Key Opinion Leaders' Interviews to Inform the Future of Benefit-Risk Planning in the Medical Total Product Life Cycle of Global Pharmaceutical and Medical Device Organizations.

BACKGROUND AND OBJECTIVES: Key opinion leader (KOL) interviews were conducted by the Benefit-Risk Assessment Planning (BRAP) Taskforce to seek expert opinion mainly from industry and regulatory bodies, about the current status and future direction of benefit-risk assessment (BRA) planning in the lifecycle of medical product development. The findings from these interviews are intended to help communication concerning planning for BRA between industry and regulators and shape future guidance. METHODS: Key opinion leader interviews consisted of 5 questions related to BRA planning, which were administered to volunteers (mainly clinicians and statisticians) within a pool of experienced pharmaceutical and medical device professionals representing academia, industry, regulatory agencies and a patient group. The interviewees' responses to the 5 questions were summarized. To analyze the qualitative data, a Coding System was developed to label themes arising from the interviews. The key findings from the interviews were summarized into a Master Template. A quantitative analysis based on descriptive statistics was also conducted. RESULTS: Of the 27 interviewees, there were 11 professionals from regulatory agencies, 11 from industry, 4 from academia and 1 from a patient advocacy group. Key findings based on the comments provided by 48% of the interviewees indicated the need of incorporating BRA into other (e.g., existing) processes with the importance of alignment between processes being stressed in the comments provided by 59% of the interviewees. Commencing BRA early in the product lifecycle was emphasized in comments provided by 44% of the interviewees. Among other needs identified were an appropriate contextualization of benefits and risks (based on comments provided by 41% of interviewees) through adoption of an integrated approach with structured support by regulatory agencies and a need for understanding the audience with better communication of benefit-risk (BR) among all stakeholders (based on comments provided by 44% of the interviewees). Almost all comments provided by interviewees (96%) highlighted the importance of utilizing patient experience/preference to guide new product development and BRA. Comments provided by 74% of the interviewees expressed the need to understand patient tolerance for risk and trade-offs, with a majority (78%) of interviewees highlighting how to gather information, and 59% stressing the need for the selection and development of appropriate methodologies as important considerations for enhancing the quality and relevance of the data collected from patients. CONCLUSIONS: Interviewees indicated that BRA should commence early in the medical product development and inform decision-making throughout the product lifecycle. Better planning and integration of BRA into existing processes within industry would be valuable. The importance of incorporating the patient voice into BRA and medical product development was emphasized. Other key findings from the KOL interviews included a need for improved communication of BR information, and establishment of methodologies for performing BRA and soliciting patient input.

A Survey to Assess the Current Status of Structured Benefit-Risk Assessment in the Global Drug and Medical Device Industry.

BACKGROUND: This industry survey was conducted to gain insight into the ways structured Benefit-Risk assessment (sBRA) of medical products is approached across drug or medical device developing companies, including frameworks and methods that are currently used and areas where future work is being planned. METHODS: A survey containing 28 questions covering five key areas of sBRA was set-up and shared with representatives from the participating companies. Each company was asked to complete a single survey response including inputs across the company's multidisciplinary key representatives involved in benefit-risk assessment. RESULTS: Of the 26 participating companies, 21 (81%) are conducting sBRA. Considering these 21 qualitative frameworks were used by almost every company (19, 90%), while only 12 (57%) have used a quantitative method. Many companies have sBRA training (17, 81%), document templates (16,76%), Standard Operating Procedures (SOPs)/checklists (13, 62%), and /or best practice manuals/examples (12,57%) available. Considering all 26 companies Software tools (15, 58%) and BR planning documents (11,42%) were identified as areas into which many companies intend to put effort. CONCLUSIONS: The industry survey confirmed a wide usage of sBRA by many companies involved in research and development. Nevertheless, sBRA is evolving and several future opportunities like the implementation of visualization tools were identified by the representatives of the pharmaceutical companies. Finally, challenges like the cross-functional comprehension of the added value of sBRA are still seen.

Prognostic biomarkers for malignant progression of oral epithelial dysplasia: an updated systematic review and meta-analysis.

Oral epithelial dysplasia (OED) is a premalignant condition that carries an appreciable risk of malignant progression. The current grading system for severity, as defined by the World Health Organization, is a valuable clinical tool, but further work is required to improve the accuracy of predicting OED malignant progression. This systematic review aimed to assess progress in prognostic biomarker discovery in OED over the past 16 years. The primary objective was to update the latest evidence on prognostic biomarkers that may predict malignant progression of OED, with strict inclusion criteria of studies with a longitudinal design and long-term follow-up data to enhance the robustness and translational clinical potential of the findings. Of 2829 studies identified through the searching of five databases, 20 met our inclusion criteria. These studies investigated a total of 32 biomarkers, 20 of which demonstrated significant potential to predict malignant progression of OED. Meta-analysis demonstrated the significant prognostic value of four biomarkers: podoplanin, EGFR expression, p16 methylation, and DNA aneuploidy. Our review has identified 20 reported biomarkers with prognostic potential to predict malignant progression in OED, but their translation into clinical practice remains elusive. Further research is required, and this should focus on validating the promising biomarkers identified in large cohort studies, with adherence to standardised reporting guidelines.

Human robotic surgery with intraoperative tissue identification using rapid evaporation ionisation mass spectrometry.

Instantaneous, continuous, and reliable information on the molecular biology of surgical target tissue could significantly contribute to the precision, safety, and speed of the intervention. In this work, we introduced a methodology for chemical tissue identification in robotic surgery using rapid evaporative ionisation mass spectrometry. We developed a surgical aerosol evacuation system that is compatible with a robotic platform enabling consistent intraoperative sample collection and assessed the feasibility of this platform during head and neck surgical cases, using two different surgical energy devices. Our data showed specific, characteristic lipid profiles associated with the tissue type including various ceramides, glycerophospholipids, and glycerolipids, as well as different ion formation mechanisms based on the energy device used. This platform allows continuous and accurate intraoperative mass spectrometry-based identification of ablated/resected tissue and in combination with robotic registration of images, time, and anatomical positions can improve the current robot-assisted surgical platforms and guide surgical strategy.

Nutritional management of chyle leak after head and neck surgery: a systematic review and proposed protocol for management.

PURPOSE: Chyle leaks are a rare complication of neck surgery causing local damage, impairing healing and compromising free flaps. High output leaks can result in electrolyte imbalances and malnutrition. Nutritional management such as restricting the absorption of triglycerides is believed to reduce chyle, allowing spontaneous resolution of a leak. Dietary preparations and management can aid in reducing chyle production. There are no clear guidelines to aid nutritional decision-making in this complex scenario. METHODS: A systematic review of the literature was carried out to identify studies evaluating nutritional management of chyle leaks in patients after neck dissections. RESULTS: Ten studies were identified evaluating the role of nutritional therapy in the management of patients with chyle leaks after neck dissections. The level of evidence was low. Several studies identified that low volume leaks (defined as < 1000 mls per day) often resolved by dietary management and other conservative measures. High volume leaks rarely resolved with conservative measures alone. Parenteral nutrition had an established role in this context. CONCLUSIONS: There is limited evidence to guide dietary restriction and introduction of oral diet in patients with chyle leak after major head and neck surgery. Based on available evidence, local guidelines for the nutritional management of patients identified with a chyle leak were produced and adopted by the Trust and the head and neck MDT. A national database for voluntary contribution of prospective data would help to generate better quality management protocols.

Diagnostic accuracy of intraoperative margin assessment techniques in surgery for head and neck squamous cell carcinoma: A meta-analysis.

BACKGROUND: Positive margins following head and neck squamous cell carcinoma (HNSCC) surgery lead to significant morbidity and mortality. Existing Intraoperative Margin Assessment (IMA) techniques are not widely used due to limitations in sampling technique, time constraints and resource requirements. We performed a meta-analysis of the diagnostic performance of existing IMA techniques in HNSCC, providing a benchmark against which emerging techniques may be judged. METHODS: The study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Studies were included if they reported diagnostic metrics of techniques used during HNSCC surgery, compared with permanent histopathology. Screening, manuscript review and data extraction was performed by multiple independent observers. Pooled sensitivity and specificity were estimated using the bivariate random effects model. RESULTS: From an initial 2344 references, 35 studies were included for meta-analysis. Sensitivity (Sens), specificity (Spec), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC) were calculated for each group (n, Sens, Spec, DOR, AUROC): frozen section = 13, 0.798, 0.991, 309.8, 0.976; tumour-targeted fluorescence (TTF) = 5, 0.957, 0.827, 66.4, 0.944; optical techniques = 10, 0.919, 0.855, 58.9, 0.925; touch imprint cytology = 3, 0.925, 0.988, 51.1, 0.919; topical staining = 4, 0.918, 0.759, 16.4, 0.833. CONCLUSIONS: Frozen section and TTF had the best diagnostic performance. Frozen section is limited by sampling error. TTF shows promise but involves administration of a systemic agent. Neither is currently in widespread clinical use. Emerging techniques must demonstrate competitive diagnostic accuracy whilst allowing rapid, reliable, cost-effective results.

Academic Training in Oral and Maxillofacial Surgery - when and how to enter the pathway.

Entering into surgical academia can seem a daunting prospect for an oral and maxillofacial surgery (OMFS) trainee. However, the streamlining of academic training by the NIHR to create the integrated academic training (IAT) pathway has simplified academic training and more clearly defined academic positions and entry points for trainees. In this article we review the current NIHR IAT pathway and the various grades and entry points available to OMF surgeons, both pre- and post-doctoral. We highlight the unique challenges facing OMF trainees and provide advice and insight from both junior and senior OMFS academics. Finally, we focus on the planning and application for a doctoral research fellowship - discussing funding streams available to OMF surgeons.

Modification of an extended total temporomandibular joint replacement (eTMJR) classification system.

The aims of this paper were to validate a modification of an extended total temporomandibular joint replacement (eTMJR) classification system and develop a classification schematic for ease of reference. High-volume TMJ surgeons were asked to score 20 separate eTMJR devices using the updated classification system, and inter-rater variability was calculated. Using the modified classification system developed, a Conger's kappa (κ) coefficient of 0.53 was returned, suggesting moderate to good levels of agreement. The final classification system was then developed in a series of standardised graphic illustrations as visual representations of the different subcategories of eTMJR devices.

An evaluation of the clinical utility of C-reactive protein and antibiotic use in patients undergoing major head and neck reconstructive surgery with outcome assessment.

PURPOSE: This ambispective observational study aims to evaluate the local utility of peri-operative CRP testing and prophylactic antibiotics in relation to post-operative complications in patients who have undergone major head and neck oncological reconstructive surgery. RESULTS: A total of 79 patients were identified for inclusion; CRP testing was undertaken within the first 3 days postoperatively in 78/79 cases. Results demonstrated no benefit of extended prophylactic antibiotic use in reducing post-operative infection. Forty-two post-operative complications arose. In the prospective arm, CRP did not influence the decision to commence antibiotic therapy for any of the surgical site infections. Age, diabetes, smoking, or high body mass index (BMI) did not appear to affect the incidence of postoperative infection (p > 0.05). There is no evidence that more than 24 h of antibiotic prophylaxis is indicated for patients undergoing head and neck reconstructive surgery. CONCLUSION: Everyone who is involved in peri-operative patient care should be educated regarding the appropriate use of CRP testing, with the implementation of protocols required to standardize CRP testing and prophylactic antibiotic prescription.

Clear Cell Odontogenic Carcinoma: First Report of Novel EWSR1-CREM Fusion Gene in Case of Long-Term Misdiagnosis.

Clear Cell odontogenic Carcinomas (CCOC) are rare, aggressive malignant odontogenic tumours which are often misdiagnosed as benign odontogenic tumours due to the non-specific histologic appearance, and benign early clinical presentation. However, due to their propensity to metastasize, the best outcomes are experienced with they are diagnosed early and treated aggressively. In this paper, we present a case of a CCOC misdiagnosed as a clear cell calcifying epithelial odontogenic tumour which was only found to be a CCOC after cervical node metastasis. The original diagnosis was questioned and confirmed to be a CCOC by identification of the chromosomal translocation EWSR1 on fluorescence in situ hybridization. This has recently been described in CCOC and a wide variety of other mesenchymal and epithelial neoplasms. Previous reports have demonstrated EWSR1-ATF1 and EWSR1-CREB1 fusions in CCOC. Next generation sequencing of this case demonstrated the EWSR1-CREM fusion gene which has not been previously reported for CCOC. CREM fusion proteins have only recently been found in several tumour types including the closely associated hyalinizing clear cell carcinoma of salivary glands. This is discussed in this paper, and the role of the discovery of the CREM fusion protein in CCOC adds to your understating of the role of CREM in oncogenesis, and the possible link between CCOCs and hyalinizing clear cell carcinomas.

Tumefactive fibroinflammatory lesion of the maxilla: Successful resection and microvascular reconstruction after failed medical therapy.

Tumefactive fibroinflammatory lesions (TFILs) of the head and neck are rare and benign but locally aggressive lesions. The etiology and pathogenesis of these lesions are unknown. Medical management is regarded the first line of treatment. Surgical management has been rarely reported for head and neck lesions. A 51-year-old female presented with a 6-month history of left facial swelling and pain that subsequently developed into progressive inframalar hollowing and asymmetry. Biopsies confirmed tumefactive fibroinflammatory lesion of the maxilla. Initial treatment with high-dose steroids led to temporary partial involution; however, symptoms progressed. Cyclophosphamide and then rituximab were commenced, with minimal response. Imaging showed progression toward the infratemporal fossa. The patient subsequently underwent a resection and microvascular free flap reconstruction This patient had a successful surgical outcome and resolution of serum inflammatory markers with no evidence of recurrence after 18-month follow-up. A multidisciplinary approach is crucial to ensure a pragmatic patient-specific management plan is developed. Surgical resection and reconstruction can be successful in these lesions and should be considered if medical therapy has failed.

Bony cystic lesion with associated submandibular lymphadenopathy on a background of breast carcinoma: an unexpected case of cervicofacial actinomycosis.

Actinomycosis is an uncommon, chronic suppurative granulomatous infection and needs to be considered as a differential diagnosis. A 56-year-old woman with a background of type 2 diabetes mellitus and breast carcinoma was referred to the Oral and Maxillofacial Surgery 2-week wait clinic, regarding a tender sublingual mass and firm erythematous swelling in the right submandibular and submental region. This was slowly progressive and had not responded to oral co-amoxiclav. An orthopantomogram showed a well-defined radiolucency and smaller radiolucent lesions throughout the edentulous right body of the mandible. A contrast-enhanced CT confirmed a right submandibular abscess communicating with cavitating lesions. The differentials included osteomyelitis, bony metastases, multiple myeloma or other cystic lesions. The patient underwent incision and drainage of the abscess, alongside biopsies, and intravenous co-amoxiclav was given. Microbiology cultures confirmed the presence of Actinomyces israelii and a diagnosis of cervicofacial actinomycosis with mandibular osteomyelitis. The patient was successfully treated with prolonged antibiotics.

The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

Factors affecting prognosis in locoregional recurrence of oral squamous cell carcinoma.

BACKGROUND: Recurrence of oral squamous cell carcinoma (rOSCC) after primary treatment is associated with poor survival outcomes. Salvage treatment with further surgery, radiotherapy and chemotherapy has high morbidity, making patient selection crucial. However, in the recurrence setting, reliable stratification data are scarce. Decision-making in this context is consequently complex. We investigated factors influencing overall survival after rOSCC. METHODS: Retrospective cohort study of patients with rOSCC (n = 83) at the Queen Elizabeth Hospital Birmingham, UK between 2006 and 2016. Associations with overall survival were analysed using univariate and multivariate analyses to identify important clinical prognostic indicators. RESULTS: Overall survival at 1 year was 32.5% and at 5 years was 18.1% after a median follow-up of 7.4 months. Multivariate analysis identified four independent predictors of overall survival following rOSCC: size of primary tumour (HR 2.077; 95% CI 1.034-4.172), extent of recurrent disease (HR 3.286; 95% CI 1.545-6.991), history of moderate alcohol consumption (HR 0.351; 95% CI 0.162-0.763), and close or positive margins at primary resection (HR 1.955; 95% CI 1.063-3.595). CONCLUSIONS: We identified four key factors that help prognostication and risk stratification of rOSCC. Given the high morbidity associated with salvage treatment, we recommend that the multidisciplinary team (MDT) and the patient weigh these factors carefully when considering further treatment. Further investigation of the biology underlying these oncophenotypes may contribute to better patient stratification.

Micro-computed tomography evaluation of microleakage of Class II composite restorations: An in vitro study.

OBJECTIVE: The aim of this study is to investigate the microleakage attained with three resin-based material used to restore deep Class II cavities. A null hypothesis was chosen: there is no difference in microleakage among the tested materials. MATERIALS AND METHODS: A total of 30 Class II cavities were prepared in freshly extracted molars with the proximal mesial and distal margins located, respectively, 1.5 mm apically and 1.5 mm coronally to the cementum-enamel junction. Restorations were completed using a three-step enamel-dentin adhesive system "Etch and Rinse," margins were relocated using a micro-hybrid, preheated, or flowable composite and restorations were then completed using a conventional composite. All samples were coated with nail varnish with the exception of an area along the margins and apex was sealed using epoxide cement and then thermocycled (30-s dwell time, 5°C/55°C, 1000 cycles). A 50% ammoniac AgNO3 solution was used as tracer according to Tay's protocol. The microleakage analysis was performed using a microtomography system Sky-scan 1072 (SKYSCAN, Kartuizersweg 3B 2550, Konitch, Belgium). RESULTS: The mean microleakage of all the tested materials showed greater leakage in the cementum margins; flowable composite exhibit greater leakage among the groups. Significant differences (P < 5%) within groups in both enamel and dentin margins were present. None of the tested materials eliminated marginal microleakage. Preheated composite showed significantly lesser microleakage. CONCLUSION: Tested materials showed statistical differences in microleakage; thus, the null hypothesis has been rejected. Within the limitations of the present experimental procedure, it can be concluded that flowable resin composite should be avoided at the dentin/cementum margin.

A severe deep neck odontogenic infection not prioritised by the emergency department triage system and National Early Warning Score.

A 62-year-old man with a background of type 2 diabetes mellitus presented to the emergency department (ED) with a 5-day history of dental pain, progressive right facial swelling, trismus, dysphagia and voice changes. The oropharynx could not be directly examined completely due to trismus. The patient had a National Early Warning Score of 0 and so was triaged into the 'minors' section of ED. Following assessment by the on-call oral and maxillofacial surgeon, an urgent contrast-enhanced CT demonstrated a large parapharyngeal collection, which required urgent anaesthetic and surgical intervention. The patient developed pulmonary complications postoperatively, but eventually made a full recovery.

Concentrations of signal transduction proteins exercise and insulin responses in rat extensor digitorum longus and soleus muscles.

Differences in the concentrations of signal transduction proteins often alter cellular function and phenotype, as is evident from numerous, heterozygous knockout mouse models for signal transduction proteins. Here, we measured signal transduction proteins involved in the adaptation to exercise and insulin signalling in fast rat extensor digitorum longus (EDL; 3% type I fibres) and the slow soleus muscles (84% type I fibres). The EDL and soleus were excised from four rats, the proteins extracted and subjected to Western blots for various signal transduction proteins. Our results show major differences in signal transduction protein concentrations between EDL and soleus. The EDL to soleus concentration ratios were: Calcineurin: 1.43 +/- 0.10; ERK1: 0.38 +/- 0.18; ERK2: 0.61 +/- 0.16; p38alpha, beta: 1.36 +/- 0.15; p38gamma/ERK6: 0.95 +/- 0.11; PKB/AKT: 1.44 +/- 0.08; p70S6k: 6.86 +/- 3.58; GSK3beta: 0.69 +/- 0.03; myostatin: 1.95 +/- 0.43; NF-kappaB: 0.32 +/- 0.10 (values >1 indicate higher expression in the EDL, and values < 1 indicate higher expression in the soleus). With the exception of p38gamma/ERK6, the concentration of each signal transduction protein was uniformly higher in one muscle than in the other in all four animals. These experiments show that signal transduction protein concentrations vary between fast and slow muscles, presumably reflecting a concentration difference on a fibre level. Proteins that promote particular functions such as growth or slow phenotype are not necessarily higher in muscles with that particular trait (e.g. higher in larger fibres or slow muscle). Interindividual differences in fibre composition might explain variable responses to training and insulin.

Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture.

Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.