[The Achievements for"7-University Joint Project of Training Plan for Oncology Professionals].

In recent years, cancer medical care in Japan is required to respond to diversifying new needs and issues. Among these, the practical application of genomic medicine, measures against rare cancer and childhood cancer, and the response to specific problems that occur in cancer patients with different life stages are urgent issues to be resolved. The aim of this plan is to train multidisciplinary oncology professionals who provide personalized medicine that meets various new needs in cancer medicine through mutual cooperation between graduate school of medicine, nursing, pharmaceutics, and genetic counseling of 7 national, public and private universities and 9 faculties located in Osaka and Hyogo.

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.

Materials And Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan.

New Era for Next-Generation Sequencing in Japan.

Recent progress in understanding the molecular basis of cancer-including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes-has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF and HER2 has already been successfully translated into clinical practice for individuals with solid tumor. Next-generation sequencing (NGS) technologies have led to the ability to test for multiple cancer-related genes at once with a small amount of cells and tissues.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

Purpose: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.

Methods: VS-6063 was administered orally twice daily (b.

Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial).

Purpose: We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM).

Methods: Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy).

Functional Alteration of Natural Killer Cells and Cytotoxic T Lymphocytes upon Asbestos Exposure and in Malignant Mesothelioma Patients.

Malignant mesothelioma is caused by exposure to asbestos, which is known to have carcinogenic effects. However, the development of mesothelioma takes a long period and results from a low or intermediate dose of exposure. These findings have motivated us to investigate the immunological effects of asbestos exposure and analyze immune functions of patients with mesothelioma and pleural plaque, a sign of exposure to asbestos.

Suppression of heme oxygenase-1 activity reduces airway hyperresponsiveness and inflammation in a mouse model of asthma.

Objective: Carbon monoxide (CO) levels in expired gas are higher in patients with bronchial asthma than in healthy individuals. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes the degradation of heme to yield biliverdin, CO and free iron. Thus, HO-1 is implicated in the pathogenesis of bronchial asthma.

Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.

Background: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

Methods: This double-blind, randomised, placebo-controlled trial was done in 90 international centres.

Isolated metastases of hepatocellular carcinoma in the left atrium, unresponsive to treatment with sorafenib.

Isolated metastases in the left atrium that are discontinuous with an intrahepatic hepatocellular carcinoma (HCC) are extremely rare. This is the case report of a 46-year-old male patient with pulmonary metastases from HCC, who presented with a tumor in the left lung, extending to the left atrium through the left pulmonary vein. Two weeks after the initiation of treatment with sorafenib, the tumor metastasized to the left parietal cerebral lobe, with an intracranial hemorrhage.

Functional properties of CD8(+) lymphocytes in patients with pleural plaque and malignant mesothelioma.

It is known that asbestos exposure can cause malignant mesothelioma (MM) and that CD8(+) T cells play a critical role in antitumor immunity. We examined the properties of peripheral blood CD8(+) lymphocytes from asbestos-exposed patients with pleural plaque (PL) and MM. The percentage of CD3(+)CD8(+) cells in PBMCs did not differ among the three groups, although the total numbers of PBMCs of the PL and MM groups were lower than those of the healthy volunteers (HV).

Cell-adhesion molecule expression and the proliferation of malignant mesothelioma: a post-mortem examination.

Aim: In order to determine if metastatic malignant mesothelioma cells are more aggressive than primary malignant mesothelioma cells, an analysis of the expression of the adhesion molecules E-cadherin and β-catenin, concomitant with an assessment of the proliferative activity at primary and metastatic sites, was conducted in post-mortem samples.

Materials And Methods: E-cadherin or β-catenin expression was graded according to the percentage of positively-stained tumor cells. The proliferative activity was quantified by the Ki-67 labeling index.

Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.

We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels.

Combined serum mesothelin and carcinoembryonic antigen measurement in the diagnosis of malignant mesothelioma.

Malignant mesothelioma (MM) is a highly aggressive tumor associated with asbestos exposure. The identification of a marker specific for MM may be of considerable value for the early detection of this tumor and may be used in particular to screen groups with a history of asbestos exposure. The aim of this study was to evaluate serum soluble mesothelin-related peptide (SMRP) levels as a diagnostic marker for MM and investigate whether its diagnostic value is enhanced by combination with other biomarkers.

Methotrexate and gemcitabine combination chemotherapy for the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor of serosal surfaces with a poor prognosis. Methotrexate and gemcitabine have exhibited single-agent activity in MPM. We evaluated the feasibility of sequential administration of these agents in the treatment of MPM.

Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM).

Purpose: To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM).

Methods: We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM.

Carboplatin plus either docetaxel or paclitaxel for Japanese patients with advanced non-small cell lung cancer.

Aim: Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: Chemotherapy-naïve patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days.

Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy.

Background: With the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE).

A feasibility study of induction pemetrexed plus cisplatin followed by pleurectomy/decortication aimed at macroscopic complete resection for malignant pleural mesothelioma.

A prospective multi-institutional study has been initiated in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by pleurectomy/decortication aimed at macroscopic complete resection in patients with resectable malignant pleural mesothelioma. The study was initiated on September 2012, for which 24 patients will be recruited over a period of 2 years. The primary endpoint is the macroscopic complete resection rate, regardless of the surgical technique employed (i.

Sphingosine suppresses mesothelioma cell proliferation by inhibiting PKC-δ and inducing cell cycle arrest at the G(0)/G(1) phase.

Background/aims: Sphingosine regulates cellular differentiation, cell growth, and apoptosis. The present study aimed at understanding sphingosine-regulated mesothelioma cell proliferation.

Methods: Human malignant mesothelioma cells such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells were cultured.

Gene therapy using adenovirus against malignant mesothelioma.

Background: Adenovirus vectors have been utilized for cancer gene therapies. The present study examined the oncolytic effects of adenovirus type 5 (Ad5) and fiber-substituted conditionally replicating adenovirus (CRAD) Ad5/F35 vectors on the human malignant mesothelioma cells MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452 cells.

Materials And Method: For the adenovirus, the first mRNA/protein to be made (~1 h after infection) is E1A.

Circulating endothelial cell (CEC) as a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM).

Background: The purpose of this study was to investigate the diagnostic and prognostic value of circulating endothelial cell (CEC), a potential surrogate of tumor angiogenesis, in malignant pleural mesothelioma (MPM).

Methods: We prospectively evaluated CEC count in 4.0 mL of peripheral blood sampled from patients with a suspicion of MPM.

A3 adenosine receptor-mediated p53-dependent apoptosis in Lu-65 human lung cancer cells.

Background/aims: A(3) adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A(3) adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line.

Methods: MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A(3) adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells.

AMP converted from intracellularly transported adenosine upregulates p53 expression to induce malignant pleural mesothelioma cell apoptosis.

Background/aims: The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells.

Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells, and p53 or A(3) adenosine receptor was knocked-down by transfecting each siRNA into cells.

Results: Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation.

Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma.

In the present study, we analyzed genomic alterations of BRCA1-associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non-epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence-level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence-level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss.