A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review.

BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.

Secrets to a successful awake fibreoptic intubation (AFOI) on a patient with odentogenous abscess.

Awake fibreoptic intubation (AFOI) is an established modality in patients with anticipated difficulty with tracheal intubation. This case demonstrates that with careful and meticulous preparations, AFOI can lead to improved airway management and excellent patient outcomes. A 38-year-old woman presented with severe trismus secondary to odentogenous abscess was identified preoperatively as having a potential difficult airway. AFOI was performed successfully using combined Spray-As-You-Go and dexmedetomidine technique.

Treatment of benzodiazepine withdrawal syndrome in a severe traumatic brain injury patient.

Prolonged exposure to benzodiazepines (BDZ) may contribute towards physical dependence, which is manifested by iatrogenic Benzodiazepine Withdrawal Syndrome (BWS), a condition often underdiagnosed. Current evidence recommends precluding BDZ infusion as sedation in the intensive care unit to avoid possible withdrawal and delirium issues. Administration of dexmedetomidine should be considered to facilitate weaning in patients with BWS.

Nasopharyngeal diffuse large B-cells lymphoma causing acute airway obstruction amid COVID-19 crisis: an anaesthetist's nightmare.

Acute stridor is often an airway emergency. We present a valuable experience handling an elderly woman who was initially treated as COVID-19 positive during the pandemic in November 2020. She needed an urgent tracheostomy due to nasopharyngeal (NP) diffuse large B-cell lymphoma causing acute airway obstruction. Fortunately, 1 hour later, her NP swab real-time PCR test result returned as SARS-CoV-2 negative. This interesting article depicts the importance of adequate preparations when handling potentially infectious patients with anticipated difficult airway and the perioperative issues associated with it.

Handheld confocal Raman spectroscopy (CRS) for objective assessment of skin barrier function and stratification of severity in atopic dermatitis (AD) patients.

BACKGROUND: We developed the first-of-its-kind handheld confocal Raman spectroscopy (CRS) system to quantify the concentration of natural moisturizing factors in the skin. OBJECTIVE: To evaluate the feasibility of our handheld CRS system and propose a novel quantitative index to measure skin barrier function. METHODS: This prospective study included 30 atopic dermatitis (AD) patients and 14 healthy volunteers. All AD participants were assessed using the Scoring Atopic Dermatitis (SCORAD) severity instrument, a vapometer for trans-epidermal water loss and a moisture meter for skin surface moisture. A handheld CRS operating at 785 nm laser was used to measure the biochemical constituents of the skin up to a depth of ∼100 µm. We trained a linear kernel-based support vector machine (SVM) model for eczema classification based on the water, ceramide and urocanic acid content. A novel Eczema Biochemical Index (EBI) was then formulated using the skin constituents measured from the AD participants to stage disease severity. RESULTS: The SVM model used to classify healthy participants and AD patients obtained high cross-validated area under the curve of 0.857 and accuracy of 0.841, with high sensitivity and specificity values of 0.857 and 0.833 respectively. EBI can be used to stratify AD patients of varying severity, based on the biochemical constituents in the skin. CONCLUSION: As compared to the standard CRS system, the handheld CRS offers higher portability and provides Raman measurements at various body regions with similar sensitivity. This suggests that a handheld CRS device could be a valuable point-of-care resource in both research and clinical use.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

BACKGROUND: The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM. METHODS: GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD). RESULTS: The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD. CONCLUSIONS: Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.

Urinary Haptoglobin Predicts Rapid Renal Function Decline in Asians With Type 2 Diabetes and Early Kidney Disease.

CONTEXT: A recent study suggested that urinary haptoglobin may be a novel biomarker to improve predictive performance of albuminuria in type 2 diabetes mellitus (T2DM). However, the finding has not been externally validated. OBJECTIVE: The objective of the study was to evaluate whether urinary haptoglobin improves predictive performance of albuminuria in Asian T2DM with an estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.73 m2 or greater. DESIGN AND PARTICIPANTS: This was a prospective study with 269 T2DM nonprogressors (eGFR changes 0.2 [-0.7 to 1.0] mL/min per 1.73 m2 per y) and 153 T2DM progressors (eGFR decline -7.1 [-10.6 to -5.1] mL/min per 1.73 m2 per y) included. MAIN OUTCOME: The main outcome was an eGFR decline of 3 mL/min per 1.73 m2 or greater per year by trajectory slope. RESULTS: Urinary haptoglobin level increased 11-fold in progressors as compared with nonprogressors at baseline. In comparison with subjects in the lowest quartile, those with haptoglobin in the third and fourth quartiles had 2.25- (1.11-4.59) and 5.41 (2.63-11.1)-fold increased odds for renal progression, whereas those with an albuminuria level in the third and fourth quartiles had 2.53- (1.17-5.51) and 9.01 (4.00-20.5)-fold increased odds. Notably, urinary haptoglobin predicted renal progression independent of albuminuria. Addition of haptoglobin significantly improved the predictive performance of albuminuria beyond traditional risk factors as reflected by a significant increase in the net reclassification index and integrated discrimination index. In the chronic kidney disease stage 3 subpopulation, urinary haptoglobin outperformed albuminuria for the prediction of rapid renal function decline. CONCLUSIONS: Our data confirmed that urinary haptoglobin may improve the predictive performance of albuminuria for renal progression in Asians with T2DM. Moreover, it may potentially outperform albuminuria for the prediction of rapid renal function decline in the T2DM chronic kidney disease stage 3 subpopulation.

Evaluation of body adiposity index as a predictor of aortic stiffness in multi-ethnic Asian population with type 2 diabetes.

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus. We evaluated the predictive ability of the recently developed body adiposity index for aortic stiffness, an intermediate endpoint of cardiovascular disease, in a cross-sectional multi-ethnic Asian type 2 diabetes mellitus cohort (N = 1408). AS was estimated using carotid-femoral pulse wave velocity measured by applanation tonometry. Body adiposity index was computed as hip circumference/(height)(1.5) - 18. Compared to body mass index, waist circumference and visceral fat area, body adiposity index displayed the weakest association with pulse wave velocity (r = 0.077, 0.096, 0.134 and 0.058, respectively; all p < 0.05). Interestingly, the relationship between measurements of obesity and pulse wave velocity was ethnic dependent - body mass index, body adiposity index, waist circumference and visceral fat area consistently predicted pulse wave velocity only in Indians but not others. In multi-variable analysis, body mass index was a significant determinant of pulse wave velocity in all ethnicities. In conclusion, body adiposity index is a weak predictor of aortic stiffness (when compared with body mass index) in Asians with type 2 diabetes mellitus.

Association of plasma soluble α-klotho with pro-endothelin-1 in patients with type 2 diabetes.

OBJECTIVES: To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM). SUBJECTS AND METHODS: In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively. RESULTS: Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure. CONCLUSIONS: Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.

Relationship between circulating irisin, renal function and body composition in type 2 diabetes.

AIMS: Chronic kidney disease (CKD) secondary to type 2 diabetes mellitus (T2DM) is associated with multifaceted energy dysmetabolism. We aim to study the relationship between renal function, body composition and irisin, the recently identified myokine which is involved in energy regulation, in T2DM. METHODS: Circulating irisin and body composition were measured in 365 T2DM subjects across a wide range of renal function. RESULTS: Circulating irisin was significantly decreased in T2DM with renal insufficiency (77.4 ± 13.7 ng/ml in T2DM with eGFR ≥ 60 ml/min/1.73 m(2) versus 72.5 ± 14.9 ng/ml in those with eGFR<60 ml/min/1.73 m(2), p = 0.001) and the reduction in irisin was most pronounced in stage 5 CKD patients. In T2DM with preserved renal function, irisin was correlated with age (r = -0.242, p = 0.001) and pulse pressure (r = -0.188, p = 0.002). Among those with renal insufficiency, irisin was correlated with BMI (r = 0.171, p = 0.022), fat mass (r = 0.191, p = 0.013), percentage of fat mass (r = 0.210, p = 0.007) and eGFR (r = 0.171, p = 0.020). Multivariate linear regression models revealed that variations in circulating irisin were mainly attributable to eGFR and age in T2DM with and without renal impairment, respectively. CONCLUSION: Our observations suggest that the level of circulating irisin may be associated with renal function in T2DM. The role of reduced irisin in energy dysmetabolism in diabetic patients with renal insufficiency deserves further investigation.

Lower circulating irisin is associated with type 2 diabetes mellitus.

AIMS: Irisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients. METHODS: In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression. RESULTS: Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p < 0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p < 0.01), BMI (r = 0.387, p < 0.01), total cholesterol (r = 0.341, p < 0.01), total triglycerides (r = 0.299, p < 0.05), fasting blood glucose (r = 0.430, p < 0.01) and diastolic blood pressure (r = 0.306, p < 0.05). Multiple linear regression model revealed that BMI (ß = 0.407, p = 0.012) and FBG (ß = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn't reveal significant association between circulating irisin and major markers of metabolic phenotype. CONCLUSIONS: Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.

Patent foramen ovale and cryptogenic stroke: a complex neuro-cardio-vascular problem.

Patent foramen ovale has been suggested to be a risk factor for cryptogenic stroke by means of paradoxical embolism. The data, however, are complex, conflicting and largely unavailable. In this review, we attempt to summarize the existing data separately for the questions of whether patent foramen ovale is associated with cryptogenic stroke and whether it is a risk factor for a first ischemic stroke and for recurrent strokes. Treatment options will be discussed, and the different viewpoints from the two specialists mainly involved in the care of those complex patients (neurologists and cardiologists) will be provided.