Levels of soluble vascular endothelial growth factor receptor 1 are elevated in the exudative pleural effusions

Purpose : Vascular endothelial growth factor (VEGF) plays a critical role in the production of malignant pleural effusions. In the present study, we examined the levels of soluble VEGF receptor-1 (sVEGFR-1) and angiopoietin-2 (Ang-2), as possible regulators of VEGF activity, in transudative and exudative pleural effusions. Methods : Forty-two patients were included in this study : 4 with transudative pleural effusions due to heart failure (HF), 38 with exudative pleural effusions (lung cancer [LC], 22 ; other malignant diseases [MD], 10 ; tuberculosis [TB], 6) . The levels of VEGF, Ang-2, and sVEGFR-1 in the pleural effusions were measured by an enzyme-linked immunosorbent assay. Results : The levels of VEGF, Ang-2, and sVEGFR-1 in exudative effusions were higher than those in transudative effusions. Interestingly, the levels of VEGF and Ang-2 in bloody effusions were significantly higher than those in non-bloody effusions (p < 0.05), but the level of sVEGFR-1 in bloody effusions was lower than that in non-bloody effusions. The levels of VEGF and Ang-2 were significantly higher in the malignant effusions, compared with effusion from HF and TB (p < 0.05). In addition, sVEGFR-1 was significantly higher in the effusion from LC, MD, and TB compared with effusion from HF (p < 0.05). In the malignant effusions, direct correlations were observed among VEGF, sVEGFR-1, and Ang-2. Conclusions : The sVEGFR-1 levels were elevated in exudative pleural effusions, and were lower in bloody effusions than in non-bloody effusions, thus suggesting the regulatory role of sVEGFR-1 in the exudative pleural effusions

The experience of a COVID-19 cluster in a clinical training hospital

We experienced a hospital cluster of COVID-19 in April 2021. The index case developed respiratory failure during hospitalization and was diagnosed with COVID-19 on day 8 of admission. Eleven people in the same ward were diagnosed with COVID-19 in relation to the case. All the patient in the ward were isolated. The ward stopped accepting new admissions. A task force was set up to conduct COVID-19 screening, infection control, patients and family support, and public information. No new cases occurred after day 12 of the outbreak. We started accepting new admissions to the ward on day 24, and declared convergence on day 47 of the outbreak. Since COVID-19 epidemic, our hospital had been developing infection control such as preoperative screening and providing education to the medical staff on infection prevention, which was not enough to prevent from the occurrence and spread of the COVID-19 nosocomial infections. The author, who was a clinical resident in the clinical training hospital at the time, experienced the outbreak and the process how it had been converged. From the resident’s perspective, we analyzed the factors that caused the outbreak, and discussed the efforts we had taken to converge it

アンシン カード オ モチイタ ガン カンジャ ノ キュウキュウ イリョウ タイセイ ノ コウチク ト ビョウビョウ ビョウシン レンケイ ノ ココロミ

Oncologic Emergency Medical（OCM）card is to guarantee medical care to be provided by Tokushima Municipal Hospital to advanced cancer patients who once receive medical care in the institution even after they are referred to other hospitals or when their medical condition is worsened. Forty-seven cancer patients have been issued with the OCM card between April２０１５ and March ２０１６. For those patients, we have retrospectively investigated the actual medical services provided by our hospital and cooperation with other hospitals and clinics. The card was issued for ３８ patients who were under palliative treatment. More than half of all the patients issued with the card were in the department of surgery, and eight of them were colon cancer patients, who consisted the largest portion. Exacerbation of pain was the most common reason for those who used the card at the emergency outpatient visit, but more than half of them could return home within the same day. Although seven of fourteen patients who were determined to be under home care were eventually re-hospitalized, all the fourteen patients were able to spend as long time as possible at their own home due to the card system. During one year after the introduction of the OCM card system, there has been no trouble with the acceptance of emergency outpatient visits and the cooperation of Tokushima Municipal Hospital with other hospitals and clinics

Pregnancy-associated plasma protein Aを悪性胸膜中皮腫細胞の遊走能を促進する遺伝子として同定 : 治療標的としての可能性

Despite recent advances in treatment, malignant pleural mesothelioma (MPM) remains a deadly disease. Targeted therapy generated broad interests and is highly expected for the treatment of MPM, yet promising preclinical results have not been translated into substantial clinical benefits for the patients. In this study, we tried to identify the genes which play functional roles in cell migration as well as to test whether they can be used as novel targets for molecular targeted therapy for MPM in preclinical model. In our study, pregnancy-associated plasma protein A (PAPPA) was identified as a gene whose expression level is correlated with MPM cell migration by correlation analysis combining MPM cell migration ability and their gene expression profiles. Highly migratory cells were selected from MPM cell lines, MSTO-211H, NCI-H290 and EHMES-1 in vitro and up-regulation of PAPPA in these cells were confirmed. In vitro, PAPPA was demonstrated to stimulate the MPM cell migration via cleavage of insulin-like growth factor-binding protein-4 and subsequent release of IGF-1. Gene silencing of PAPPA in MPM cells led to reduced migration, invasion and proliferation. Furthermore, PAPPA shRNA transfected NCI-H290 when orthotopically inoculated into pleural cavity of severe combined immunodeficiency recipient mice, failed to develop tumors and produce bloody pleural effusion as control shRNA transfected cells did. Our study suggests that PAPPA plays a functional role in promoting MPM cell migration and it might serve as a potential therapeutic target for the treatment of MPM

Lysophosphatidic acid stimulates the proliferation and motility of malignant pleural mesothelioma cells through lysophosphatidic acid receptors, LPA1 and LPA2

金沢大学がん研究所分子標的がん医療研究開発センターLysophosphatidic acid (LPA) is one of the simplest natural phospholipids. This phospholipid is recognized as an extracellular potent lipid mediator with diverse effects on various cells. Although LPA is shown to stimulate proliferation and motility via LPA receptors, LPA1 and LPA2, in several cancer cell lines, the role of LPA and LPA receptors for malignant pleural mesothelioma (MPM) has been unknown. MPM is an aggressive malignancy with a poor prognosis and the incidence is increasing and is expected to increase further for another 10-20 years worldwide. Therefore, the development of novel effective therapies is needed urgently. In this study, we investigated the effect of LPA on the proliferation and motility of MPM cells. We found that all 12 cell lines and four clinical samples of MPM expressed LPA1, and some of them expressed LPA2, LPA3, LPA4 and LPA5. LPA stimulated the proliferation and motility of MPM cells in a dose-dependent manner. Moreover, LPA-induced proliferation was inhibited by Ki16425, an inhibitor of LPA1, and small interfering RNA against LPA1, but not LPA2. Interestingly, LPA-induced motility was inhibited by small interfering RNA against LPA2, but not LPA1, unlike a number of previous reports. These results indicate that LPA is a critical factor on proliferation though LPA1, and on motility though LPA2 in MPM cells. Therefore, LPA and LPA receptors, LPA2 as well as LPA1, represent potential therapeutic targets for patients with MPM. © 2008 Japanese Cancer Association

Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice

金沢大学附属病院がん高度先進治療センターBone metastases occur in more than one-third of patients with advanced lung cancer and are difficult to treat. We showed previously the therapeutic effect of a third-generation bisphosphonate, minodronate, and antiparathyroid hormone-related protein (PTHrP) neutralizing antibody on bone metastases induced by the human small cell lung cancer cell line, SBC-5, in natural killer cell-depleted severe combined immunodeficient mice. The purpose of our current study was to examine the effect of the combination of PTHrP antibody and zoledronic acid, which has been approved to treat bone metastases, against bone metastases produced by SBC-5 cells expressing PTHrP. Treatment with PTHrP antibody and/or zoledronic acid did not affect the proliferation of SBC-5 cells in vitro. Repeated treatments with either PTHrP antibody or zoledronic acid inhibited the formation of osteolytic bone metastases of SBC-5 cells but had no effect on metastases to visceral organs. Importantly, combined treatment with PTHrP antibody and zoledronic acid further inhibited the formation of bone metastases. Histologic assays showed that, compared with either PTHrP antibody or zoledronic acid alone, their combination decreased the number of tumor-associated osteoclasts and increased the number of apoptotic tumor cells. These findings suggest that this novel dual-targeting therapy may be useful for controlling bone metastases in a subpopulation of small cell lung cancer patients. Copyright © 2009 American Association for Cancer Research.全文公開20100

Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats

Background : Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiationinduced lung disorders in an experimental model. Methods : The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. Results : Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1β), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. Conclusions : In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation

Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy

Analysis of the Prognostic Factors of Extensive Disease Small-Cell Lung Cancer Patients in Tokushima University Hospital

Background : Small-cell lung cancer (SCLC) presents aggressive clinical behavior, and its prognosis is still poor. Previously, performance status (PS), or the existence of brain, bone, or liver metastasis were reported to be unfavorable prognostic factors. Given the recent progress of treatment modalities such as radiotherapy techniques and bone modifying agents, the prognostic factors might be different from previous findings. Therefore, we analyzed the prognostic factors of extensive disease SCLC (ED-SCLC) in recent years. Methods : ED-SCLC patients treated in Tokushima University Hospital between 2010 and 2016 were analyzed. Log-rank test and the Cox proportional hazards regression model was used in univariate and multivariate analysis, respectively. Results : Totally, 79 patients were analyzed. In the univariate analysis, age, PS, interstitial pneumonia (IP), liver metastasis, pleural dissemination, neutrophil counts, hypoalbuminemia, hypercalcemia and several liver and biliary enzymes were identified as poor prognostic factors. In the multivariate analysis, age, PS, IP, and liver and biliary enzymes were identified. Moreover, the PS in patients with liver metastasis was significantly worsened. Conclusions : In this study, we newly demonstrated that IP was a significant poor prognostic factor of ED-SCLC. Although liver metastasis was not extracted in multivariate analysis, it may have an impact on the prognosis of ED-SCLC

Investigation of the outpatient chemotherapy for lung cancer patients in Tokushima University Hospital

Platinum-doublet regimens and docetaxel as first- and second-line chemotherapy, respectively, are shown to prolong the survival of lung cancer patients in various randomized phase III studies. However, the evidence for the efficacy of chemotherapy for lung cancer in the clinical practice is still insufficient. In the present study, we investigated the effectiveness and safety of outpatient chemotherapy for lung cancer in the clinical practice. Ninety-four lung cancer cases were retrospectively analyzed. Among these cases, 67 (71.3%) were non-small cell lung cancer (NSCLC) and 27 (28.7%) were small cell lung cancer (SCLC). The response rates in SCLC and NSCLC patients were 55.6% (15/27) and 16.9% (11/65), respectively. Objective tumor response rates for the patients were found to decrease substantially with each line of treatment as described previously. All adverse events were well tolerated and no treatment-related death was observed. Median time to treatment failures (TTFs) of first-line treatment were 10.1 months and 4.8 months in SCLC and NSCLC, respectively. These findings indicate that even in the setting of clinical practice, the efficacy and safety of chemotherapy is strictly insured by the appropriate therapeutic management