Feasibility of recruitment to an oral dysplasia trial in the United Kingdom

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555

Conservative management of oesophageal soft food bolus impaction

Background: Impaction of a soft food bolus in the oesophagus causes dysphagia and regurgitation. If the bolus does not pass spontaneously, then the patient is at risk of aspiration, dehydration, perforation, and death. Definitive management is with endoscopic intervention, recommended within 24 hours. Prior to endoscopy, many patients undergo a period of observation, awaiting spontaneous disimpaction, or may undergo enteral or parenteral treatments to attempt to dislodge the bolus. There is little consensus as to which of these conservative strategies is safe and effective to be used in this initial period, before resorting to definitive endoscopic management for persistent impaction. Objectives: To evaluate the efficacy of non-endoscopic conservative treatments in the management of soft food boluses impacted within the oesophagus. Search methods: We searched the following databases, using relevant search terms: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL. The date of the search was 18 August 2019. We screened the reference lists of relevant studies and reviews on the topic to identify any additional studies. Selection criteria: We included randomised controlled trials of the management of acute oesophageal soft food bolus impaction, in adults and children, reporting the incidence of disimpaction (confirmed radiologically or clinically by return to oral diet) without the need for endoscopic intervention. We did not include studies focusing on sharp or solid object impaction. Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Main results: We identified 890 unique records through the electronic searches. We excluded 809 clearly irrelevant records and retrieved 81 records for further assessment. We subsequently included one randomised controlled trial that met the eligibility criteria, which was conducted in four Swedish centres and randomised 43 participants to receive either intravenous diazepam followed by glucagon, or intravenous placebos. The effect of the active substances compared with placebo on rates of disimpaction without intervention is uncertain, as the numbers from this single study were small, and the rates were similar (38% versus 32%; risk ratio 1.19, 95% confidence interval 0.51 to 2.75, P = 0.69). The certainty of the evidence using GRADE for this outcome is low. Data on adverse events were lacking. Authors' conclusions: There is currently inadequate data to recommend the use of any enteral or parenteral treatments in the management of acute oesophageal soft food bolus impaction. There is also inadequate data regarding potential adverse events from the use of these treatments, or from potential delays in definitive endoscopic management. Caution should be exercised when using any conservative management strategies in these patients.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published versio

Lack of predictive tools for conventional and targeted cancer therapy:barriers to biomarker development and clinical translation

Predictive tools, utilising biomarkers, aim to objectively assess the potential response to a particular clinical intervention in order to direct treatment. Conventional cancer therapy remains poorly served by predictive biomarkers, despite being the mainstay of treatment for most patients. In contrast, targeted therapy benefits from a clearly defined protein target for potential biomarker assessment. We discuss potential data sources of predictive biomarkers for conventional and targeted therapy, including patient clinical data and multi-omic biomarkers (genomic, transcriptomic and protein expression). Key examples, either clinically adopted or demonstrating promise for clinical translation, are highlighted. Following this, we provide an outline of potential barriers to predictive biomarker development; broadly discussing themes of approaches to translational research and study/trial design, and the impact of cellular and molecular tumor heterogeneity. Future avenues of research are also highlighted

Circulating tumour cell expression of immune-markers as prognostic and therapeutic biomarkers in head and neck squamous cell carcinoma:a systematic review and meta-analysis

Rates of loco-regional recurrence and distant metastasis remain high among head and neck squamous cell carcinoma (HNSCC) patients, despite advancing cancer treatment modalities and therapeutic agents. One area that has generated considerable interest is the immune landscape of the tumour, heralding a wave of immune checkpoint inhibitors with notable efficacy in recurrent/metastatic HNSCC patients. However, HNSCC remains poorly served by biomarkers that can direct treatment in a personalised fashion to target the tumour heterogeneity seen between patients. Detection and analysis of circulating tumour cells (CTCs) in HNSCC has provided a previously unseen view of the metastasis forming cells that are potentially contributing to poor clinical outcomes. In particular, identifying CTC expression of phenotypic and druggable protein markers has allowed CTC sub-populations to be defined that hold prognostic value or are potential therapeutic targets themselves. The aim of this systematic review was to examine the role of CTC immune-marker expression as prognostic/therapeutic biomarkers in HNSCC by evaluating progress to date and discussing areas for future research. Our results highlight how few studies have been able to demonstrate prognostic significance of immune-marker expression in CTCs. As expected, the immune checkpoint PD-L1 was the most widely investigated marker. However, no studies evaluated CTC target immune marker expression in immunotherapy cohorts. Despite these findings, the data presented demonstrate promise that CTCs may be a source of future biomarkers for immunotherapy and will provide valuable information regarding the potential immune evasion of these metastasis forming cells