Search

Reena P Thomas, Lawrence Recht, Seema NagpalDepartment of Neurological Sciences, Stanford University Hospital, Stanford, CA, USAAbstract: Glioblastoma (GB) is one of the most lethal forms of cancer, with an invasive growth pattern that requires the use of adjuvant therapies, including chemotherapy and radiation, to prolong survival. Temozolomide (TMZ) is an oral chemotherapy with a limited side effect profile that has become the standard of care in GB treatment. While TMZ has made an impact on survival, tumor recurrence and TMZ resistance remain major challenges. Molecular markers, such as O6-methylguanine-DNA methyltransferase methylation status, can be helpful in predicting tumor response to TMZ, and therefore guides clinical decision making. This review will discuss the epidemiology and possible genetic underpinnings of GB, how TMZ became the standard of care for GB patients, the pharmacology of TMZ, the practical aspects of using TMZ in clinic, and how molecular diagnostics – particularly the use of O6-methylguanine-DNA methyltransferase status – affect clinical management.Keywords: glioblastoma, temozolomide, PredictMDx™, MGMT

Background: Bacterial vaginosis (BV) is a common clinical manifestation of a perturbed vaginal ecology associated with adverse sexual and reproductive health outcomes if left untreated. The existing diagnostic modalities are either cumbersome or require skilled expertise, warranting alternate tests. Application of machine‐learning tools to heterogeneous and high‐dimensional multi‐omics datasets finds promising potential in data integration and may aid biomarker discovery. Objectives: The present study aimed to evaluate the potential of the microbiome and metabolome‐derived biomarkers in BV diagnosis. Interpretable machine‐learning algorithms were used to evaluate the utility of an integrated‐omics‐derived classification model. Methods: Vaginal samples obtained from reproductive‐age group women with (n = 40) and without BV (n = 40) were subjected to 16S rRNA amplicon sequencing and LC–MS‐based metabolomics. The vaginal microbiome and metabolome were characterized, and machine‐learning analysis was performed to build a classification model using biomarkers with the highest diagnostic accuracy. Results: Microbiome‐based diagnostic model exhibited a ROC‐AUC (10‐fold CV) of 0.84 ± 0.21 and accuracy of 0.79 ± 0.18, and important features were Aerococcus spp., Mycoplasma hominis, Sneathia spp., Lactobacillus spp., Prevotella spp., Gardnerella spp. and Fannyhessea vaginae. The metabolome‐derived model displayed superior performance with a ROC‐AUC of 0.97 ± 0.07 and an accuracy of 0.92 ± 0.08. Beta‐leucine, methylimidazole acetaldehyde, dimethylethanolamine, L‐arginine and beta cortol were among key predictive metabolites for BV. A predictive model combining both microbial and metabolite features exhibited a high ROC‐AUC of 0.97 ± 0.07 and accuracy of 0.94 ± 0.08 with diagnostic performance only slightly superior to the metabolite‐based model. Conclusion: Application of machine‐learning tools to multi‐omics datasets aid biomarker discovery with high predictive performance. Metabolome‐derived classification models were observed to have superior diagnostic performance in predicting BV than microbiome‐based biomarkers. [ABSTRACT FROM AUTHOR]

Summary: In this state‐of‐the‐art review, we discuss the presenting symptoms and management strategies for vascular emergencies. Although vascular emergencies are best treated at a vascular surgical centre, patients may present to any emergency department and may require both immediate management and safe transport to a vascular centre. We describe the surgical and anaesthetic considerations for management of aortic dissection, aortic rupture, carotid endarterectomy, acute limb ischaemia and mesenteric ischaemia. Important issues to consider in aortic dissection are extent of the dissection and surgical need for bypasses in addition to endovascular repair. From an anaesthetist's perspective, aortic dissection requires infrastructure for massive transfusion, smooth management should an endovascular procedure require conversion to an open procedure, haemodynamic manipulation during stent deployment and prevention of spinal cord ischaemia. Principles in management of aortic rupture, whether open or endovascular treatment is chosen, include immediate transfer to a vascular care centre; minimising haemodynamic changes to reduce aortic shear stress; permissive hypotension in the pre‐operative period; and initiation of massive transfusion protocol. Carotid endarterectomy for carotid stenosis is managed with general or regional techniques, and anaesthetists must be prepared to manage haemodynamic, neurological and airway issues peri‐operatively. Acute limb ischaemia is a result of embolism, thrombosis, dissection or trauma, and may be treated with open repair or embolectomy, under either general or local anaesthesia. Due to hypercoagulability, there may be higher numbers of acutely ischaemic limbs among patients with COVID‐19, which is important to consider in the current pandemic. Mesenteric ischaemia is a rare vascular emergency, but it is challenging to diagnose and associated with high morbidity and mortality. Several peri‐operative issues are common to all vascular emergencies: acute renal injury; management of transfusion; need for heparinisation and reversal; and challenging postoperative care. Finally, the important development of endovascular techniques for repair in many vascular emergencies has improved care, and the availability of transoesophageal echocardiography has improved monitoring as well as aids in surgical placement of endovascular grafts and for post‐procedural evaluation. [ABSTRACT FROM AUTHOR]