Kawasaki Disease Newburger, Jane W., MD, MPH; Takahashi, Masato, MD; Burns, Jane C., MD
Journal of the American College of Cardiology,
04/2016, Letnik:
67, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Abstract Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 ...in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis.
BACKGROUND:Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired ...heart disease in children in developed countries.
METHODS AND RESULTS:To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.
CONCLUSIONS:These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.
CO
2
and O
2
in the Sakaguchi flask headspace during culture was monitored via circulation direct monitoring and sampling system (CDMSS), a device with circulation bypass system. In static culture ...with
Saccharomyces cerevisiae
(circulation rate, 50 mL/min), a vertical CO
2
concentration gradient (maximum gap ~ 2% (
v
/
v
) height from the bottom of flask 45 mm, 7%; 155 mm, 5%) in the Sakaguchi flask headspace was observed; no concentration O
2
gradient was observed. However, shake flask culture showed vertical gradient concentrations for both CO
2
and O
2
(maximum gap of CO
2
and O
2
concentrations: 2 and 4% heights from the bottom of flask 115 mm, 6.0 and 9.5%; 175 mm, 4.0 and 13.5%, respectively). When the CDMSS circulation rate in the Sakaguchi flask headspace was 300 or 400 mL/min, the gaseous environment was uniformly distributed so that no vertical gradient concentration was observed. In shaking culture with
Escherichia coli
under these conditions, CO
2
was accumulated at high concentrations in the headspace and culture broth (maximum values 8%, in the headspace; 120 mg/L, in the culture broth). Most of the accumulated CO
2
in the headspace could be removed by inserting a column packed with CO
2
adsorbent at the bypass port of the CDMSS gaseous circulation. Thus, dissolved CO
2
was maintained at a lower concentration, and the final UOD (unit optical density) value of culture was increased compared with that of the control. This study is the first to demonstrate that vertical gradients of CO
2
and O
2
concentrations exist in the headspace of Sakaguchi flask during culture.
In this study, we found that opening breathable culture plugs for 30 s during periodic and aseptic sampling affects the community structure of cultured soil microbes. Similar effects were observed ...using an automatic aeration flask system that mimics aseptic opening of the breathable culture plug during sampling, but without interruption in shaking. Thus, the observed changes in the microbial consortia appear to be due exclusively to the intermittent ventilation of the flask headspace. To elucidate the mechanism driving this phenomenon, we monitored CO2 and O2 concentrations in both headspace and culture broth using the new system termed as circulation direct monitoring and sampling system. The data show that the CO2 concentration in the culture broth temporarily decreased with the CO2 concentration in the headspace, strongly suggesting that the effect of intermittent ventilation of the headspace on the microbial consortia depends on CO2. Importantly, the data also imply that environmental variables during shake flask culture, especially CO2 concentration, is important for screening aerobic microorganisms.
Abstract Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other ...docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m 2 )-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2–4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14–0.86, P = 0.02 for all cycles; 0.26, 0.11–0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.
Background
The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or ...programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression.
Methods
Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as “% stromal”, and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry.
Results
TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (
p
= 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (
p
= 0.0383), but overall survival (OS) showed no significance (
p
= 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (
p
= 0.0032,
p
= 0.0002).
Conclusion
The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.
Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the ...efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio HR 0·78 95% CI 0·67–0·89; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 95% CI 0·68–0·94; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 0·60–0·97, one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 25% of 573 patients vs six 1% of 570), increased aspartate aminotransferase (103 18% vs 16 3%), hyperglycaemia (88 15% vs one <1%), and rash (45 8% vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 16% of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 3% of 573 vs one <1% of 570) and increased aspartate aminotransferase (14 2% vs one <1%). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.
Insoluble aggregated proteins are often associated with neurodegenerative diseases. Previously, we investigated chemical chaperones that prevent the aggregation of denatured proteins. Among these, ...4-phenyl butyric acid (4-PBA) has well-documented chemical chaperone activity, but is required at doses that have multiple effects on cells, warranting further optimization of treatment regimens. In this study, we demonstrate chemical chaperone activities of the novel compound indole-3-propionic acid (IPA). Although it has already been reported that IPA prevents β-amyloid aggregation, herein we show that this compound suppresses aggregation of denatured proteins. Our experiments with a cell culture model of Parkinson's disease are the first to show that IPA prevents endoplasmic reticulum (ER) stress and thereby protects against neuronal cell death. We suggest that IPA has potential for the treatment of neurodegenerative diseases and other diseases for which ER stress has been implicated.
•IPA is the new chemical chaperone with equal or better efficacy than 4-PBA.•IPA suppresses denatured protein aggregation in vitro.•IPA suppresses the ER stress-induced neuronal cell death.•IPA suppressed oxidative stress-induced neuronal cell death in a PD model.•Contribution of IPA to HDAC inhibition during cell death suppression was evaluated.
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