Derivation and validation of a novel risk score to predict need for haemostatic intervention in acute upper gastrointestinal bleeding (London Haemostat Score).

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency, which takes up considerable healthcare resources. However, only approximately 20%-30% of bleeds require urgent haemostatic intervention. Current standard of care is for all patients admitted to hospital to undergo endoscopy within 24 hours for risk stratification, but this is difficult to achieve in practice, invasive and costly. AIM: To develop a novel non-endoscopic risk stratification tool for AUGIB to predict the need for haemostatic intervention by endoscopic, radiological or surgical treatments. We compared this with the Glasgow-Blatchford Score (GBS). DESIGN: Model development was carried out using a derivation (n=466) and prospectively collected validation cohort (n=404) of patients who were admitted with AUGIB to three large hospitals in London, UK (2015-2020). Univariable and multivariable logistic regression analysis was used to identify variables that were associated with increased or decreased chances of requiring haemostatic intervention. This model was converted into a risk scoring system, the London Haemostat Score (LHS). RESULTS: The LHS was more accurate at predicting need for haemostatic intervention than the GBS, in the derivation cohort (area under the receiver operating curve (AUROC) 0.82; 95% CI 0.78 to 0.86 vs 0.72; 95% CI 0.67 to 0.77; p<0.001) and validation cohort (AUROC 0.80; 95% CI 0.75 to 0.85 vs 0.72; 95% CI 0.67 to 0.78; p<0.001). At cut-off scores at which LHS and GBS identified patients who required haemostatic intervention with 98% sensitivity, the specificity of the LHS was 41% vs 18% with the GBS (p<0.001). This could translate to 32% of inpatient endoscopies for AUGIB being avoided at a cost of only a 0.5% false negative rate. CONCLUSIONS: The LHS is accurate at predicting the need for haemostatic intervention in AUGIB and could be used to identify a proportion of low-risk patients who can undergo delayed or outpatient endoscopy. Validation in other geographical settings is required before routine clinical use.

Folate receptor alpha in ovarian cancer tissue and patient serum is associated with disease burden and treatment outcomes.

BACKGROUND: Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. METHODS: We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. RESULTS: Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses. CONCLUSIONS: sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.

Antibody therapies for melanoma: new and emerging opportunities to activate immunity (Review).

The interface between malignant melanoma and patient immunity has long been recognised and efforts to treat this most lethal form of skin cancer by activating immune responses with cytokine, vaccine and also antibody immunotherapies have demonstrated promise in limited subsets of patients. In the present study, we discuss different antibody immunotherapy approaches evaluated in the context of melanoma, each designed to act on distinct targets and to employ different mechanisms to restrict tumour growth and spread. Monoclonal antibodies recognising melanoma-associated antigens such as CSPG4/MCSP and targeting elements of tumour-associated vasculature (VEGF) have constituted long-standing translational approaches aimed at reducing melanoma growth and metastasis. Recent insights into mechanisms of immune regulation and tumour-immune cell interactions have helped to identify checkpoint molecules on immune (CTLA4, PD-1) and tumour (PD-L1) cells as promising therapeutic targets. Checkpoint blockade with antibodies to activate immune responses and perhaps to counteract melanoma-associated immunomodulatory mechanisms led to the first clinical breakthrough in the form of an anti-CTLA4 monoclonal antibody. Novel modalities to target key mechanisms of immune suppression and to redirect potent effector cell subsets against tumours are expected to improve clinical outcomes and to provide previously unexplored avenues for therapeutic interventions.