INTRODUCTION: We aimed to describe the extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including their frequency, onset with respect to respiratory symptoms, pathogenesis and association with disease severity. METHODS: We searched the MEDLINE and Embase databases for SARS-CoV-2-related studies. Meta-analysis, observational studies, case series and case reports published in English or Chinese between 1 January 2020 and 1 May 2020 were included. Reports with only paediatric or obstetric cases were excluded. RESULTS: 169 articles were included. Early manifestations (preceding respiratory symptoms until Day 6 of onset) included olfactory and gustatory disturbance (self-reported in up to 68% and 85% of cases, respectively), gastrointestinal symptoms (up to 65.9%) and rash (up to 20.4%). From Day 7 onwards, hypercytokinaemia, paralleled multi-organ complications including acute cardiac injury (pooled incidence of 17.7% in 1,412 patients, mostly with severe disease and 17.4% mortality), kidney and liver injury (up to 17% and 33%, respectively) and thrombocytopenia (up to 30%). Hypercoagulability resulted in venous thromboembolic events in up to 31% of all patients. Uncommon disease presentation and complications comprised Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis and spontaneous pneumomediastinum. CONCLUSION Although the systemic manifestations of SARS-CoV-2 infection are variegated, they are deeply interwoven by shared mechanisms. Two phases of extrapulmonary disease were identified: (a) an early phase with possible gastrointestinal, ocular and cutaneous involvement; and (b) a late phase characterised by multiorgan dysfunction and clinical deterioration. A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome in SARS-CoV-2 is needed.
Humans ; Asian People ; COVID-19/complications* ; Inflammation/complications* ; SARS-CoV-2 ; Thrombosis

Purpose: We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL).We investigated the prognostic value of maximum tumor dissemination (Dmax), the distance between malignant lesions that were farthest apart, as assessed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and other clinical factors in patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients who underwent FDG PET/CT for initial staging and treatment response evaluation of DLBCL were reviewed retrospectively. Baseline Dmax, maximum standardized uptake value, total summation of all metabolic tumor volumes (tMTV), and total summation of all total lesion glycolysis (tTLG) were measured. The treatment response was evaluated at the interim and end of first-line treatment (EOT) using the Deauville score (DS). FDG PET/CT parameters and other clinical factors including sex, age, serum lactate dehydrogenase (LDH) level, stage, performance status, and the International Prognostic Index (IPI) were analyzed to identify factors prognostic of the time to progression (TTP) and disease-specific survival (DSS). Results: A total of 63 patients were included. Univariate survival analysis identified Dmax (> 275 mm), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) as significant predictors of poor TTP. Serum LDH level (> 640 IU/L), IPI (≥ 4), tMTV (> 180 mL), tTLG (> 1300), interim DS (≥ 4), and EOT DS (≥ 4) were significant predictors of DSS. After multivariate survival analysis, Dmax (P = 0.008) and EOT DS (P = 0.005) were independent predictors of TTP. EOT DS was an independent predictor of DSS (P = 0.029). Conclusions Dmax at the time of diagnosis and the EOT response assessed by FDG PET/CT provide useful prognostic information additive to the IPI in patients with DLBCL.

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.

Purpose: Low-profile, self-expandable stents have broadened therapeutic options available for definitive treatment of intracranial aneurysms. The novel Low-Profile Visualized Intraluminal Support (LVIS) EVO stent extends upon the success of its predecessor, the LVIS Jr stent, aiming to enable higher visibility and greater opening ability within a self-expandable and fully retrievable microstent system. In this study, we aim to report the early safety and feasibility experience with the LVIS EVO stent. Materials and Methods: A multicenter, retrospective, observational study was conducted on patients who had intracranial aneurysms treated with the LVIS EVO stent across 3 Australian neurovascular centers between February 2020 and September 2020. Short-term technical and clinical outcomes were evaluated. Results: A total of 22 LVIS EVO stents were successfully implanted to treat 15 aneurysms (3 ruptured, 12 unruptured) in 15 patients. Aneurysms ranged from 2 mm to 35 mm in dome height. The LVIS EVO stent was used for stent-assisted coiling in 11 patients and flow diversion in 4 patients. There were no device-related procedural complications. There were 2 cases of peri-procedural symptomatic thromboembolic complications and no procedure-related mortality. At early radiological follow up, 10 patients had complete occlusion, 4 patients had small neck remnants, and 1 patient who was managed with flow diversion had a residual aneurysm. Conclusion Early experience with the LVIS EVO stent demonstrated safety and feasibility for stent-assisted coiling as well as flow diversion for intracranial aneurysms. In this heterogeneous cohort, including ruptured, complex, and large aneurysms, all cases were technically successful.

Purpose: Low-profile, self-expandable stents have broadened therapeutic options available for definitive treatment of intracranial aneurysms. The novel Low-Profile Visualized Intraluminal Support (LVIS) EVO stent extends upon the success of its predecessor, the LVIS Jr stent, aiming to enable higher visibility and greater opening ability within a self-expandable and fully retrievable microstent system. In this study, we aim to report the early safety and feasibility experience with the LVIS EVO stent. Materials and Methods: A multicenter, retrospective, observational study was conducted on patients who had intracranial aneurysms treated with the LVIS EVO stent across 3 Australian neurovascular centers between February 2020 and September 2020. Short-term technical and clinical outcomes were evaluated. Results: A total of 22 LVIS EVO stents were successfully implanted to treat 15 aneurysms (3 ruptured, 12 unruptured) in 15 patients. Aneurysms ranged from 2 mm to 35 mm in dome height. The LVIS EVO stent was used for stent-assisted coiling in 11 patients and flow diversion in 4 patients. There were no device-related procedural complications. There were 2 cases of peri-procedural symptomatic thromboembolic complications and no procedure-related mortality. At early radiological follow up, 10 patients had complete occlusion, 4 patients had small neck remnants, and 1 patient who was managed with flow diversion had a residual aneurysm. Conclusion Early experience with the LVIS EVO stent demonstrated safety and feasibility for stent-assisted coiling as well as flow diversion for intracranial aneurysms. In this heterogeneous cohort, including ruptured, complex, and large aneurysms, all cases were technically successful.

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.

Mucormycosis is a fungal infection, which is difficult to treat due to its rapid dissemination and low susceptibility to anti-fungal agents. Peritonitis preceded by gastrointestinal mucormycosis is very rare, and only a few cases have been reported. We present a case of peritonitis and disseminated mucormycosis caused by Mucor circinelloides in an immunocompromised patient. A 59-year-old man, diagnosed with nodal marginal zone B-cell lymphoma, was diagnosed with liver failure due to severe septic shock. A white, woolly cotton-like growth, which was consistent with that of Mucor species, was isolated from ascites and sputum specimens. Targeted DNA sequencing confirmed the isolate as M. circinelloides with 100% identity. Despite anti-fungal treatment, the patient died after four days. This is a rare case of peritonitis and disseminated mucormycosis that was probably preceded by gastrointestinal mucormycosis caused by M. circinelloides, as determined by molecular methods. Accurate and rapid identification of mold using molecular methods might be necessary for early treatment in critical cases, and more cases should be clinically evaluated further.

BACKGROUND AND OBJECTIVES: Impaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y12 receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI. METHODS: High platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol. CONCLUSIONS: HEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02224534
Blood Platelets ; Echocardiography, Three-Dimensional ; Follow-Up Studies ; Humans ; Korea ; Models, Animal ; Myocardial Infarction ; Myocardium ; Natriuretic Peptide, Brain ; Percutaneous Coronary Intervention ; Random Allocation ; Reperfusion Injury ; Ventricular Remodeling

BACKGROUND AND OBJECTIVES: Impaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y12 receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI. METHODS: High platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol. CONCLUSIONS HEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02224534

Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, the characterization of these secretomes and the molecular events that associate them with acquired drug resistance remain poorly understood. In this study, we show that secretomes of cancer cells with high-level paclitaxel resistance stimulated cell proliferation and suppressed drug-induced apoptosis of drug-sensitive cells. We also found that drug (docetaxel)-stimulated induction of interferon-α (IFN-α), IFN-λ and tumor necrosis factor-α (TNF-α) release in drug-sensitive cells was lowered by these secretomes. The promotion of cell proliferation by paclitaxel-resistant (PacR) cancer cell secretomes was associated, in part, with an increase in S phase of the cell cycle and downregulation of the cell death pathway that supports escape from apoptosis. In addition, we also found that the regulation of targeted glycolysis in PacR cancer cells alters the effects of the secretomes on cell growth, apoptosis, ATP generation and acquired drug resistance. Further study revealed that the deletion of FOXO3a transcription exacerbates glycolytic shift-induced apoptosis by rescuing TRAIL expression. By generating a docetaxel–cross-resistant PacR cancer cell line (PacR/DCT), we further clarified the role of FOXO3a in glycolysis-associated mediation of P-glycoprotein/ABCB1 hyperactivity that induces docetaxel cross-resistance. These findings suggest that suppression of the cellular energy supply by targeting glycolysis may inhibit the multiplicity of acquired chemotherapy resistance. Therefore, the therapeutic inhibition of FOXO3a might direct glycolysis to induce apoptosis and overcome multidrug resistance in cancer cells.
Adenosine Triphosphate ; Apoptosis* ; Cell Cycle ; Cell Death ; Cell Line ; Cell Proliferation ; Down-Regulation ; Drug Resistance ; Drug Resistance, Multiple ; Drug Therapy ; Energy Metabolism ; Glycolysis ; Necrosis ; Negotiating ; Paclitaxel ; S Phase ; United Nations*