Role of the VEGF-Flt-1-FAK pathway in the pathogenesis of osteoclastic bone destruction of giant cell tumors of bone

BACKGROUND: Giant cell tumors (GCTs) of bone are primary benign bone tumors that are characterized by a high number of osteoclast-like multinuclear giant cells (MNCs). Recent studies suggest that the spindle-shaped stromal cells in GCTs are tumor cells, while monocyte-like cells and MNCs are reactive osteoclast precursor cells (OPCs) and osteoclasts (OCs), respectively. In this study, we investigated the pathogenesis of osteoclastic bone destruction in GCTs by focusing on the role of the vascular endothelial growth factor (VEGF)-Flt-1 (type-1 VEGF receptor)-focal adhesion kinase (FAK) pathway. METHODS: The motility of OPCs cells was assessed by a chemotaxis assay and the growth of OPCs was examined using a cell proliferation assay. The expression of VEGF and activation of Flt-1 and FAK in clinical GCT samples and in OPCs were detected by immunohistochemistry and immunoblotting. The correlation between the expression levels of activated Flt-1 and FAK and clinical stages of GCTs was investigated by immunohistochemistry. RESULTS: In GCT samples, CD68, a marker of OPCs and OCs, co-localized with Flt-1. Conditioned media from GCT tissue (GCT-CM) enhanced the chemotaxis and proliferation of OPCs. GCT-CM also stimulated FAK activation in OPCs in vitro. Moreover, there was a correlation between the clinical stage of GCTs and the expression of tyrosine-phosphorylated Flt-1 and FAK. CONCLUSIONS: Our results suggest that the VEGF-Flt-1-FAK pathway is involved in the pathogenesis of bone destruction of GCTs

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

重症例からみた気管支喘息治療の現状と危機管理に関する検討

1998年よりステロイド剤規則的吸入療法を主体としたガイドライン療法が導入され喘息死は徐々に減少してきたが,2000年度の本邦における喘息死は4,473名を数える.標準的治療が確立されたにもかかわらずなぜ死亡例が多いのかを,救命救急センターに3次救急搬送された重症気管支喘息患者54例を対象に検討した.救急搬送前の投薬内容をみると,ガイドラインにそった治療は行われず,喘息発作時だけβ受容体刺激剤(スプレー)を使用していた症例が平均92.9%でCPA(cardio pulmonary arrest)症例では100%であった.それに対してステロイド剤規則的吸入療法は2例3.7%にしか行われていなかった.気管支喘息を専門とする呼吸器専門医やアレルギー専門医はガイドラインにそった治療を行っているが,一般臨床医には未だ浸透していない可能性が示唆された.気管支喘息死を減少させるには,一般臨床医による患者教育の徹底,ステロイド剤規則的吸入療法をベースにした適切な定期的通院・治療の厳守,発作急変時に備えた病歴カードの常時携帯,救急医療機関側は救急隊のオーバートリアージを容認するなど危機管理の徹底を図ることが重要と考えられた.Asthmatic deaths have been gradually reduced since 1998 when regular steroid inhalation therapy was proved effective and widely introduced as guideline therapy. There were, however, still as many as 4,473 Japanese people who died of asthma in 2000. We examined the reasons for this large number of deaths, despite establishment of the guideline therapy, by investigating emergency patients who were carried to our emergency care center by ambulance as tertiary emergency cases for treatment of serious asthma. The investigation of medications used before emergency arrival showed that patients were not treated according to the guideline therapy: 92.9% of all patients and 100% of CPA (cardio pulmonary arrest) patients were treated with β-receptor stimulators (spray) only when they had asthmatic fits, and regular steroid inhalation therapy was performed on only 2 patients (3.7%). Although respiratory and allergy experts specializing in bronchial asthma follow the guideline therapy, it may not be widespread among general clinicians. To reduce the deaths from bronchial asthma, it is important to fully manage the possible risks of bronchial asthma by making general practitioners give patients full information on the disease; making patients strictly follow the appropriate hospital visit and treatment schedule based on regular steroid inhalation therapy; instructing patients to always carry their medical history cards for sudden attacks of bronchial asthma; and persuading emergency care centers to permit over-triaging by ambulance teams

重症例からみた気管支喘息治療の現状と危機管理に関する検討

1998年よりステロイド剤規則的吸入療法を主体としたガイドライン療法が導入され喘息死は徐々に減少してきたが,2000年度の本邦における喘息死は4,473名を数える.標準的治療が確立されたにもかかわらずなぜ死亡例が多いのかを,救命救急センターに3次救急搬送された重症気管支喘息患者54例を対象に検討した.救急搬送前の投薬内容をみると,ガイドラインにそった治療は行われず,喘息発作時だけβ受容体刺激剤(スプレー)を使用していた症例が平均92.9%でCPA(cardio pulmonary arrest)症例では100%であった.それに対してステロイド剤規則的吸入療法は2例3.7%にしか行われていなかった.気管支喘息を専門とする呼吸器専門医やアレルギー専門医はガイドラインにそった治療を行っているが,一般臨床医には未だ浸透していない可能性が示唆された.気管支喘息死を減少させるには,一般臨床医による患者教育の徹底,ステロイド剤規則的吸入療法をベースにした適切な定期的通院・治療の厳守,発作急変時に備えた病歴カードの常時携帯,救急医療機関側は救急隊のオーバートリアージを容認するなど危機管理の徹底を図ることが重要と考えられた.Asthmatic deaths have been gradually reduced since 1998 when regular steroid inhalation therapy was proved effective and widely introduced as guideline therapy. There were, however, still as many as 4,473 Japanese people who died of asthma in 2000. We examined the reasons for this large number of deaths, despite establishment of the guideline therapy, by investigating emergency patients who were carried to our emergency care center by ambulance as tertiary emergency cases for treatment of serious asthma. The investigation of medications used before emergency arrival showed that patients were not treated according to the guideline therapy: 92.9% of all patients and 100% of CPA (cardio pulmonary arrest) patients were treated with β-receptor stimulators (spray) only when they had asthmatic fits, and regular steroid inhalation therapy was performed on only 2 patients (3.7%). Although respiratory and allergy experts specializing in bronchial asthma follow the guideline therapy, it may not be widespread among general clinicians. To reduce the deaths from bronchial asthma, it is important to fully manage the possible risks of bronchial asthma by making general practitioners give patients full information on the disease; making patients strictly follow the appropriate hospital visit and treatment schedule based on regular steroid inhalation therapy; instructing patients to always carry their medical history cards for sudden attacks of bronchial asthma; and persuading emergency care centers to permit over-triaging by ambulance teams

在宅静脈栄養(Home Parenteral Nutrition: HPN)が著効している重度短腸症候群(Short Bowel Syndrome: SBS)の1例

短腸症候群は大腸が正常でも残存小腸が60cm以下では完全静脈栄養(TPN)からの離脱は困難とされる重症病態で,それにともない日常生活範囲も制限されることが多い.我々は残存腸管が食道・胃・十二指腸・S状結腸・直腸の重度短腸症候群で,在宅静脈栄養(以下HPN)に大部分が依存しているが,術後9年間にわたり海外出張をこなすまで社会復帰しているQOLの高い1症例を経験したので報告する.患者は38歳,女性.29歳時,過食後の腹痛・血圧低下により救急搬送され,汎発性腹膜炎の診断で緊急手術を施行した.2期的手術の後,現状となり退院後はHPNによる栄養管理を行い現在に至っている.HPNは皮下埋め込みリザーバーポートを留置し,輸液ポンプを用いて夜間間歇的投与で自由摂食としている.輸液は清潔操作の簡便性と製剤の安定性よりシングルバッグ製剤を用いており,H_2-blockerを800mg/日,微量元素製剤および脂肪乳剤を週2日投与している.また夏季には脱水予防のため細胞外液輸液を追加投与している.退院後9年目の現在,代償性に肥大した十二指腸,軽度骨密度低下を認めるが,栄養状態は良好である.合併症としてTPNの観点からの肝機能障害(脂肪肝)とHPNの観点からのカテーテル感染症があるが,どちらも重症化することなく対処している.国内の長距離移動にはクール宅急便を,海外には郵便輸送によって輸液製剤を搬送しているが,大きなトラブルもなく良好な社会生活を営んでいる.Short bowel syndrome (SBS) is a serious condition that often limits daily activities. This paper reports a case with serious SBS where the residual intestine is limited to the esophagus, stomach, duodenum, sigmoid colon, and rectum (there is no small intestine). Although the patient largely depends on HPN, she has been successfully rehabilitated for 9 years postoperatively and obtained a high QOL. She arrived at our hospital in 1993 in an ambulance due to abdominal pain and hypotension (shock state) after overeating when she was 29 years old. She was diagnosed with general peritonitis and had an emergency operation. After she discharged from hospital, a subcutaneous implantable reservoir port for HPN was placed. She has been allowed to intermittently administer HPN adlibitum with the infusion pump at night. The port had to be replaced twice due to infection and once due to the occlusion of the catheter in 9 years. The following tests were performed to determine her digestion and absorption ability were low, indicating poor digestion. The duodenum and sigmoid colon was enlarged to compensate for the loss of the intestine. For the delivery of infusion preparations for traveling, it is useful to use home delivery services with refrigerated cars for domestic travel and the postal service for travel abroad. The applicable regulations differ between countries