilia is small, this case suggests that a subset of patients with thymoma may have clonal expansion of T-lymphocytes with abnormal phenotypes that affect clinical manifestations, including hypereosinophilia.

Antigens, CD↗
PubMed2006

Present status of clinical proteomic analysis for the early detection and determination of therapeutic strategy in lung cancer.

Although human DNA sequences have already been successfully decoded, there is still much we do not understand about the pathogenesis of human diseases. Proteomic analysis is comprehensive analysis of proteins, and there is a high probability that recent advances in this field will enable its application to individualized therapy based on thorough understanding of the pathogenesis of human diseases. Two-dimensional polyacrylamide gel electrophoresis (2-DE) and mass spectrometry (MS) are indispensable tools for proteomic analysis, and these technologies enable discovery of tiny changes of protein expression associated with pathogenesis. In this review we introduce the present status of proteomic analysis for cancer-related proteins, and especially lung cancer-related proteins in the attempt to discover new biomarkers for early detection and determine novel target-molecules for treatment. We believe that proteomic analysis will provide crucial information for diagnosis and treatment.

Adenocarcinoma↗
PubMed2006

Ultraflex expandable stents for the management of air leaks.

Postoperative empyema and aspergillosis were diagnosed in a 66-year-old man. Since non-operative therapy was not effective, we performed surgery. On the 8th postoperative day, a covered Ultraflex expandable stent (Boston Scientific, Galway, Ireland) was implanted to make a one-way airway for blocking a major air leak from a bronchopleural fistula causing respiratory distress. His general condition improved gradually, and he was discharged 30 days after stenting. In conclusion, we used a covered Ultraflex expandable stent to make an airway to block an air leak. This may be a new application for this stent.

Aged↗
PubMed2006

Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na).

ATX-s10 is a novel and second-generation photosensitizer for photodynamic therapy (PDT). In order to conduct clinical trials of ATX-s10-PDT and/or extend its clinical applications, it is very important to elucidate the mechanisms of the action of ATX-s10-PDT. We examined the apoptic response against ATX-s10-PDT using a Bcl-2 or Bcl-2 mutant overexpressing cells. Using fluorescent microscopy, ATX-s10 localized not only to mitochondria but also to lysosomes and possibly other intracellular organelles, but not to the plasma membrane or the nucleus. These results suggest that ATX-s10-PDT can damage mitochondria and lysosomes. By Western blot analysis, ATX-s10-PDT damaged Bcl-2, which localized preferentially at mitochondrial membranes, and caused Bcl-2 to cross-link immediately after laser irradiation. However, ATX-s10-PDT was not able to rapidly induce morphologically typical apoptosis (i.e. chromatin condensation and fragmentation) as PDT using mitochondria targeted photosensitizers, such as phthalocyanine 4 (Pc 4). Pharmacological inhibitions of lysosomal cytokine protease cathepsins, such as cathepsin B and D, protected MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) from apoptosis caused by ATX-s10-PDT. Overexpression of wild-type Bcl-2 or Bcl-2Delta33-54 resulted in relative resistance of cells to ATX-s10-PDT, as assessed by the degree of morphological apoptosis or loss of clonogenicity. We conclude that lysosomal damage by ATX-s10-PDT can initiate apoptotic response and this apoptotic pathway can be regulated by photodamage to Bcl-2 via mitochondrial damage.

Apoptosis↗
PubMed2006

[An advanced pulmonary adenocarcinoma case in which TS-1 proved effective].

A sixty-two-year-old female presented with non-small-cell lung carcinoma with multiple bone metastasis. Combination chemotherapy with CBDCA and GEM was implemented, but as no effect was obtained, TS-1 was begun with a single course of oral administration of 100 mg/day continuously for 28 days followed by a 14-day rest. Following the start of TS-1, PR of the primary tumor was obtained, and whole-body bone scintigraphy revealed a reduction in abnormal areas of uptake. The woman continues to receive TS-1 orally as an outpatient.

Adenocarcinoma↗
PubMed2006

[A possibility of overcoming local tumor immune tolerance by radiofrequency ablation in combination with intratumoral injection of naïve dendritic cell].

Recently we reported the systemic antitumor efficacy of intratumoral naive dendritic cell injection (IT-DC) in combination with local photodynamic therapy in Clinical Cancer Research 2006. In general, tumor cells secrete several immune suppression cytokines which could induce immune tolerance in a tumor microenvironment. The rationale and advantages of IT DC in combination with conventional antitumor therapy are as follows: (1) dying tumor cells release some tumor antigens, (2) sufficient number of DC recruiting occurs at tumor site, (3) there is naive DC capturing some tumor antigens in vivo, (4) DC activation by inflammatory cytokines are released from dying tumor cells, and (5) DC migration happens in regional lymph nodes and induces adoptive tumor immunity. Conventional antitumor therapy before IT DC could destroy the immune tolerance at a tumor site and induce durable DC vaccination. In this report, we demonstrated the mechanism of (4) and (5) by radiofrequency ablation plus IT DC using mouse tumor model.

Animals↗
PubMed2005

Percutaneous CT-guided fine needle aspiration for lung cancer smaller than 2 cm and revealed by ground-glass opacity at CT.

The purpose of this retrospective study was to evaluate the value of preoperative percutaneous CT-guided fine needle aspiration biopsy (CTNB) for peripheral lung cancers less than 2 cm in size, especially in cases showing of ground-glass opacities (GGO). From 1999 to 2002, 151 small lung cancers were resected in Tokyo Medical University Hospital. Among them, 96 patients (63.6%) in whom the lesions were located in the outer half of the lung field underwent CTNB in order to obtain a preoperative diagnosis. The factors influencing the diagnostic yield were analyzed. The overall diagnostic yield of CTNB was 64.6%: 48.5% for lesions smaller than 10 mm, 62.5% for those 11-15 mm, and 83.9% for those 16-20 mm, respectively. The diagnostic yield in GGO-dominant lesions (GGO ratio < 50%) and solid-dominant lesions (GGO ratio < 50%) were 51.2% and 75.6% (p = 0.018). In the GGO-dominant group, the diagnostic yields were 35.2% for lesions smaller than 10 mm, 50.0% for those 11-15 mm, and 80.0% for those 16-20 mm. In the solid-dominant group, diagnostic yield was 62.5% for cases smaller than 10 mm, 75% for 11-15 mm and 85.7% for 16-20 mm, respectively. Satisfactory diagnostic yield (>80%) was obtained by CTNB in cases larger than 15 mm. CTNB is a useful diagnostic modality for peripheral small lung cancers; however, for GGO-dominant lesions, the preoperative diagnostic yield is not significantly better than for solid-dominant lesions.

Biopsy, Needle↗
PubMed2005

Identification of postoperative adjuvant chemotherapy responders in non-small cell lung cancer by novel biomarker.

Cisplatin-based (CDDP-based) adjuvant chemotherapy of non-small cell lung cancer (NSCLC) was reported to yield 5-15% improvement in 5-year survival compared to complete resection alone. The importance of information concerning preselection of good responders has become increasingly evident. The purpose of our study is the establishment of a preselection of good responders for CDDP-based adjuvant chemotherapy. We investigated protein expressions comparing intensity between parent strains (H69 and PC14 lung cancer cultured cells) and resistant strains against CDDP using 2-dimensional polyacrylamide gel electrophoresis (2-DE). Immunohistochemically, we evaluated the relationship between protein expression associated with CDDP-resistance and the clinical effects of platinum-based postoperative adjuvant chemotherapy using 126 surgically-resected NCLC materials. We detected 2 kinds of polypeptides that changed expression levels on 2-DE gels. The analyses of the amino acid sequence showed that these polypeptides were reticulocalbin (RCN) and glutathione-S-transferase-pi (GST-pi). The 2-DE analysis showed decreased expression in RCN and overexpression in GST-pi with the acquisition of CDDP-drug resistance. RCN-transfectant of H69 CDDP-resistant strain showed intermediate sensitivity between the parent strain and the CDDP-resistant strain. RCN-positive cases showed a statistically significant better disease-free survival only in the cases receiving postoperative platinum-based adjuvant chemotherapy after curative resection (p = 0.007). In addition, cases that were both RCN-positive and GST-pi-negative showed a statistically significantly better outcome (p = 0.0150). In the cases without postoperative adjuvant chemotherapy no relationship between the outcome and these expressions was seen. The evaluation of RCN and GST-pi might provide valuable information concerning postoperatively therapeutic strategy from the standpoint of individualized postoperative therapy.

Amino Acid Sequence↗