DOI： 10.1101/2025.02.05.25321727

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Background and objective Sepsis is a life-threatening condition associated with high morbidity and mortality, and hence early recognition and treatment are crucial. The 2016 Sepsis-3 guidelines introduced the quick Sequential Organ Failure Assessment (qSOFA), but its low sensitivity limits early detection. The 2021 Surviving Sepsis Campaign Guidelines (SSCG) discourage relying solely on qSOFA and recommend additional tools such as the systemic inflammatory response syndrome (SIRS) score, the National Early Warning Score (NEWS), and the Modified Early Warning Score (MEWS) along with lactate measurement. This study assessed whether combining qSOFA with quantitative capillary refill time (Q-CRT) or lactate levels enhances early sepsis diagnosis in emergency departments. Methods This retrospective, multi-facility observational study was conducted at two hospitals in Yokohama, Japan. Patients with suspected infections who underwent Q-CRT measurement were included. Q-CRT was measured using a pulse oximeter-based device that records the time taken for blood flow to return to 90% after compression. Receiver operating characteristic (ROC) curves determined the area under the curve (AUC), sensitivity, and specificity. Statistical significance was set at p<0.05. Results Of the 357 patients who underwent Q-CRT measurement, 75 (21%) were suspected of having an infection, with 48 (64%) classified as having sepsis with organ dysfunction. Patients in the sepsis group had higher age, heart rate, lactate level, creatinine level, NEWS, MEWS, and Sequential Organ Failure Assessment (SOFA) scores compared to those without organ dysfunction. Among individual tools, the qSOFA, NEWS, and MEWS scores showed high AUCs (>0.8), while Q-CRT and lactate levels demonstrated moderate predictive accuracy with AUCs exceeding 0.7. The SIRS score had the lowest predictive ability, with an AUC of approximately 0.6. Combining qSOFA with Q-CRT or lactate levels significantly improved sensitivity and specificity. The qSOFA+Q-CRT combination resulted in an AUC of 0.821, sensitivity of 83.3%, and specificity of 81.4%, while the qSOFA+lactate combination yielded an AUC of 0.844, sensitivity of 87.5%, and specificity of 81.4%. These combinations exceeded 80% in both sensitivity and specificity, unlike the SIRS-based combinations, which showed limited improvement and specificity below 40%. While the qSOFA score alone demonstrated limited sensitivity, combining it with Q-CRT or lactate levels enhanced its predictive performance for early sepsis detection. This approach improved sensitivity without compromising specificity. The increase in sensitivity and specificity is likely due to Q-CRT and lactate identifying sepsis cases not detected by qSOFA, thereby making the combined approach more reliable for clinical use. Lactate levels are well-established markers associated with sepsis severity, and Q-CRT offers a non-invasive means of assessing peripheral perfusion. Conclusions Combining qSOFA with Q-CRT or lactate levels significantly improves early sepsis detection by enhancing both sensitivity and specificity. These combinations offer superior diagnostic accuracy compared to standalone tools, supporting their potential integration into clinical protocols for better patient outcomes. Further prospective studies are needed to validate these findings across diverse clinical settings.

DOI： 10.7759/cureus.78728

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INTRODUCTION: The vascular endothelial glycocalyx, crucial for blood vessel integrity and homeostasis, is vulnerable to oxidative stress, leading to endothelial dysfunction, which strongly correlates with cardiovascular disease (CVD). This study investigates the protective effects of rivaroxaban, a FXa inhibitor, on the glycocalyx under oxidative stress condition. METHODS: We examined the impact of rivaroxaban on human umbilical vein endothelial cells (HUVECs) exposed to acute and chronic H₂O₂-induced oxidative stress. RESULTS: Rivaroxaban dose-dependently suppressed syndecan-1, a key component of the glycocalyx, shedding from cell surface, and enhanced protease-activated receptor (PAR)1-PAR2/ phosphatidylinositol-3-kinase (PI3K)-dependent cell viability after acute induction of H2O2. This protective effect was linked to the translocation of IQGAP1, a scaffold protein that modulates the actin cytoskeleton, to the perinucleus from the cell membrane. Under chronic H2O2 treatments, rivaroxaban improves cell viability accompanied by an increase in hyaluronidase activities, aiding the turnover and remodeling of hyaluronic acid within the glycocalyx. CONCLUSION: We identify that rivaroxaban protects against oxidative stress-induced endothelial glycocalyx damage and cell viability through IQGAP1/PAR1-2/PI3K/Akt pathway, offering a potential to be a therapeutic target for CVD prevention.

DOI： 10.1159/000542419

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The increasing requirement of mechanical ventilation (MV) due to the novel coronavirus disease (COVID-19) is still a global threat. The aim of this study is to identify markers that can easily stratify the impending use of MV in the emergency room (ER). A total of 106 patients with COVID-19 requiring oxygen support were enrolled. Fifty-nine patients were provided MV 0.5 h (interquartile range: 0.3 to 1.4) post-admission. Clinical and laboratory data before intubation were collected. Using a multivariate logistic regression model, we identified four markers associated with the impending use of MV, including the ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2 ratio), alanine aminotransferase, blood glucose (BG), and lymphocyte counts. Among these markers, SpO2/FiO2 ratio and BG, which can be measured easily and immediately, showed higher accuracy (AUC: 0.88) than SpO2/FiO2 ratio alone (AUC: 0.84), despite no significant difference (DeLong test: P = 0.591). Moreover, even in patients without severe respiratory failure (SpO2/FiO2 ratio > 300), BG (> 138 mg/dL) was predictive of MV use. Measuring BG and SpO2/FiO2 ratio may be a simple and versatile new strategy to accurately identify ER patients with COVID-19 at high risk for the imminent need of MV.

DOI： 10.1038/s41598-023-50075-7

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

We aimed to develop a method to determine the CT score that can be easily obtained from CT images and examine its prognostic value for severe COVID pneumonia. Patients with COVID pneumonia who required ventilatory management by intubation were included. CT score was based on anatomical information in axial CT images and were divided into three sections of height from the apex to the bottom. The extent of pneumonia in each section was rated from 0 to 5 and summed. The primary outcome was the prediction of patients who died or were managed on extracorporeal membrane oxygenation (ECMO) based on the CT score at admission. Of the 71 patients included, 12 (16.9%) died or required ECMO management, and the CT score predicted death or ECMO management with ROC of 0.718 (0.561-0.875). The death or ECMO versus survival group (median [quartiles]) had a CT score of 17.75 (14.75-20) versus 13 (11-16.5), p = 0.017. In conclusion, a higher score on our generated CT score could predict the likelihood of death or ECMO management. A CT score at the time of admission allows for early preparation and transfer to a hospital that can manage patients who may need ECMO.

DOI： 10.1038/s41598-023-31312-5

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AIM: Although the obesity paradox is known for various diseases, including cancer and acute respiratory distress syndrome, little is known about veno-venous extracorporeal membrane oxygenation (VV-ECMO) in patients with coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the association between body mass index (BMI) and prognosis in critical patients with COVID-19 requiring VV-ECMO. METHODS: We conducted a retrospective observational single-center study at Yokohama City University Civic General Medical Center between March 2020 and October 2021. Participants were patients with COVID-19 who required VV-ECMO. They were classified into two groups: BMI ≤30 kg/m2 and >30 kg/m2. RESULTS: In total, 23 patients were included in the analysis, with a median BMI of 28.7 kg/m2. Overall, 22 patients were successfully weaned from the ECMO. When comparing the two groups, there was a trend toward fewer days from onset to ECMO induction in the BMI >30 kg/m2 group. Moreover, the two groups had a similar prognosis. There were no statistically significant differences in the number of days from onset to hospitalization or the duration of ECMO induction between the groups. CONCLUSION: VV-ECMO induction for patients with COVID-19 may lead to earlier indications in patients with BMI >30 kg/m2 than in those with BMI ≤30 kg/m2.

DOI： 10.1002/ams2.871

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AIMS: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signaling could contribute to recovery from ischemic conditions by promoting the accumulation of Tregs. METHODS AND RESULTS: Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice 6-8 weeks old were used. Hindlimb ischemia was induced by femoral artery ligation. Recovery from ischemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 (FR4) in WT mice but not in mPges-1-/- mice. Recovery from ischemia was significantly suppressed in Ep4-/- mice compared with WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the numbers of accumulated FoxP3+ cells in ischemic tissue were diminished in Ep4-/- mice compared with Ep4+/+ mice. CONCLUSIONS: These findings suggested that mPGES-1/PGE2 induced neovascularization from ischemia via EP4 by promoting accumulation of Tregs. Highly selective EP4 agonists could be useful for treatment of peripheral artery disease (PAD). TRANSLATIONAL PERSPECTIVE: Although surgical treatment for PAD in patients improved, some patients with advanced disease have no other option for treatments other than amputation. In the present study, we revealed that endogenous mPGES-1/PGE2-EP4 signaling induced recovery from ischemia by promoting Tregs accumulation at the ischemic site. In addition, we showed that selective EP4 agonist, or transplantation of Tregs, induced recovery from ischemic conditions. These results indicate that the use of selective EP4 agonist, or cell therapy of Tregs, may be a potential treatment option for severe critical limb ischemia patients.

DOI： 10.1093/cvr/cvac137

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/md9.0000000000000210

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Arterial lactate (AL) level is an important predictor of patient prognosis. AL and peripheral venous lactate (PVL) in blood gas analysis have a low concordance rate, and PVL cannot be used as a substitute for AL. However, if the AL range can be predicted from PVL, PVL may be an alternative method for predicting patient prognosis, and the risk of arterial puncture complications with AL may be reduced. This could be a safe and rapid test method. METHODS: This was a retrospective observational study of 125 cases in which blood gas analysis was performed on both arterial and venous blood with an infectious disease in an emergency department. Spearman's rank correlation coefficient (r) and Bland-Altman analyses were performed. Sensitivity, specificity, and area under the curve (AUC) were calculated for PVL to predict AL < 2 mmol/L or < 4 mmol/L. RESULTS: The median [interquartile range] AL and PVL were 1.82 [1.25-2.46] vs. 2.08 [1.57-3.28], respectively, r was 0.93 (p < 0.0001), and a strong correlation was observed; however, Bland-Altman analysis showed disagreement. When AL < 2 mmol/L was used as the outcome, AUC was 0.970, the PVL cutoff value was 2.55 mmol/L, sensitivity was 85.71%, and specificity was 96.05%. If PVL < 2 mmol/L was the outcome, the sensitivity for AL < 2mmol/L was 100%, and for PVL levels ≥ 3 mmol/L, the specificity was 100%. When AL < 4 mmol/L was used as the outcome, AUC was 0.967, the PVL cutoff value was 3.4 mmol/L, sensitivity was 100%, and specificity was 85.84%. When PVL < 3.5 mmol/L was the outcome, the sensitivity for AL < 4 mmol/L was 100%, and for PVL levels ≥ 4 mmol/L, the specificity was 93.81%. CONCLUSIONS: This study revealed that PVL and AL levels in the same critically ill patients did not perfectly agree with each other but were strongly correlated. Furthermore, the high accuracy for predicting AL ranges from PVL levels explains why PVL levels could be used as a substitute for AL level ranges.

DOI： 10.1186/s12245-022-00410-y

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BACKGROUND: The outcomes of coronavirus disease 2019 (COVID-19) treatment have improved due to vaccination and the establishment of better treatment regimens. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, and the corresponding changes in the characteristics of the disease present new challenges in patient management. This study aimed to analyze predictors of COVID-19 severity caused by the delta and omicron variants of SARS-CoV-2. METHODS: We retrospectively analyzed the data of patients who were admitted for COVID-19 at Yokohama City University Hospital from August 2021 to March 2022. RESULTS: A total of 141 patients were included in this study. Of these, 91 had moderate COVID-19, whereas 50 had severe COVID-19. There were significant differences in sex, vaccination status, dyspnea, sore throat symptoms, and body mass index (BMI) (p <0.0001, p <0.001, p <0.001, p = 0.02, p< 0.0001, respectively) between the moderate and severe COVID-19 groups. Regarding comorbidities, smoking habit and renal dysfunction were significantly different between the two groups (p = 0.007 and p = 0.01, respectively). Regarding laboratory data, only LDH level on the first day of hospitalization was significantly different between the two groups (p<0.001). Multiple logistic regression analysis revealed that time from the onset of COVID-19 to hospitalization, BMI, smoking habit, and LDH level were significantly different between the two groups (p<0.03, p = 0.039, p = 0.008, p<0.001, respectively). The cut-off value for the time from onset of COVID-19 to hospitalization was four days (sensitivity, 0.73; specificity, 0.70). CONCLUSIONS: Time from the onset of COVID-19 to hospitalization is the most important factor in the prevention of the aggravation of COVID-19 caused by the delta and omicron SARS-CoV-2 variants. Appropriate medical management within four days after the onset of COVID-19 is essential for preventing the progression of COVID-19, especially in patients with smoking habits.

DOI： 10.1371/journal.pone.0273134

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Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.

DOI： 10.1038/s41598-021-99930-5

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jiph.2021.08.016

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Language：English  

DOI： 10.1038/s41598-021-96408-2

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Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

DOI： 10.1038/s41598-021-92921-6

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ABSTRACT: The Coronavirus disease 2019 pandemic continues to spread worldwide. Because of the absence of reliable rapid diagnostic systems, patients with symptoms of Coronavirus disease 2019 are treated as suspected of the disease. Use of computed tomography findings in Coronavirus disease 2019 are expected to be a reasonable method for triaging patients, and computed tomography-first triage strategies have been proposed. However, clinical evaluation of a computed tomography-first triage protocol is lacking.The aim of this study is to investigate the real-world efficacy and limitations of a computed tomography-first triage strategy in patients with suspected Coronavirus disease 2019.This was a single-center cohort study evaluating outpatients with fever who received medical examination at Yokohama City University Hospital, prospectively registered between 9 February and 5 May 2020. We treated according to the computed tomography-first triage protocol. The primary outcome was efficacy of the computed tomography-first triage protocol for patients with fever in an outpatient clinic. Efficacy of the computed tomography-first triage protocol for outpatients with fever was evaluated using sensitivity, specificity, positive predictive value, and negative predictive value. We conducted additional analyses of the isolation time of feverish outpatients and final diagnoses.In total, 108 consecutive outpatients with fever were examined at our hospital. Using the computed tomography-first triage protocol, 48 (44.9%) patients were classified as suspected Coronavirus disease 2019. Nine patients (18.8%) in this group were positive for severe acute respiratory syndrome coronavirus 2 using polymerase chain reaction; no patients in the group considered less likely to have Coronavirus disease 2019 tested positive for the virus. The protocol significantly shortened the duration of isolation for the not-suspected versus the suspected group (70.5 vs 1037.0 minutes, P < .001).Our computed tomography-first triage protocol was acceptable for screening patients with suspected Coronavirus disease 2019. This protocol will be helpful for appropriate triage, especially in areas where polymerase chain reaction is inadequate.

DOI： 10.1097/MD.0000000000026161

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ABSTRACT: The long-term exercise capacity of coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS) is not clear. The 6-minute walking distance (6MWD) of four patients with COVID-19-associated ARDS was followed for 6 months after admission to the hospital. These four patients were admitted to the intensive care unit (ICU) of our hospital and received mechanical ventilation. Rehabilitation therapy (positioning, postural drainage, and passive range of motion exercises) was started after ICU admission. Mobilization therapy, including muscle power training, sitting on the edge of the bed, and endurance training, was performed after the end of sedation. The Medical Research Council sum scores and Barthel Indexes for the patients improved after ICU discharge and completely recovered 6 months after admission to the hospital. However, the 6MWD of the four patients remained shorter than those of healthy persons of the same age at 6 months after admission to the hospital. Furthermore, the minimum SpO2 during the 6-minute walking test remained below 96%. It is possible that patients who receive mechanical ventilation due to COVID-19-associated ARDS have decreased long-term exercise capacity, despite muscle power and activities of daily living recovering completely.

DOI： 10.1097/PHM.0000000000001803

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BACKGROUND: Coronavirus disease (COVID-19) pneumonitis associated with severe respiratory failure has a high mortality rate. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently observed. Coagulopathy has emerged as a significant contributor to thrombotic complications. Although recommendations have been made for anticoagulant use for COVID-19, no guidelines have been specified. We describe four cases of critical COVID-19 with thrombosis detected by enhanced CT scan. The CT findings of all cases demonstrated typical findings of COVID-19 and pulmonary embolism or deep venous thrombus without critical exacerbation. Two patients died of respiratory failure due to COVID-19. DISCUSSION: Previous reports have suggested coagulopathy with thrombotic signs as the main pathological feature of COVID-19, but no previous reports have focused on coagulopathy evaluated by whole-body enhanced CT scan. Changes in hemostatic biomarkers, represented by an increase in D-dimer and fibrin/fibrinogen degradation products, indicated that the essence of coagulopathy was massive fibrin formation. Although there were no clinical symptoms related to their prognosis, critical COVID-19-induced systemic thrombus formation was observed. CONCLUSIONS: Therapeutic dose anticoagulants should be considered for critical COVID-19 because of induced coagulopathy, and aggressive follow-up by whole body enhanced CT scan for systemic venous thromboembolism (VTE) is necessary.

DOI： 10.1186/s12959-021-00280-z

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Publisher：Cold Spring Harbor Laboratory  

<title>Abstract</title><sec><title>Objective</title>To evaluate the association between iron metabolism indicators and disease severity in hospitalized patients with coronavirus disease 2019 (COVID-19).

</sec><sec><title>Design</title>Two-center observational study

</sec><sec><title>Setting</title>A university hospital and a core hospital in Yokohama, Japan

</sec><sec><title>Patients</title>Adults with COVID-19 whose serum iron levels were measured within the first 5 days of hospitalization were included. Patients who refused mechanical ventilation were excluded from the study.

</sec><sec><title>Measurements and Main Results</title>One hundred thirty-six patients were included in this study. We analyzed the association between COVID-19 severity and serum iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT) levels. Disease severity was defined as the worst respiratory status during hospitalization. Serum iron levels were significantly lower in patients with mild respiratory failure (RF) (n=55, median serum iron level: 24 [interquartile range: 19–42] mg/dL) than in the non-RF group (n=44, 40 [24–80] mg/dL) and the severe RF group (n=37, 60 [23.5–87] mg/dL); however, there were no significant differences in iron levels between the non-RF and severe RF groups (non-RF <italic>vs</italic>. mild RF: p=0.019, non-RF <italic>vs</italic>. severe RF: p&gt;0.999, and mild RF <italic>vs</italic>. severe RF: p=0.009). That is, there was a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron or TSAT levels were independently associated with development of severe RF.

</sec><sec><title>Conclusions</title>A U-shaped association between serum iron level and RF severity in hospitalized COVID-19 patients was observed. Higher serum iron levels in COVID-19 patients with RF are associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

</sec>

DOI： 10.1101/2021.02.19.21252061

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Language：English  

Central pontine myelinolysis (CPM) is a rare demyelinating condition which has been reported to occur in a variety of clinical settings, but most commonly in association with a rapid rise in plasma osmolality during correction of chronic hyponatremia. The clinical consequences can vary from a mild motor weakness that resolves completely over time to the devastating locked-in syndrome. In this presentation, we report a case of hyperosmolar hyperglycemic syndrome (HHS) with ponto-occipital disintegration. A 71-year-old female was transferred to our ER by an ambulance due to consciousness disorder and continuous fever for 10 days. We diagnosed septic shock caused by urinary tract infection (UTI), cerebral multiple infarctions, acute kidney injury (AKI) and HHS without treatment for diabetes. Then, we started therapeutic interventions for them based on the guideline with severe control for blood sugar (BS; primary 1635 mg/dl) under insulin therapy and hypernatremia (primary 153 mEq/l) under crystal infusion control in advanced care unit, apparently on routine lab data. However, the initial serum sodium value of 153 mEq/l was slowly compensated to 148 mEq/l in 60 hours under guideline on routine lab data, the initial compensated sodium value with osmolality was changed from 178 mEq/l to 150 mEq/l in the period. She recovered from her primary diagnosis and unconsciousness. After stabilized sepsis and HHS, we detected CPM on brain MRI due to following up multiple cerebral infarctions with left leg paralysis and verbal disorder. She gradually recovered over several months with intensive rehabilitation and eventually regained near normal functional capacity with stabilized BS. When we consider HHS with hypernatremia, it may be necessary to pay attention to not only to BS control and sodium control according to the guideline but also to osmolality changes to prevent CPM.

DOI： 10.2147/IMCRJ.S316943

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DOI： 10.1016/j.jinf.2020.08.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

A 65-yr-old man visited a primary care hospital with a continued fever of 38°C for 3 days. As his fever did not improve until 8 days after, he was admitted into another acute care hospital, where his respiratory condition rapidly worsened. Therefore, the patient was transferred to our hospital. On the day of transfer (day 1), he was started on mechanical ventilation. COVID-19 was diagnosed using a polymerase chain reaction assay 6 days after admission (day 6). The rehabilitation therapy was begun on day 6. The initial rehabilitation programs focused on positioning and postural drainage. The patient was extubated on day 19, and he began standing and stepping on the same day. Gait exercises began on day 22, and endurance training was initiated on day 28. The patient was discharged from our hospital on day 34 as he met the physical function milestones. One month after discharge, the Medical Research Council sum score and Barthel Index had each improved; therefore, muscle strength and daily activities had returned to normal. It was assumed that mobilization should be performed as soon as possible after the end of sedation during the acute phase of severe COVID-19 infection in patients receiving mechanical ventilation.

DOI： 10.1097/phm.0000000000001545

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Publishing type：Research paper (scientific journal)  

DOI： 10.21203/rs.3.rs-47469/v1

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DOI： 10.1016/j.mayocp.2020.04.007

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Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is one of the ultimate treatments for acute respiratory failure. However, the effectiveness of ECMO in patients with novel coronavirus disease (COVID-19) is unknown. CASE PRESENTATION: A 72-year-old woman who was a passenger of a cruise ship tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) while in quarantine on board using throat swab. Three days after admission, her condition deteriorated, and she was subsequently intubated. On day 6, VV-ECMO was introduced. Lopinavir/ritonavir was given; continuous renal replacement therapy was also introduced. On day 10, her chest radiography and lung compliance improved. She was weaned off ECMO on day 12. CONCLUSION: Treatment of severe pneumonia in COVID-19 by ECMO should recognize lung plasticity considering time to ECMO introduction and interstitial biomarkers. In Japan, centralization of ECMO patients has not been sufficient. Thus, we suggest nationwide centralization and further research to respond to the crisis caused by COVID-19.

DOI： 10.1002/ams2.509

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ams2.509

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China, and has resulted in global pandemic. There is currently no effective therapeutic strategy for the management of mechanical ventilation or antiviral drugs for the treatment of this disease. As such, the development of a therapeutic strategy is urgently needed and should be established as soon as possible. In this case series, a therapeutic strategy was initially developed based on previous treatment methods used for the treatment of SARS and MERS in the absence of treatment options for COVID-19 due to a lack of information. During the search for a potential treatment, clinical findings were obtained from patients with severe COVID-19, and one therapeutic strategy was established. This therapeutic strategy was then applied to severe COVID-19 patients. In addition, we can require some interesting clinical features and characteristics of COVID-19 from blood analysis and physical findings. Here, we reported on the clinical features and characteristics of a therapeutic strategy for the treatment of severe COVID-19 pneumonia at our institution.

DOI： 10.1177/2058739220961591

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Language：Japanese  

J-GLOBAL

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00276&link_issn=&doc_id=20200812300021&doc_link_id=10.11150%2Fkansenshogakuzasshi.94.591&url=https%3A%2F%2Fdoi.org%2F10.11150%2Fkansenshogakuzasshi.94.591&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/s12931-019-1129-4

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Other Link： http://link.springer.com/article/10.1186/s12931-019-1129-4/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a poor prognosis. Fibroblast proliferation amplifies extracellular matrix deposition and increases angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. VEGF interacts with VEGF receptors (VEGFR1 and VEGFR2). A previous study showed that VEGFR1 tyrosine kinase (TK) signaling induced blood flow recovery mediated by bone marrow (BM)-derived stem cells. We hypothesized that VEGFR1-TK signaling might be related to pulmonary fibrosis. MATERIAL AND METHODS: Six-week-old male C57Bl/6 wild-type (WT) mice and VEGFR1 TK knockout mice (TKKO mice) were treated with a single intratracheal injection of bleomycin (BLM; 0.1 μg in 50 μl saline) or vehicle (saline; 50 μl). Lung fibrosis was evaluated by histology, real-time PCR and ELISA for pro-fibrotic factors, and assessment of lung mechanics. RESULTS: The fibrotic area in the lung and the lung elastance were significantly reduced in TKKO mice (P < 0.01). The expression of the fibrosis-related factors type I collagen, S100A4, and transforming growth factor (TGF)-β was also significantly reduced in TKKO mice on day 21 after BLM injection. TKKO mice also had significantly lower levels of stromal cell-derived factor (SDF)-1 in the lungs and plasma on days 14 and 21 after BLM treatment (P < 0.05). Moreover, the expression of C-X-C chemokine receptor type 7 (CXCR7) and CXCR4, the receptors for SDF-1, was also suppressed in TKKO mice. Immunohistochemical analysis showed that treatment with a CXCR4 antibody decreased the accumulation of VEGFR1+ cells in the lung in WT mice but not in TKKO mice. CONCLUSION: These results suggest that VEGFR1 TK signaling promotes BLM-induced pulmonary fibrosis by activating the SDF-1/CXCR4 axis in infiltrating VEGFR1+ cells.

DOI： 10.1016/j.biopha.2019.109067

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Publisher：S. Karger {AG}  

DOI： 10.1159/000500880

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INTRODUCTION: The use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in trauma patients has been controversial, but VV-ECMO plays a crucial role when the lungs are extensively damaged and when conventional management has failed. VV-ECMO provides adequate tissue oxygenation and an opportunity for lung recovery. However, VV-ECMO remains contraindicated in patients with a risk of bleeding because of systemic anticoagulation during the treatment. The most important point is controlling the bleeding from severe trauma. CASE: A 32-year-old male experienced blunt trauma due to a traffic accident. He presented with bilateral hemopneumothorax and bilateral flail chest. We performed emergency thoracotomy for active bleeding and established circulatory stability. After surgery, the oxygenation deteriorated under mechanical ventilation, so we decided to establish VV-ECMO. However, bleeding from the bilateral lung contusions increased after VV-ECMO was established, and the patient was switched to heparin-free ECMO. After conversion, we could control the bronchial bleeding, especially the lung hematomas, and the oxygenation recovered. The patient was discharged without significant complications. VV-ECMO and mechanical ventilation were stopped on days 10 and 11, respectively. He was discharged from the ICU on day 15. CONCLUSION: When we consider the use of ECMO for patients with uncontrollable, severe bleeding caused by blunt trauma, it may be necessary to use a higher flow setting for heparin-free ECMO than typically used for patients without trauma to prevent thrombosis.

File： Ogawa_et_al-2019-Journal_of_Cardiothoracic_Surgery.pdf

DOI： 10.1186/s13019-019-0908-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

The vascular endothelial growth factor (VEGF) family has a key role in the formation of blood vessels and lymphatics. Among the members of this family, VEGF-C is one of the most important factors involved in lymphangiogenesis via binding with two receptors (vascular endothelial growth factor receptor-2 and -3: VEGFR-2 and VEGFR-3). Soluble VEGFR-2 (sVEGFR-2) has a role in maintaining the alymphatic state of the cornea associated with binding to VEGF-C, and selectively inhibits lymphangiogenesis but not angiogenesis. In this study, we introduced sVEGFR-2 into lung cancer cells and evaluated the influence on tumor progression and on genes regulating lymphatic formation and metastasis in vivo. A retroviral vector was used to introduce the sVEGFR-2 gene into Lewis lung carcinoma cells (LLC), which were designated as LLC-sVEGFR-2 cells. Proteins secreted into the culture supernatant by these cells were detected by western blotting using specific antibodies. To examine lymphangiogenesis by primary lung cancer in vivo, LLC-sVEGFR-2 cells were subcutaneously injected into C57BL/6 mice. At 14days after injection, immunohistochemistry was performed using an antibody directed against lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a marker of lymphatics. Expression of mRNA for VEGFR-2, VEGFR-3 and matrix metalloproteinases (MMPs) was also determined by real-time PCR. Furthermore, LLC-sVEGFR-2 cells were directly inoculated into the left lung in C57BL/6 mice and the number of micro-metastases in pulmonary lymph nodes was determined. Introduction of sVEGFR-2 into LLC cells resulted in secretion of sVEGFR-2 protein into the culture supernatant. There were fewer LYVE-1 positive lymphatics after inoculation of LLC-sVEGFR-2 into mice compared with the control group. In addition, VEGFR-2, VEGFR-3, and MMPs gene expression was suppressed in the primary tumors of the LLC-sVEGFR-2 group compared with the control group. Furthermore, there were fewer micro-metastases in the pulmonary lymph nodes of the LLC-sVEGFR-2 group compared with the control group after cells were directly inoculated into the lung. These findings indicate that introduction of sVEGFR-2 suppressed lymphangiogenesis in primary lung cancer and also suppressed lymphogenic metastasis by inhibiting VEGF-C, followed by down-regulation of VEGFR-2, VEGFR-3 and MMPs. Accordingly, sVEGFR-2 might be a promising target for treatment of cancer by regulating lymphangiogenesis and lymphogenic metastasis.

DOI： 10.1016/j.biopha.2016.09.083

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AIMS: Thromboxane A2 (TXA2) induces platelet adhesion through thromboxane prostanoid (TP) receptor. Platelets contain many pro-angiogenic factors and are recruited to the site of vascular injury. However, the cellular and molecular mechanisms of platelet-dependent angiogenesis, especially the involvement of TP signalling, have not been fully elucidated. The present study hypothesized that TP-dependent platelet adhesion would contribute to angiogenesis in a mouse hindlimb ischaemic model. METHODS AND RESULTS: Blood flow recovery was suppressed by the TXA2 receptor antagonist (S-1452) and the TXA2 synthase inhibitor (OKY-046) compared with control mice. TP knockout mice (TP(-/-)) showed delayed blood flow recovery from ischaemia and impaired angiogenesis compared with wild-type (WT) mice and prostacyclin receptor knockout mice (IP(-/-)). Selective platelet adhesion to ischaemic endothelial cells (ECs) via P-selectin was identified in WT and IP(-/-), but not in TP(-/-), via in vivo microscopy. IF analysis showed that P-selectin glycoprotein ligand-1 (PSGL-1) co-localized with endothelial CD31 in ischaemic muscle in WT and IP(-/-) but not diminished in TP(-/-). Platelet-rich plasma levels of stromal cell-derived factor-1 and VEGF were increased after ischaemia in WT, and suppressed by antibody against P-selectin in WT but not in TP(-/-). Furthermore, the blood flow recovery was suppressed by neutralizing antibodies against VEGF or C-X-C chemokine receptor type 4 in WT and IP(-/-) but not in TP(-/-). CONCLUSION: These results indicated that TP signalling facilitates ischaemia-induced angiogenesis via P-selectin-mediated platelet adhesion to PSGL-1 on the ECs at ischaemic sites and the supply of pro-angiogenic factors by the adherent platelets.

DOI： 10.1093/cvr/cvv139

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Compensatory lung growth models have been widely used to investigate alveolization because the remaining lung can be kept intact and volume loss can be controlled. Vascular endothelial growth factor (VEGF) plays an important role in blood formation during lung growth and repair, but the precise mechanisms involved are poorly understood; therefore, the aim of this study was to investigate the role of VEGF signaling in compensatory lung growth. After left pneumonectomy, the right lung weight was higher in VEGF transgenic mice than wild-type (WT) mice. Compensatory lung growth was suppressed significantly in mice injected with a VEGF neutralizing antibody and in VEGF receptor-1 tyrosine kinase-deficient mice (TK(-/-) mice). The mobilization of progenitor cells expressing VEGFR1(+) cells from bone marrow and the recruitment of these cells to lung tissue were also suppressed in the TK(-/-) mice. WT mice transplanted with bone marrow from TK(-/-)transgenic GFP(+) mice had significantly lower numbers of GFP(+)/aquaporin 5(+), GFP(+)/surfactant protein A(+), and GFP(+)/VEGFR1(+) cells than WT mice transplanted with bone marrow from WTGFP(+) mice. The GFP(+)/VEGFR1(+) cells also co-stained for aquaporin 5 and surfactant protein A. Overall, these results suggest that VEGF signaling contributes to compensatory lung growth by mobilizing VEGFR1(+) cells.

DOI： 10.1038/labinvest.2014.159

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Vascular endothelial growth factor (VEGF) is one of the most potent angiogenesis stimulators. VEGF binds to VEGF receptor 1 (VEGFR1), inducing angiogenesis through the receptor's tyrosine kinase domain (TK), but the mechanism is not well understood. We investigated the role of VEGFR1 tyrosine kinase signaling in angiogenesis using the ischemic hind limb model. Relative to control mice, blood flow recovery was significantly impaired in mice treated with VEGFA-neutralizing antibody. VEGFR1 tyrosine kinase knockout mice (TK-/-) had delayed blood flow recovery from ischemia and impaired angiogenesis, and this phenotype was unaffected by treatment with a VEGFR2 inhibitor. Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced. The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed. Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM. These results suggest that VEGFR1-TK signaling facilitates angiogenesis by recruiting CXCR4+VEGFR1+ cells from BM.

DOI： 10.1371/journal.pone.0131445

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

DOI： 10.1186/1749-8090-8-205

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Other Link： http://link.springer.com/content/pdf/10.1186/1749-8090-8-205.pdf

Language：English   Publisher：WILEY-BLACKWELL  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

DOI： 10.1177/0218492312457359

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0218492312457359

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/mco.2013.80

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The prognosis of patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor and the optimal treatment for these patients has yet to be determined. In this study, we described the clinicopathological characteristics of LCNECs and compared the prognoses of corresponding stages determined by the guidelines of the 6th and 7th editions of the TNM classification of malignant tumors. Clinical data from 42 patients diagnosed with primary LCNEC who underwent treatment at Kitasato University Hospital between 1991 and 2009 were retrospectively analyzed. On follow-up of 42 patients, 22 (52.4%) had confirmed recurrent tumors, including 8 patients with mediastinal lymph node recurrences and 19 with distant metastases. The sites of distant metastases included the brain in 8, bone in 8, liver in 7, lungs in 5 and adrenal glands in 4 patients. For all the patients, the 5-year overall survival rate was 34.7% and the 5-year disease-free survival rate was 32.9%. The 5-year overall survival rates of patients with stage I cancers according to the 6th and 7th staging editions was 51.3% (6th n=18, 7th n=16). Thirteen of 42 patients (31.0%) also had metachronous or synchronous primary cancers. Patients with LCNEC had poor outcomes, even those with stage I tumors classified according to the 7th edition of the TNM classification. Therefore, frequent recurrences in addition to metachronous or synchronous primary cancers in patients with LCNEC should be treated.

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Because the cavopulmonary shunt procedure is widely used for palliation of complex congenital heart diseases, pulmonary arteriovenous malformations (PAVMs) are relatively well-known complications. The reported patient was a 23-year-old woman who experienced PAVMs in the right lower lobe after a classical Glenn anastomosis and Björk procedure for tricuspid atresia. Her arterial oxygen saturation (SaO2) 14 years after the Björk procedure was ~80 %. She then underwent a total cavopulmonary connection (TCPC) conversion to reduce her PAVMs in the right lower lobe using the "hepatic factor." However, her situation remained unchanged, and she experienced severe systemic cyanosis (SaO2, 70 %) and dyspnea during physical exertion without hemoptysis due to increased blood flow to the PAVMs. Although interventional embolization was considered, it was impossible due to considerable dilation of the main PAVM. Thus, right lower lung lobectomy was performed. After surgery, the patient's SaO2 increased to 90 %. To the authors' knowledge, this is the first case report of a lung resection for residual PAVMs after TCPC conversion. © 2012 Springer Science+Business Media, LLC.

DOI： 10.1007/s00246-012-0336-2

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Angiotensin II is involved in tumor growth
however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a-/-) and wild-type littermates (WT)
the AT1a-/- mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a -/- mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a-/- mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a-/- mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a-/- mice. In AT1a-/- mice, and both mobilization of progenitor cells expressing CXCR4 +VEGFR1+ cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4+VEGFR1+ cells. © 2013 American Society for Investigative Pathology.

DOI： 10.1016/j.ajpath.2012.10.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Thromboxane A2 (TXA2) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product, prostaglandin H(2), as the substrate. TXA2 was shown to enhance tumor metastasis, but the underlying mechanism remains unclear. B16F1 melanoma cells were intravenously injected into TXA2 receptor (TP) knockout mice (TP-/-) and wild-type littermates (WT). TP-/- showed a reduction in B16F1 lung colonization and mortality rate, which were associated with a decreased number of platelets. Platelet activation as assessed by P-selectin expression was suppressed in TP-/-. A selective P-selectin neutralizing antibody decreased the lung colonization in WT mice, but not in TP-/-. The expression of P-selectin glycoprotein ligand-1 in B16F1 and HUVEC were enhanced by treatment with U46619, a thromboxane analog. The plasma levels of vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1 were lower in TP-/-. In TP-/-, the mobilization of progenitor cells expressing CXCR4+VEGFR1+ from bone marrow and the recruitment of those cells to lung tissues were suppressed. These results suggest that TP signaling plays a critical role in tumor colonization through P-selectin-mediated interactions between platelets-tumor cells and tumor cells-endothelial cells through the TP signaling-dependent production of VEGF and SDF-1, which might be involved in the mobilization of VEGFR1+CXCR4+ cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis. (Cancer Sci 2012; 103: 700707)

DOI： 10.1111/j.1349-7006.2012.02200.x

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Postoperative exacerbation of interstitial pneumonia in patients with lung cancer and interstitial lung disease has emerged as a serious problem. Therefore, the risk factors for postoperative exacerbation of interstitial pneumonia in patients with interstitial lung disease must be identified. We analyzed 22 patients diagnosed as having lung cancer with interstitial lung disease who underwent surgical treatment at the Kitasato University Hospital. Among the patients with lung cancer and interstitial lung disease, 5 patients (22.7%) had postoperative exacerbation of interstitial pneumonia. The prognosis of the patients with postoperative exacerbation was significantly poorer than that of patients without. Patients with postoperative exacerbation had a significantly higher age (&gt;= 75 years) and a significantly lower frequency of postoperative administration of steroid than patients without postoperative exacerbation. Almost all patients with postoperative exacerbation underwent lobectomy, had elevated KL-6 levels in the serum pre-operatively, and had significantly advanced stages of disease. Of the 5 patients with postoperative exacerbation, 2 had a history of inflammation prior to their exacerbation: 1 had a common cold and the other pyothorax. In patients with lung cancer and interstitial lung disease, advanced age, advanced stage disease, no postoperative administration of steroid and a pre-operative episode of inflammation are all risk factors for postoperative exacerbation of interstitial pneumonia.

DOI： 10.3892/etm.2011.342

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Thymic large cell neuroendocrine carcinomas (LCNECs) are very rare. We here describe a case in which the tumor could be completely resected. A 55-year-old male was admitted to our hospital for treatment of an anterior mediastinal tumor found at a regular health check-up. The patient underwent an extended thymectomy of an invasive thymoma of Masaoka&apos;s stage II that had been suspected preoperatively. The tumor was located in the right lobe of the thymus and was completely resected. Final pathological diagnosis of the surgical specimen was thymic LCNEC. The patient underwent adjuvant chemotherapy with irinotecan and cisplatin in accordance with the diagnosis of a lung LCNEC, and is alive without recurrence or metastasis 16 months after surgery.

DOI： 10.1186/1749-8090-5-115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Cyclooxygenase (COX)-2 is known to correlate with poor cancer prognosis and to contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal prostaglandin E(2) (PGE(2))-prostaglandin E2 receptor (EP)3 signaling appears critical for tumor-associated angiogenesis and tumor growth. Here we tested whether the EP3 receptor has a critical role in tumor metastasis. Lewis lung carcinoma (LLC) cells were intravenously injected into WT mice and mice treated with the COX-2 inhibitor NS-398. The nonselective COX inhibitor aspirin reduced lung metastasis, but the COX-1 inhibitor SC560 did not. The expression of matrix metalloproteinases (MMP)-9 and vascular endothelial growth factor (VEGF)-A was suppressed in NS-398-treated mice compared with PBS-treated mice. Lungs containing LLC colonies were markedly reduced in EP3 receptor knockout (EP3-/-) mice compared with WT mice. The expression of MMP-9 and VEGF-A was downregulated in metastatic lungs of EP3-/- mice. An immunohistochemical study revealed that MMP-9-expressing endothelial cells were markedly reduced in EP3-/- mice compared with WT mice. When HUVEC were treated with agonists for EP1, EP2, EP3, or EP4, only the EP3 agonist enhanced MMP-9 expression. These results suggested that EP3 receptor signaling on endothelial cells is essential for the MMP-9 upregulation that enhances tumor metastasis and angiogenesis. An EP3 receptor antagonist may be useful to protect against tumor metastasis. (Cancer Sci 2009; 100: 2318-2324).

DOI： 10.1111/j.1349-7006.2009.01322.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press ({OUP})  

We describe a rare case of thymic neuroblastoma with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A 60-year-old male patient was admitted to our hospital for further examination and treatment of anterior mediastinal tumor found at a regular health check-up. On examination there was hyponatremia, decrease in plasma osmolarity and elevation of plasma antidiuretic hormone (ADH) level. Thus, he underwent total thymectomy under the diagnosis of thymoma with SIADH. The tumor was located in the right lobe of the thymus and the final diagnosis was thymic neuroblastoma. To our knowledge, this is the first reported case of thymic neuroblastoma in which production of ADH by tumor cells is demonstrated immunohistochemically. This case highlights the need to consider functional activity of thymic neuroblastoma and complete resection of the tumor is warranted for treatment.

DOI： 10.1510/icvts.2009.210229

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Objective. Computer-controlled stapling systems can improve lung tissue approximation during thoracic surgery. We report our experience with a handy system with computer-controlled placement of staples for lung resection in Japan. Methods. The iDrive system is the improved second version of the SurgAssist stapling system. It comprises a self-contained computer microprocessor and hand-held control unit combined with a digital loading unit (a power linear cutter with a blue or green cartridge) for use in open and minimally invasive thoracic surgery. The mounted control unit has two uses: (1) controlling accurate placement of the cartridge by orientating the tip of the rigid and curved shaft and (2) controlling the closure of the stapler and the firing. Each cartridge contains a programmed electronic device that triggers activation of the appropriate program in the self-contained microprocessor. The compression level on lung tissue is determined by the computer. Results. From March to October 2008, the iDrive system was used 53 times in a consecutive series of 39 patients during open thoracic lung surgery. There were 12 women and 27 men. The following procedures were performed: lobectomy, segmentectomy, and wedge resection. The power linear cutters were used for stapling lung parenchyma for wedge resection in 6 patients, bullectomy in 1, segmentectomy in 2, and fissure division in 33. There were no stapling failures and no complications related to the staplers. Conclusion. The new computer-controlled stapling system may be safe and efficient for lung parenchymal tissue resection during open thoracic surgery. © The Japanese Association for Thoracic Surgery 2009.

DOI： 10.1007/s11748-009-0407-3

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

2019年末から世界中に蔓延し,多くの犠牲者を出した新型コロナウイルス感染症(corona virus infection 2019:COVID-19)は,その驚異的な感染力と重症化が発生当初より問題となっており,呼吸器系器官を中心とした実質臓器の障害とともに,血管内皮細胞障害と付随する凝固障害がその病態として注目されてきた.ウイルス感染による全身性炎症生反応(systemic inflammatory response syndrome:SIRS)を端とするサイトカインストームによる播種生血管内凝固障害(disseminated intravascular coagulation:DIC)や静脈血栓塞栓症(venous thromboembolism:VTE)に代表される血管内血栓形成が高頻度に確認されている.血管内皮障害や凝固障害といった微小循環障害について,さまざまな研究がなされており,COVID-19における微小血管障害については病態が徐々に解明されつつあり,ワクチン療法や抗ウイルス薬の開発とその効果の向上とともに,抗凝固療法の併用による重症化予防により随分コントロールできる感染症になりつつある.本稿では,COVID-19に関連する微小循環障害に焦点をあて,そのメカニズムについて述べる.(著者抄録)

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

2019年末から世界中に蔓延し,多くの犠牲者を出した新型コロナウイルス感染症(corona virus infection 2019:COVID-19)は,その驚異的な感染力と重症化が発生当初より問題となっており,呼吸器系器官を中心とした実質臓器の障害とともに,血管内皮細胞障害と付随する凝固障害がその病態として注目されてきた.ウイルス感染による全身性炎症生反応(systemic inflammatory response syndrome:SIRS)を端とするサイトカインストームによる播種生血管内凝固障害(disseminated intravascular coagulation:DIC)や静脈血栓塞栓症(venous thromboembolism:VTE)に代表される血管内血栓形成が高頻度に確認されている.血管内皮障害や凝固障害といった微小循環障害について,さまざまな研究がなされており,COVID-19における微小血管障害については病態が徐々に解明されつつあり,ワクチン療法や抗ウイルス薬の開発とその効果の向上とともに,抗凝固療法の併用による重症化予防により随分コントロールできる感染症になりつつある.本稿では,COVID-19に関連する微小循環障害に焦点をあて,そのメカニズムについて述べる.(著者抄録)

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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Language：Japanese   Publisher：日本臨床倫理学会  

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Language：Japanese   Publisher：日本救急医学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：医歯薬出版(株)  

新型コロナウイルス感染症(COVID-19)パンデミックは、その驚異的な感染力と罹患者数の急増から全世界で問題になっている。最近の報告では、最重症患者は凝固障害を呈し、播種性血管内凝固症候群(DIC)や静脈血栓塞栓症(VTE)に代表される血管内血栓形成が高頻繁に確認されている。そのため、凝固機能はCOVID-19の重症化を識別するのに役立つと考えられている。COVID-19関連凝固障害の臨床症状は主に臓器機能障害であるが、出血性イベントはほとんど報告されていない。D-ダイマーおよびフィブリン/フィブリノーゲン分解産物(FDP)の増加は、凝固障害の本質が大量のフィブリン形成であることを表している。しかし、COVID-19凝固障害のメカニズムはいまだ完全には解明されておらず、炎症性サイトカイン、リンパ球細胞死、低酸素症、および血管内皮損傷によって組織化された調節不全の免疫応答が関与していると推測されている。その凝固障害に対する治療についてもいまだ確立されたものがなく、さらなる検討が必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(NPO)日本急性血液浄化学会  

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Language：Japanese   Publisher：(株)じほう  

＜Points＞▼敗血症(sepsis)は、感染に伴い制御不能となった免疫によって臓器障害が引き起こされた状態であると定義される。▼敗血症による臓器障害の評価には、SOFAスコアが臨床的に広く用いられている。▼集中治療室以外の敗血症による臓器障害を評価するのに、簡便なqSOFAスコアが用いられている。▼敗血症の病態として、血管内皮障害とそれに伴う凝固系異常により臓器障害を呈する。▼敗血症の治療は、感染症など原病に対する治療、臓器障害に対する支持療法、および病態の主座である血管内皮障害、凝固系異常の是正が重要である。(著者抄録)

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Language：Japanese   Publisher：医学図書出版(株)  

非常に強い感染力で全世界で猛威をふるっている新型コロナウイルス感染症(COVID-19)に対する対応が世界各国で行われており、その特徴的な画像所見、高い感度と特異性を備えた遺伝子診断法やウイルス診断法などの診断法の開発、症状を考慮した重症度別分類によるトリアージ、重症度を判別するバイオマーカーの検討、抗ウイルス薬を含む効果的な治療法の確立などさまざまな研究が競争的に行われている。さらに、院内感染や院内クラスター形成などにより生じる医療崩壊を防ぎ、通常診療を抑制しないようにするための院内環境整備などが非常に重要である。とくに、重症COVID-19患者に対する集中治療管理に伴う環境整備が重要と考える。ここでは、COVID-19に対する診断方法、症状による重症度分類、COVID-19の環境管理を含む集中治療管理に関する注意点について説明する。(著者抄録)

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Language：Japanese   Publisher：医学図書出版(株)  

非常に強い感染力で全世界で猛威をふるっている新型コロナウイルス感染症(COVID-19)に対する対応が世界各国で行われており、その特徴的な画像所見、高い感度と特異性を備えた遺伝子診断法やウイルス診断法などの診断法の開発、症状を考慮した重症度別分類によるトリアージ、重症度を判別するバイオマーカーの検討、抗ウイルス薬を含む効果的な治療法の確立などさまざまな研究が競争的に行われている。さらに、院内感染や院内クラスター形成などにより生じる医療崩壊を防ぎ、通常診療を抑制しないようにするための院内環境整備などが非常に重要である。とくに、重症COVID-19患者に対する集中治療管理に伴う環境整備が重要と考える。ここでは、COVID-19に対する診断方法、症状による重症度分類、COVID-19の環境管理を含む集中治療管理に関する注意点について説明する。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本胸部外科学会-関東甲信越地方会  

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Language：Japanese   Publisher：北里医学会  

背景:小児徐脈性不整脈に対するペーシング導入は成長および,リード自体の耐久性にもとづき物理的破損のリスクを有する。その破損の要因としてはリード素材,本体挿入部位,ペーシングリードの通過部位等が考慮される。今回我々は小児ペースメーカー植込み患者において,ペーシングリード破損例につき検討をした。方法:1979年4月より2003年3月まで当院でペースメーカ植込み術を施行した17症例の小児例において,ペーシングリード破損につながる危険因子につき破損例,非破損例間で検討を行い,後ろ向きに検討を行った。結果:リード破損の相対危険因子として女児,ポリウレタン,腹部植込み例に破損が多かった。身長,年齢,初回植込み時年齢,成長率においては有意差を認めなかったが,新生児期,乳児期に手術を施行した先天性房室ブロック患者での破損率は高度であった。結語:小児期,殊に新生時期に植え込み手術を施行した症例での破損の頻度は高い。小児におけるペーシング確立は体が小さいことや,活動度,運動を自制させることが困難でありペーシングリード破損を来しやすい状況下にある。(著者抄録)

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Language：Japanese   Publisher：(一社)日本外科学会  

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背景。気管支カルチノイドの治療は肺癌の手術に準じた外科的治療が一般的であるが、中枢発生の腔内型定型的気管支カルチノイドに対しては、レーザー焼灼や光線力学的治療、凝固子などを用いた気管支鏡下治療の有用性が報告されている。今回われわれは腔内型定型的気管支カルチノイドが、肝細胞癌に対するインターフェロン(IFN)療法中に縮小・退縮し、さらに気管支鏡下切除により腫瘍の消失をえた1例を経験したので報告する。症例。59歳、男性。肝細胞癌術後IFN療法中に血痰出現。胸部CTにて右肺中葉支を閉塞する結節と中葉の無気肺を認め、気管支鏡下生検にて腔内型定型的気管支カルチノイドと診断された。外科的切除の適応と考えたが、肝細胞癌の予後を考慮し、本人に十分な説明の上、経過観察とした。その後の気管支鏡検査で徐々に腫瘍の縮小を認め、最終的にホットバイオプシーによる気管支鏡下切除にて腫瘍は消失した。この間に行われていた治療は肝細胞癌に対するIFN療法のみであった。腫瘍消失後約1年6ヵ月の経過観察で局所再発を認めていない。結論。腔内型定型的気管支カルチノイドに対するIFNの効果が推定され、また気管支鏡下切除は腔内型定型的気管支カルチノイドの治療法の選択肢の一つとなる可能性が示唆された。(著者抄録)

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高齢化社会の進行とともに増加していると推定される80歳以上非小細胞肺癌症例に対する治療方針について述べる。外科的治療における適応は、年齢に規定されず、Performance Status(PS)2以下・臨床病期I期症例であることが望ましく、術式は部分切除や区域切除などの縮小手術を考慮すべきである。また、手術非適応症例に関しては、放射線療法・定位放射線療法や荷電粒子療法も選択肢としてあげられる。化学療法は、年齢に規定されず、PS・合併症に注意し行うべきである。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2007&ichushi_jid=J01244&link_issn=&doc_id=20071019290745&doc_link_id=%2Fec7jaluc%2F2007%2F004705%2F745%2F0631-0631%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2007%2F004705%2F745%2F0631-0631%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2007&ichushi_jid=J01244&link_issn=&doc_id=20071019290765&doc_link_id=%2Fec7jaluc%2F2007%2F004705%2F765%2F0636-0636%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2007%2F004705%2F765%2F0636-0636%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2007&ichushi_jid=J01244&link_issn=&doc_id=20071019290732&doc_link_id=%2Fec7jaluc%2F2007%2F004705%2F732%2F0628-0628%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2007%2F004705%2F732%2F0628-0628%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J01244&link_issn=&doc_id=20061120260257&doc_link_id=%2Fec7jaluc%2F2006%2F004605%2F255%2F0514-0514%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2006%2F004605%2F255%2F0514-0514%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J01244&link_issn=&doc_id=20061120260195&doc_link_id=%2Fec7jaluc%2F2006%2F004605%2F194%2F0498-0498%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2006%2F004605%2F194%2F0498-0498%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2006&ichushi_jid=J01244&link_issn=&doc_id=20061120260384&doc_link_id=%2Fec7jaluc%2F2006%2F004605%2F382%2F0547-0547%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2006%2F004605%2F382%2F0547-0547%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2006&ichushi_jid=J01244&link_issn=&doc_id=20061120260412&doc_link_id=%2Fec7jaluc%2F2006%2F004605%2F410%2F0554-0554%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2006%2F004605%2F410%2F0554-0554%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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Language：Japanese   Publisher：日本胸部外科学会-関東甲信越地方会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本小児循環器学会  

J-GLOBAL

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Language：Japanese   Publisher：シュプリンガー・ジャパン(株)  

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Language：Japanese   Publisher：日本胸部外科学会-関東甲信越地方会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：シュプリンガー・ジャパン(株)  

J-GLOBAL

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

J-GLOBAL

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Language：Japanese   Publisher：北里医学会  

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Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Poster presentation  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Poster presentation  

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