Giant coronary aneurysm in a toddler with Kawasaki disease: technical challenges in CT coronary angiography.

Kawasaki disease is the most common vasculitis causing acquired coronary artery aneurysm (CAA) and affects mostly children. Computed tomography coronary angiography (CTCA) has unique diagnostic and prognostic values in cases of giant CAA. Here, we report technical challenges encountered when performed CTCA for a case of Kawasaki disease complicated with giant CAA. In particular, there was significant flow alteration caused by the giant CAA(s) causing suboptimal enhancement when the standard protocol was applied. We share our experience in optimizing the scan and propose the use of either manual bolus tracking or test bolus technique in similar scenarios, as well as multidisciplinary approach to optimize patient preparation.

Arabidopsis retromer subunit AtVPS29 is involved in SLY1-mediated gibberellin signaling.

KEY MESSAGE: Retromer protein AtVPS29 upregulates the SLY1 protein and downregulates the RGA protein, positively stimulating the development of the root meristematic zone, which indicates an important role of AtVPS29 in gibberellin signaling. In plants, the large retromer complex is known to play roles in multiple development processes, including cell polarity, programmed cell death, and root hair growth in Arabidopsis. However, many of its roles in plant development remain unknown. Here, we show that Arabidopsis trimeric retromer protein AtVPS29 (vacuolar protein sorting 29) modulates gibberellin signaling. The SLEEPY1 (SLY1) protein, known as a positive regulator of gibberellic acid (GA) signaling, exhibited lower abundance in vps29-3 mutants compared to wild-type (WT) plants. Conversely, the DELLA repressor protein, targeted by the E3 ubiquitin ligase SCF (Skp, Cullin, F-box) complex and acting as a negative regulator of GA signaling, showed increased abundance in vps29-3 mutants compared to WT. The vps29-3 mutants exhibited decreased sensitivity to exogenous GA supply in contrast to WT, despite an upregulation in the expression of GA receptor genes within the vps29-3 mutants. In addition, the expression of the GA synthesis genes was downregulated in vps29-3 mutants, implying that the loss of AtVPS29 causes the downregulation of GA synthesis and signaling. Furthermore, vps29-3 mutants exhibited a reduced meristematic zone accompanied by a decreased cell number. Together, these data indicate that AtVPS29 positively regulates SLY1-mediated GA signaling and plant growth.

Arabidopsis COP1 guides stomatal response in guard cells through pH regulation.

Plants rely on precise regulation of their stomatal pores to effectively carry out photosynthesis while managing water status. The Arabidopsis CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a critical light signaling repressor, is known to repress stomatal opening, but the exact cellular mechanisms remain unknown. Here, we show that COP1 regulates stomatal movement by controlling the pH levels in guard cells. cop1-4 mutants have larger stomatal apertures and disrupted pH dynamics within guard cells, characterized by increased vacuolar and cytosolic pH and reduced apoplastic pH, leading to abnormal stomatal responses. The altered pH profiles are attributed to the increased plasma membrane (PM) H+-ATPase activity of cop1-4 mutants. Moreover, cop1-4 mutants resist to growth defect caused by alkali stress posed on roots. Overall, our study highlights the crucial role of COP1 in maintaining pH homeostasis of guard cells by regulating PM H+-ATPase activity, and demonstrates how proton movement affects stomatal movement and plant growth.

Focal cerebral arteriopathy-inflammatory type in a child - MR diagnosis using vessel wall imaging technique with review of classification and diagnostic evaluation criteria.

Acute ischemic stroke (AIS) in childhood is defined by a stroke occurring after 28 days of life to 18 years of age. This presents a distinct clinical challenge in terms of both diagnosis and treatment. The overlapping clinical presentations of acute ischemic stroke and its mimics such as migraine with aura, seizure with Todd paresis and encephalitis renders early accurate diagnosis of this time-sensitive condition difficult, with a change in the final diagnosis in up to 40% of patients. Identification of the etiology after establishing the diagnosis of ischemic stroke is paramount for prognostication and treatment decisions. These include cardioembolic, arteriopathy, thrombophilia and inflammatory causes. Magnetic resonance imaging (MRI) plays an indispensable role towards tackling the initial diagnostic dilemma and subsequent evaluation of the underlying etiology, particularly in patients with arteriopathy. Here we present the MRI findings including vessel wall imaging with longitudinal follow-up, which support the diagnosis of focal cerebral arteriopathy-inflammatory type (FCAi) in a pediatric patient.

COP1 mutation causes low leaf temperature under various abiotic stresses in Arabidopsis thaliana.

Stomata are microscopic pores on epidermal cells of leaves and stems that regulate water loss and gas exchange between the plant and its environment. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase that is involved in plant growth and development and multiple abiotic stress responses by regulating the stability of various target proteins. However, little is known about how COP1 controls stomatal aperture and leaf temperature under various environmental conditions. Here, we show that COP1 participates in leaf temperature and stomatal closure regulation under normal and stress conditions in Arabidopsis. Leaf temperature of cop1 mutants was relatively lower than that of wild type (WT) under drought, salt, and heat stress and after abscisic acid (ABA), CaCl2, and H2O2 treatments. However, leaf temperature was generally higher in both WT and cop1 mutants after abiotic stress and chemical treatment than that of untreated WT and cop1 mutants. Stomatal aperture was wider in cop1 mutants than that in WT under all conditions tested, although the extent of stomatal closure varied between WT and cop1 mutants. Under dark conditions, leaf temperature was also lower in cop1 mutants than that in WT. Expression of the genes encoding ABA receptors, ABA biosynthesis proteins, positive regulators of stomatal closure and heat tolerance, and ABA-responsive proteins was lower in cop1 mutants that that in WT. In addition, expression of respiration-related genes was lower in cop1 mutants that that in WT. Taken together, the data provide evidence that mutations in COP1 lead to wider stomatal aperture and higher leaf temperature under normal and stress conditions, indicating that leaf temperature is highly correlated with stomatal aperture.

COP1 controls salt stress tolerance by modulating sucrose content.

The E3 ubiquitin ligase Constitutive Photomorphogenic 1 (COP1) plays evolutionarily conserved and divergent roles. In plants, COP1 regulates a large number of developmental processes including photomorphogenesis, seedling emergence, and gravitropism. Nevertheless, its function in abiotic stress tolerance remains largely unknown. Here, we demonstrate the role of COP1 in salt stress tolerance in Arabidopsis thaliana. In soil, cop1-4 and cop1-6 mutants were more tolerant to high salinity than wild-type (WT) plants during vegetative growth. However, in high salt-containing Murashige and Skoog (MS) medium, cop1-4 and cop1-6 seedlings exhibited significantly impaired growth compared with WT plants. Notably, cop1-4 and cop1-6 seedlings recovered their growth to the WT level upon exogenous sucrose treatment even under high salinity conditions. Compared with WT plants, the sucrose content of cop1-4 mutants was much higher at the vegetative growth stage but similar at the seedling stage. Upon exogenous sucrose supply, root elongation was significantly stimulated in cop1-4 seedlings but only slightly stimulated in WT plants. Thus, no significant difference was observed in root length between the two genotypes. Altogether, our data indicate that cop1 mutants are more tolerant to salt stress than WT plants, and the salt tolerance of cop1 mutants is correlated with their sucrose content.

Oro-pharyngo-esophageal radionuclide scintigraphy predicts aspiration pneumonia risk and associated survival in post-irradiated nasopharyngeal carcinoma patients.

OBJECTIVE: To demonstrate that oro-pharyngo-esophageal radionuclide scintigraphy (OPERS) not only detects tracheobronchial aspiration after swallowing, but also quantifies the amount of aspiration and subsequent clearance. METHODS: Data collected between 2014 and 2019 were reviewed for aspiration pneumonia at 12 and 24-months after OPERS. The predictive value for aspiration pneumonia on flexible endoscopic evaluation of swallowing (FEES), videofluoroscopic swallowing study (VFSS), and OPERS, and the overall survival of patients with or without aspiration were determined. RESULTS: Thirty-seven patients treated with radiotherapy for nasopharyngeal carcinoma (NPC) were reviewed. The incidence of aspiration detected on FEES, VFSS, and OPERS was 78.4%, 66.7%, and 44.4%, respectively. Using VFSS as a gold standard, the sensitivity and specificity of OPERS for aspiration was 73.7% and 100%. The positive and negative predictive values for aspiration were 100% and 66.7%, respectively, with an overall accuracy of 82.8%. A history of aspiration pneumonia was one factor associated with a higher chance of subsequent aspiration pneumonia within 12 months (odds ratio: 15.5, 95% CI 1.67-145.8, p < .05) and 24 months (odds ratio: 23.8, 95% CI 3.69-152.89, p < .01) of the swallowing assessment. Aspiration detected by OPERS was a significant risk factor for future aspiration pneumonia at 12 and 24 months respectively. Significantly, better survival was associated with an absence of aspiration on OPERS only, but not on FEES or VFSS. CONCLUSION: OPERS predicts the safety of swallowing, the incidence of subsequent aspiration pneumonia, and the survival prognosis in post-irradiated NPC dysphagia patients. LEVEL OF EVIDENCE: 3.

ATOM: A phase II study to assess efficacy of preemptive local ablative therapy to residual oligometastases of NSCLC after EGFR TKI.

OBJECTIVES: NSCLC patients harboring EGFR mutation invariably developed resistance to EGFR TKI. We postulated that oligoresidual disease (ORD) after initial TKI might harbor resistant clones. This study aimed to test if preemptive local ablative therapy (LAT) can improve progression free survival (PFS) or not compared to historic data. MATERIALS AND METHODS: Patients indicated for EGFR TKI who possessed ORD (≤ 4 PET-avid lesions) after an initial 3-month TKI therapy were enrolled. After screening PET-CT, eligible patients with PET-avid ORDs were treated by LAT, either by stereotactic ablative radiotherapy (SABR) or surgery per clinicians' discretion. TKI was continued after LAT until it was considered ineffective. PET-CT was repeated on the 3rd and 12th month post-LAT (or at progression) apart from regular imaging. Further LAT was allowed in oligoprogressive disease. Primary endpoint was PFS rate at one-year from enrollment. Overall survival (OS), PFS and treatment safety were secondary endpoints. A post hoc comparison with screen failure cohort was performed. RESULTS: Eighteen patients were enrolled from 2014-17. Recruitment was stopped before the planned number (34) due to slow accrual. Two were excluded due to consent withdrawal and significant protocol violation. Median follow up was 39.1 months. Among the 16 analyzed patients, the one-year PFS rate (i.e. 15 month post TKI) was 68.8 %. Median OS was 43.3 months. All LAT were done by SABR, and none experienced ≥ grade 3 SABR related toxicities. Compared with screen failure cohort (n = 48), pre-emptive LAT effectively reduced risk of progression (HR 0.41, p = 0.0097). CONCLUSION: Preemptive LAT in ORD appeared to be safe and feasible. The 1-year PFS rate was encouraging. However, potential biases and the limitations of the study should not be overlooked. Further randomized studies are warranted.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Prospective evaluation of plasma Epstein-Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma.

BACKGROUND: Plasma Epstein-Barr virus (pEBV) DNA and fluorodeoxyglucose positron emission (PET) reflect tumour burden in advanced NPC. This study hypothesised that a dual endpoint based on assessing pEBV DNA clearance and PET response could predict early drug response. METHODS: Eligible patients underwent a computed tomography (CT) scan and dual PET-CT at baseline, a PET-CT at 4 weeks, and then a CT scan at 10 weeks after starting palliative or induction chemotherapy. Plasma EBV DNA clearance was determined. RESULTS: Fifty-eight out of 70 enrolled patients completed all imaging and 50/58 had falling pEBV DNA level, which allowed calculation of the clearance. At a median follow-up of 29.1 months, the dual endpoint (pEBV DNA clearance ≤ 10 days and > 50% drop in sum of SUVmax of target lesions) was an independent indicator of overall survival (hazard ratio (HR) = 0.135, 95% CI = 0.039 to 0.466, p = 0.0015) and progression-free survival (HR = 0.136, 95% CI = 0.048 to 0.385, p = 0002). This dual endpoint could predict subsequent response by Response Evaluation Criteria In Solid Tumours (RECIST) criteria at 10 weeks after chemotherapy. CONCLUSIONS: Early PET-CT response and pEBV DNA clearance could predict survival and subsequent response. This dual endpoint is an innovative tool for assessing early drug response.

Efficacy, Safety, and Pharmacokinetics of Axitinib in Nasopharyngeal Carcinoma: A Preclinical and Phase II Correlative Study.

Purpose: We hypothesized that axitinib is active with an improved safety profile in nasopharyngeal carcinoma (NPC).Experimental Design: We evaluated axitinib in preclinical models of NPC and studied its efficacy in a phase II clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice daily in continuous 4-week cycles. Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria for more than 3 months.Results: We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) receiving ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI, 65.6%-91.2%) at 3 months and 43.2% (30.4%-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%), and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during the first 3 months of axitinib treatment was significantly associated with improved overall survival (HR, 0.29; 95% CI, 0.13-0.64, P = 0.0012). Patient-reported fatigue symptom was associated with hypothyroidism (P = 0.039). Axitinib PK parameters (Cmax and AUC(0-t)) were significantly correlated with tumor response, toxicity, and serum thyroid-stimulating hormone changes.Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients. Clin Cancer Res; 24(5); 1030-7. ©2018 AACR.

Efficacy of 18F-FDG PET/CT in investigation of elevated CEA without known primary malignancy.

AIM: To evaluate the efficacy of 18flurodeoxyglucose positron emission tomography/computer tomography (18F-FDG PET/CT) in investigating patients with elevated carcinoembryonic antigen (CEA) and without known primary malignancy, and the impact of PET/CT findings on patient management. SETTING AND DESIGN: PET/CT scans done in a tertiary hospital between December 2007 and February 2012 for elevated CEA in patients without known primary malignancy were retrospectively reviewed. MATERIALS AND METHODS: The PET/CT findings, patients' clinical information, level of CEA, histological diagnosis, and subsequent management were retrieved by the electronic patient record for analysis. STATISTICAL ANALYSIS: Data were analyzed using SPSS version 19. RESULTS: One hundred and one PET/CT scans were performed for patients with elevated CEA. Fifty-eight of these were performed for patients with known primary malignancy and were excluded; 43 PET/CT scans were performed for patients without known primary malignancy and were included. Thirty-three (77%) had a positive PET/CT. Among the 32 patients with malignancy, 15 (47%) suffered from lung cancer and 8 (25%) suffered from colorectal cancer. The sensitivity (97%), specificity (82%), positive predictive value (94%), negative predictive value (90%), and accuracy (93%) were calculated. Thirty (91%) patients had resultant change in management. The mean CEA level for patients with malignancy (46.1 ng/ml) was significantly higher than those without malignancy (3.82 ng/ml) (P < 0.05). In predicting the presence of malignancy, a CEA cutoff at 7.55 ng/ml will achieve a sensitivity of 91% and a specificity of 73%. CONCLUSION: PET/CT, in our study population, appears to be sensitive, specific, and accurate in investigating patients with elevated CEA and without known primary malignancy. In addition to diagnosis of underlying primary malignancy, PET/CT also reveals occult metastases which would affect patient treatment options. Its role in investigating patients with elevated CEA and without known primary, compared with other investigation modalities, remains to be studied.

Association between mean arterial blood gas tension and outcome in cardiac arrest patients treated with therapeutic hypothermia.

BACKGROUND: Studies investigating the relationship between blood gas tension and outcome in cardiac arrest survivors have reported conflicting results. This might have resulted from the use of a blood gas value at a single time point and the difference in the proportion of patients treated with therapeutic hypothermia (TH). We investigated the association of the mean blood gas tensions calculated from blood gas values obtained between restoration of spontaneous circulation and end of TH with the outcome in cardiac arrest patients treated with TH. METHODS: This was a retrospective observational study including 213 adult cardiac arrest patients. The cohort was divided into four categories based on the distribution of the mean Pao2 data using quartiles as cut-off values between categories. According to the mean Paco2, the cohort was divided into hypocarbia, normocarbia, and hypercarbia. The primary outcome was in-hospital mortality. RESULTS: In multivariate analysis, the mean Pao2 quartile was not associated with in-hospital mortality, but hypocarbia was significantly associated with increased risk of in-hospital mortality (odds ratio 2.522; 95% confidence interval 1.184-5.372; P = .016). We found a V-shaped independent association between the mean Pao2 and poor neurologic outcome at hospital discharge, with the risk of poor neurologic outcome increasing with a descending and ascending Pao2 ranges. CONCLUSION: Mean Pao2 had no independent association with in-hospital mortality whereas hypocarbia was independently associated with in-hospital mortality. We also found a V-shaped independent association between the mean Pao2 and poor neurologic outcome at hospital discharge.

A rare anatomical variant: median anterior cerebral artery fenestration associated with an azygous infra-optic anterior cerebral artery.

We present a patient who had a median anterior cerebral artery fenestration with a congenital azygous infra-optic anterior cerebral artery. This rare combination of abnormalities was an incidental finding in a patient who suffered spontaneous subarachnoid haemorrhage from a ruptured anterior cerebral artery aneurysm.

Comparison of flow cytometry and immunohistochemistry in non-radioisotopic murine lymph node assay using bromodeoxyuridine.

Non-radioisotopic local lymph node assay (LLNA) employing 5-bromo-2'-deoxyuridine (BrdU) with flow cytometry (FACS) or immunohistochemistry (IHC) is gaining attention due to a regulatory issue of using radioisotope, (3)H-thymidine, in vivo in traditional LLNA. In this study, to compare the performance of these non-radioisotopic endpoints, 7 chemicals with known sensitizing potencies were examined in LLNA. Mice were topically treated with chemicals or vehicle on both ears for 3 days. After intraperitoneal injection of BrdU, bilateral lymph nodes were isolated separately and undergone respectively, FACS or IHC to determine BrdU incorporated lymph node cells (LNCs). Weight and histology of treated ears were also examined to evaluate chemical-induced edema and irritation. Both FACS and IHC could successively identify the skin sensitizers from non-sensitizers. Comparison of FACS and IHC with traditional LLNA revealed that FACS has a higher sensitivity although both assays produced comparable sensitivity and performance to traditional LLNA. In conclusion, non-radioisotopic LLNA using FACS and IHC can successfully detect sensitizers with a good correlation to traditional LLNA. Notably, FACS showed almost equivalent sensitivity and accuracy to traditional LLNA.

The validity, reliability and clinical utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease.

BACKGROUND/AIMS: To evaluate the psychometric properties of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease (SVD). METHODS: 40 SVD patients and 40 matched controls were recruited. Concurrent and criterion validity, inter-rater and test-retest reliability, internal consistency of the HK-MoCA were examined and clinical observations were made. RESULTS: Performance on the HK-MoCA was significantly predicted by both executive (beta = 0.23, p = 0.013) and non-executive (beta = 0.64, p < 0.001) composite scores. It differentiated SVD patients from controls (area under the curve = 0.81, p < 0.001) with an optimal cutoff at 21/22. Reliability, internal consistency and clinical utility were good. CONCLUSION: The HK-MoCA is a useful cognitive screening instrument for use in SVD patients.