Decoding the role of platelets in tumour metastasis: enigmatic accomplices and intricate targets for anticancer treatments.

The canonical role of platelets as central players in cardiovascular disease by way of their fundamental role in mediating thrombosis and haemostasis is well appreciated. However, there is now a large body of experimental evidence demonstrating that platelets are also pivotal in various physiological and pathophysiological processes other than maintaining haemostasis. Foremost amongst these is the emerging data highlighting the key role of platelets in driving cancer growth, metastasis and modulating the tumour microenvironment. As such, there is significant interest in targeting platelets therapeutically for the treatment of cancer. Therefore, the purpose of this review is to provide an overview of how platelets contribute to the cancer landscape and why platelets present as valuable targets for the development of novel cancer diagnosis tools and therapeutics.

Development of a risk score to predict peripherally inserted central catheter thrombosis in active cancer.

BACKGROUND: Peripherally inserted central catheter (PICC) thrombosis is common. AIMS: To explore the prevalence of symptomatic PICC thrombosis and pulmonary embolism (PE)/deep vein thrombosis (DVT) in cancer and non-cancer cohorts. In active cancer, we assessed the Khorana risk score (KRS) and Michigan risk score (MRS) for predicting PICC thrombosis and modifications to improve discriminative accuracy. METHODS: We reviewed consecutive cancer patients receiving chemotherapy through a PICC inserted April 2017 to July 2018. For each case, we identified a contemporaneous non-cancer control. RESULTS: Among 147 cancer patients, median age 64 years, PICC duration 70 days (range, 2-452), 7% developed PICC thrombosis (95% confidence interval (CI) 3.6-12.2) and 4% (95% CI 2-9) PE/DVT. Among 147 controls, median age 68 years, PICC duration 18.3 days (range, 0.5-210), 0.7% (95% CI 0-4) developed PICC thrombosis and 2% (95% CI 0.4-6) PE/DVT. In our cancer cohort, no KRS < 1 patients developed PICC thrombosis (95% CI 0-11) compared with 9% (95% CI 5-16) in KRS ≥ 1 (P = 0.12). PICC thrombosis occurred in 4.7% (95% CI 1.5-11.7) MRS ≤ 3 compared with 10.9% (95% CI 4.1-22.2) MRS > 3 (P = 0.32). The addition of thrombocytosis, a variable from KRS, to MRS (modified MRS (mMRS)) improved discriminative value for PICC thrombosis (c-statistic MRS 0.63 (95% CI 0.44-0.82), mMRS 0.72 (95% CI 0.58-0.85)). PICC thrombosis occurred in 1.4% (95% CI 0-8.3) mMRS ≤ 3 and 11.8% (95% CI 6.1-21.2) mMRS > 3 (P = 0.02). More patients were categorised as low risk using mMRS ≤ 3 (47%) than KRS < 1 (22%). CONCLUSION: Cancer patients had longer PICC durations and higher PICC thrombosis rates than those without (7% vs 0.7%). mMRS more accurately classified low PICC thrombosis risk than KRS <1(47% vs 22%). Prospective validation of mMRS is warranted.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021.

Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.

Is an Abnormal ECG Just the Tip of the ICE-berg? Examining the Utility of Electrocardiography in Detecting Methamphetamine-Induced Cardiac Pathology.

BACKGROUND: Methamphetamine use is escalating in Australia and New Zealand, with increasing emergency department attendance and mortality. Cardiac complications play a large role in methamphetamine-related mortality, and it would be informative to assess the frequency of abnormal electrocardiograms (ECGs) amongst methamphetamine users. OBJECTIVE: To determine the frequency and severity of ECG abnormalities amongst methamphetamine users compared to a control group. METHODS: We conducted a retrospective cohort analysis on 212 patients admitted to a tertiary hospital (106 patients with methamphetamine use, 106 age and gender-matched control patients). Electrocardiograms were analysed according to American College of Cardiology guidelines. RESULTS: Mean age was 33.4 years, with 73.6% male gender, with no significant differences between groups in smoking status, ECG indication, or coronary angiography rates. Methamphetamine users were more likely to have psychiatric admissions (22.6% vs 1.9%, p<0.0001). Overall, ECG abnormalities were significantly more common (71.7% vs 32.1%, p<0.0001) in methamphetamine users, particularly tachyarrhythmias (38.7% vs 26.4%, p<0.0001), right axis deviation (7.5% vs 0.0%, p=0.004), left ventricular hypertrophy (26.4% vs 4.7%, p<0.0001), P pulmonale pattern (7.5% vs 0.9%, p=0.017), inferior Q waves (10.4% vs 0.0%, p=0.001), lateral T wave inversion (3.8% vs 0.0%, p=0.043), and longer QTc interval (436.41±31.61ms vs 407.28±24.38ms, p<0.0001). Transthoracic echocardiogram (n=24) demonstrated left ventricular dysfunction (38%), thrombus (8%), valvular lesions (17%), infective endocarditis (17%), and pulmonary hypertension (13%). Electrocardiograms were only moderately sensitive at predicting abnormal TTE. CONCLUSION: Electrocardiographic abnormalities are more common in methamphetamine users than age and gender-matched controls. Due to the high frequency of abnormalities, ECGs should be performed in all methamphetamine users who present to hospital. Methamphetamine users with abnormal ECGs should undergo further cardiac investigations.

A platform for constructing, evaluating, and screening bioconjugates on the yeast surface.

The combination of protein display technologies and noncanonical amino acids (ncAAs) offers unprecedented opportunities for the high throughput discovery and characterization of molecules suitable for addressing fundamental and applied problems in biological systems. Here we demonstrate that ncAA-compatible yeast display facilitates evaluations of conjugation chemistry and stability that would be challenging or impossible to perform with existing mRNA, phage, or E. coli platforms. Our approach enables site-specific introduction of ncAAs into displayed proteins, robust modification at azide-containing residues, and quantitative evaluation of conjugates directly on the yeast surface. Moreover, screening allows for the selective enrichment of chemically modified constructs while maintaining a genotype-phenotype linkage with encoded azide functionalities. Thus, this platform is suitable for the high throughput characterization and screening of libraries of chemically modified polypeptides for therapeutic lead discovery and other biological applications.