Pleural Mesothelioma Instigates Tumor-Associated Fibroblasts To Promote Progression via a Malignant Cytokine Network

The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.Malignant pleural mesothelioma (MPM) is a unique form of tumor, the development of which is highly related to asbestos exposure.¹ Even after bans on asbestos were initiated in the 1970s, MPM remains a serious problem worldwide because of its long latency period (30 to 40 years) and high mortality rate. In the United States, 2000 to 3000 patients die of MPM every year. Deaths from this disease are expected to peak in 2020 to 2025, with more than 250,000 deaths expected to occur in Western Europe and Japan over the next 40 years.² MPM grows aggressively, with dissemination in the thoracic cavity, and frequently produces a malignant pleural effusion.³ MPM is rarely diagnosed at an operable stage, and it is refractory to conventional chemotherapy and radiotherapy. Thus, the prognosis of patients with this disease is extremely poor, with median survival varying between 8 and 14 months after diagnosis, despite the recent development of a chemotherapy regimen combining cisplatin and an antifolate agent such as pemetrexed or raltitrexed.⁴The tumor microenvironment is crucial for the progression and chemosensitivity of various malignant diseases.⁵ For example, the tumor microenvironment mediates endocrine instigation of indolent metastatic tumor progression via osteopontin.⁶ Moreover, EGFR-TKI resistance may be induced by microenvironmental fibroblasts in epidermal growth factor receptor mutant lung cancer.⁷ Thus, innovative therapies may target the microenvironment. For example, antiangiogenic therapy targeting host endothelial cells and bisphosphonate targeting host osteoclasts have been successfully used to treat several malignant diseases, including colon cancer,⁸ non-small cell lung cancer,^9,10 and metastatic bone tumors.¹¹In MPM, angiogenesis inhibition using an anti-VEGF antibody targeting endothelial cells can successfully control the progression of MPM cells that produce high concentrations of VEGF.¹² Tumor-associated fibroblasts (TAFs), also known as cancer-associated fibroblasts, are the major component of tumor microenvironments.¹³ TAFs regulate tumor behavior through several mediators. Although recent studies show that many populations of MPM contain TAFs,¹⁴ little is known about interactions between TAFs and MPM. We therefore investigated the molecular interaction between MPM and TAFs, using an orthotopic implantation SCID mice model and clinical specimens taken from MPM patients. We show here that MPMs produce fibroblast-growth factor 2 (FGF-2) and platelet-derived growth factor-AA (PDGF-AA), and that these growth factors stimulate TAFs to produce hepatocyte growth factor (HGF), thus promoting tumor progression through a malignant cytokine network.     

A novel method for systematic analysis of rigidity in Parkinson's disease

We propose a novel system that analyzes the components of rigidity in Parkinson's disease (PD) usually perceived by physicians, in a very simple and systematic way for routine clinical practice. Our system is composed of two compact force sensors, a gyroscope, and EMG surface electrodes. Muscle tone was assessed in 24 healthy elderly subjects and 27 PD patients by passive extension and flexion of the elbow joint with ramp‐and‐hold trajectory. Torque and angle data in the dynamic phase were used to calculate “elastic coefficients” in extension and flexion, and the mean value of torque in each dynamic phase at each joint angle (defined as “Bias”) was also calculated. The muscle activity index in the static phase (EMG Index) was obtained for both biceps brachii (BB) and triceps brachii (TB) muscles. “Elastic coefficients,” sum of the “difference of Bias” and “EMG Index” for BB all correlated well with UPDRS score. Based on our results, Parkinsonian rigidity consists of both an “elastic” component and a “difference of Bias” component, and neurologists may assess greater rigidity when either one or both components are high in value. The EMG index was useful for differentiating PD patients with slight rigidity from healthy elderly adults. © 2009 Movement Disorder Society     

Enlarged accessory spleen presenting stomach submucosal tumor

A 62-year-old man presented with upper abdominal discomfort underwent upper gastrointestinal endoscopy. Gastroscopy and endoscopic ultrasonography revealed a submucosal tumor (SMT) with homogenous echogenicity originated from extragastric organs. An abdominal contrast-enhanced computed tomography (CT) showed that the well-marginated ovoid mass, approximately 6 cm in diameter, enhanced homogenously to a similar degree as splenic parenchyma. 99mTechnetium sulfur colloid scintigraphy revealed the splenic nature of the mass. A diagnosis of accessory spleen mimicking gastric SMT was made. Subsequent follow-up was uneventful without performing splenectomy.     

The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population

BACKGROUND/AIMS: The genetic predisposition on the development of nonalcoholic steatohepatitis (NASH) has been poorly understood. A functional polymorphism Val175Met was reported in phosphatidylethanolamine N-methyltransferase (PEMT) that catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine. The aim of this study was to investigate whether the carriers of Val175Met variant impaired in PEMT activity are more susceptible to NASH. METHODS: Blood samples of 107 patients with biopsy-proven NASH and of 150 healthy volunteers were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism. RESULTS: Val175Met variant allele of the PEMT gene was significantly more frequent in NASH patients than in healthy volunteers (p<0.001), and carriers of Val175Met variant were significantly more frequent in NASH patients than in healthy volunteers (p<0.01). Among NASH patients, body mass index was significantly lower (p<0.05), and non-obese patients were significantly more frequent (p<0.001) in carriers of Val175Met variant than in homozygotes of wild type PEMT. CONCLUSIONS: Val175Met variant of PEMT could be a candidate molecule that determines the susceptibility to NASH, because it is more frequently observed in NASH patients and non-obese persons with Val175Met variant of PEMT are facilitated to develop NASH.     

Unexpected tracheobronchomalacia during cardiac operation in a patient with Marfan's syndrome

A 56-year-old man with Marfan's syndrome was scheduled for a valve-sparing aortic root replacement operation because of annuloaortic ectasia and aortic regurgitation. He had severe dyspnea. When the operation started, SpO2 decreased at the time of the median sternotomy, and increased by manual inflation. After sternal closure, PIP increased from 20 cmH2O to 28 cmH2O, SpO2 decreased from 98% to 66%, and the expiratory pattern indicated airway obstruction. Because hypoxemia persisted, we reopened the sternum, resulting in increased SpO2 and decreased PIP, but hypercapnea remained. Fiberoptic bronchoscopy revealed a narrowing of the tracheal and bronchial lumen. We suspected tracheobronchomalacia, and the tracheal tube was advanced to just above the carina. We succeeded in extubating 7 days after the operation. Since he had severe persisting dyspnea, we suggested reopening the partial sternum to decompress the intrathoracic pressure, and closing the skin. The sternum was reopened, and he had no dyspnea after the second operation. The mechanism of tracheobronchomalacia is considered to be related to the connective tissue defect of Marfan's syndrome. Suddenly SpO2 is decreased and PIP and Et(CO2) are increased after closure of the sternum. Bronchoscopy was useful in making the diagnosis.     

The mucosal adjuvanticity of the oligodeoxynucleotides containing a non-methylated CpG motif on BCG and diphtheria toxoid

CpG-DNA is currently attracting attention as an effective and safe vaccine adjuvant to prevent from microbial infections. In this report, we examined the effects of oligo B, which is a synthetic CpG-DNA, in mucosal administration of Bacillus Calmette-Guérin (BCG) and diphtheria toxoid (DT). Co-administration with oligo B enhanced BCG-induced delayed type hypersensitivity to purified protein derivative (PPD) in guinea pigs. The titers of anti-DT serum IgG, IgA and mucosal IgA antibodies induced by intranasal administration with DT plus oligo B were significantly higher than that with DT alone. In both C57BL/6 and BALB/c mice, intranasal administration of DT with oligo B induced enough level of antibodies to prevent onset of diphtheria. The analysis of antibody subclasses showed that intranasal administration of oligo B induced not only IgG1 but also IgG2a, IgG2c and IgA anti-DT antibodies. In contrast, there was no or little production of the anti-DT serum IgE. Taken together our data suggest that oligo B is a powerful adjuvant in mucosal immunization.     

Reconstruction of the middle hepatic vein tributaries draining segments V and VIII of a right liver graft by using the recipient’s own middle hepatic vein and vascular closure staples

A right liver graft lacking the middle hepatic vein can result in congestion of the anterior segment. We describe a method of reconstructing the middle hepatic vein tributaries by using the recipient’s own middle hepatic vein with vascular closure staples. During a living donor right liver transplantation, the middle hepatic vein tributaries draining segments V (V5) and VIII (V8) of the right lobe graft were reconstructed using the recipient’s own middle hepatic vein and secured with vascular closure staples. Computed tomography showed good venous outflow from the middle hepatic vein and no congestion or atrophy of the anterior segment of the right liver grafts. Thus, using the recipient’s own middle hepatic vein is a suitable option for reconstructing the middle hepatic vein tributaries (V8 and V5) in right-liver living donor transplantation and the application of vascular closure staples helps to accomplish this.     

MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) as a low-dose salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma

We conducted a clinical study of MTX-HOPE (day 1, methotrexate 20 mg per os (po); day 2, hydrocortisone 100 mg intravenous (iv), vincristine 1 mg iv; day 3,4 sobuzoxane 400 mg po; etoposide 25 mg po, repeating every 2 or 3 weeks) in 14 relapsed or refractory patients with non-Hodgkin's lymphoma. Ten responders were obtained 5 CR and 5 PR), and heavily treated patients were included in the responders. The median duration of over all survival which was estimated with Kaplan-Meier curve was 11.1 months (range, 2-18+ months), and the median duration of response was 6.9 months (range, 0.8+ -16.4+ months).Out of the 14 patients,eleven were treated with this regimen in an outpatient setting. Grade 4 neutropenia and thrombocytopenia were observed in 4 and 2 patients,and grade 3 GPT-elevation and stomatitis in two and one, respectively. This newly developed MTX-HOPE therapy may be a promising treatment option for such patients as are intolerable for high-dose chemotherapies with PBSC rescue or wish for outpatient therapy.