Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey.

AIM: To test the hypothesis that higher seizure burden in Dravet syndrome is associated with increased comorbidities and lower quality of life (QoL) in a large cohort of patients with Dravet syndrome and their caregivers in Europe. METHOD: An extensive survey of caregivers of patients with Dravet syndrome on experiences of diagnosis, seizure burden, management, social and financial impact, and health services use was administered online in 10 languages. RESULTS: The survey received 584 unique responses from caregivers of paediatric (83%) and adult (17%) patients with Dravet syndrome (aged <1-48y). Despite broadly following current treatment guidance, less than 10% of patients were seizure free in the previous 3 months. Nearly all (99.6%) patients aged 5 years or older experienced at least one or more motor, speech, learning, or behavioural impairment. High seizure frequency was related to more reports of emergency treatment, comorbidities, and a lower QoL (as measured by the standardized instrument EQ-5D-5L). If not diagnosed at the first instance, the majority (83%) of adults, but less than 20% of 6- to 11-year-olds were diagnosed after 4 or more years. INTERPRETATION: Patients with Dravet syndrome with the highest current seizure frequency suffer from more comorbidities and have a lower QoL. Therefore, more effective antiepileptic treatments are needed. WHAT THIS PAPER ADDS: The survey captured about 15% of all patients with Dravet syndrome in Europe. Less than 10% of patients had current seizure freedom. Patients with a high current seizure burden have more comorbidities and lower quality of life.

Bedside physician led US-guided supra-clavicular lymph node biopsy and ROSE (rapid on-site evaluation): SVC obstruction swift management in lung cancer.

Superior vena cava obstruction (SVCO) is an oncological emergency and can often be linked to an underlying lung malignancy. Due to the potential life-threatening risks associated with SVCO, it necessitates urgent diagnosis and management. In this report, we discuss 3 case studies where the use of ultrasound-guided supraclavicular lymph node biopsy was used to obtain a biopsy from patients with SVCO, followed by rapid on-site evaluation (ROSE). The benefits of this technique ensure a more rapid histological diagnosis, while also involving a less invasive procedure for the patient. The histological diagnosis is essential in improving patient outcomes when treating those with SVCO as the recommended treatments vary depending on the underlying type of lung malignancy. Having this information can help the clinician swiftly employ the optimal treatment pathway for the patient.

Rule of Prevention: a potential framework to evaluate preventive interventions for rare diseases.

Background: The benefits of preventive interventions lack comprehensive evaluation in standard health technology assessments (HTA), particularly for rare and transmissible diseases. Objective: To identify possible considerations for future HTA using analogies between the treatment and prevention of rare diseases. Study design: An Expert panel meeting assessed whether one HTA assessment framework can be applied to assess both rare disease treatments and preventive interventions. Experts also evaluated the range of value elements currently included in HTAs and their applicability to rare, transmissible, and/or preventable diseases. Results: A broad range of value should be considered when assessing rare, transmissible disease prevention. Although standard HTA can be applied to transmissible diseases, the risk of local outbreaks and the need for large-scale prevention programs suggest a modified assessment framework, capable of incorporating prevention-specific value elements in HTAs. A 'Rule of Prevention' framework was proposed to allow broader value considerations anchored to severity, equity, and prevention benefits in decision-making for preventive interventions for rare transmissible diseases. Conclusion: The proposed prevention framework introduces an explicit initial approach to consistently assess rare transmissible diseases, and to incorporate the broader value of preventive interventions compared with treatment.

Exploring the relationships between composite scores of disease severity, seizure-freedom and quality of life in Dravet syndrome.

BACKGROUND: In Dravet syndrome (DS), a rare epileptic and developmental encephalopathy, the effectiveness of a new treatment is predominantly measured in terms of seizure frequency. However, this may not fully capture the impact of a treatment on the broader aspects of the syndrome and patients' health-related quality of life (HRQoL). Using a previously published survey which collected data from DS patients and their carers on the broader manifestations of their syndrome, their HRQoL, and their experience of seizures, this study created composite measures of symptom severity to offer new perspectives on the multifaceted aspects of this rare condition. METHODS: Survey responses on the severity of physical and psychosocial symptoms were combined with independent assessments of disability and care need, to generate three composite symptom scores assessing the manifestations of DS (physical, psychosocial and care requirements). Variation in HRQoL was investigated in multiple regression analyses to assess the strength of association between each of these composite measures and three forms of seizure measures (seizure frequency, days with no seizures and longest interval without seizures), as experienced over a 4- and 12-week period. RESULTS: Composite scores were calculated for a cohort of 75 primarily paediatric patients who were enrolled in the study. Strong associations were found between each of the three composite symptom scores and each of the three seizure measures, with the regression coefficient on symptom score highly significant (p ≤ 0.001) in all nine comparisons. Separate regressions using predictors of HRQoL (Kiddy KINDL and Kid KINDL) as the dependent variable were inconclusive, identifying only behavioural/attention problems and status epilepticus as significant predictors of HRQoL. CONCLUSIONS: These results allow the development of a composite score that may be useful in developing a clinical understanding of the severity of DS for an individual patient and establishing their treatment goals. Where measurement of long-term sequalae of disease is not feasible, such as clinical trials, correlation of the composite score with experience of seizures and seizure-free periods may allow a better contextualisation of the results of short-term assessments. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00011894. Registered 16 March 2017, http://www.drks.de/ DRKS00011894.

Thoracic ultrasonic narration of Covid-19 pneumonia.

Covid-19 (SARS-CoV-2) is a new coronavirus. Since the declaration of a global pandemic, a lot has been learnt about its spread, disease pattern, diagnosis and management. The lungs remain the prime organs to incur serious insult and when lung complications embark, significant morbidity and mortality is observed. Predominantly, patchy and peripheral lung distribution in the Covid-19 pneumonia has been described in the radiology experience and literature. There are a range of imaging modes useable in diagnosis, prognosis, monitoring, and therapy of Covid-19. However, when it comes to the appropriateness and the potential benefits of imaging, resource utilization and infectious risk must be considered. The use of ultrasound during this pandemic has provided us with an alternate imaging modality that is easily performed at the bedside, with real time images available to the clinician. This case highlights the role played by the thoracic ultrasound in the diagnosis and progression of Covid-19 pneumonia.

Economic Evaluation of Single versus Combination Immuno-Oncology Therapies: Application of a Novel Modelling Approach in Metastatic Melanoma.

BACKGROUND: Existing economic model frameworks may not adequately capture the atypical treatment response patterns in immuno-oncology (I-O) compared with conventional therapies and thus may fail to represent the full clinical value associated with disease dynamics and improved survival. OBJECTIVE: A cost-effectiveness analysis (CEA) of the I-O Regimen (nivolumab/ipilimumab) versus ipilimumab alone in advanced melanoma was carried out by applying a 5-state partitioned survival model (PSM) as a case study, to explore the I-O treatment response and clinical outcomes. The findings were compared with those of a conventional 3-state PSM. MATERIALS AND METHODS: The case study extends the conventional 3-state PSM, by separating the pre-progression state into non-responders and responders, and the post-progression state into normal and I-O progression to account for delayed treatment effects preceding clinical response. Model states were populated using patient-level data (where possible), mapping from the best overall response (BOR), and survival analysis with flexible and traditional parametric methods. Survival functions were applied to progression-free survival (PFS) and overall survival (OS) endpoints across treatment arms using the 4-year follow-up data (data available at the time of the research; since then 5-year follow-up data have been published) from the CheckMate 067 trial. Information on BOR was used as a means of differentiating the I-O treatment response in addition to the outcomes of progression-free and progressed disease. A UK National Health Service and personal social services (NHS/PSS) perspective over a lifetime horizon was used with outcomes discounted at 3.5% annually. RESULTS: The 5-state PSM generated an increase in quality adjusted life years (QALYs) in both treatment arms and gave a more granular description of patients' health profiles compared with the traditional 3-state PSM. The incremental QALY increased by 13% (from 2.62 to 2.95 QALYs) and the incremental cost decreased by 12% (£29,125 to £25,678) with the 5-state model. In both models, the Regimen had an incremental cost-effectiveness ratio (ICER) relative to ipilimumab alone within the lower bound of the National Institute for Health and Care Excellence (NICE) reference range (£20,000 per QALY gained). CONCLUSION: A 5-state economic model, incorporating relevant I-O health states, can be more informative to gain insight into treatment response and progression differences that are not commonly captured in existing economic models. Clinical trial endpoints, including those relating to treatment response, which are not directly reported in ongoing I-O trials, can be mapped on to the proposed modelled health states (although assumptions are required to do so). Improvements in reporting treatment response in future I-O clinical trials could help to further validate and improve the proposed model framework.

Caregiver impact and health service use in high and low severity Dravet syndrome: A multinational cohort study.

PURPOSE: To estimate costs associated with the current management of Dravet syndrome (DS), explore psychosocial aspects of the disease in caregivers and siblings, and identify patient characteristics associated with higher costs in a large, predominantly European survey cohort of patients and their caregivers conducted in 2016. METHODS: Health and social care resource use, productivity and quality of life (QoL) data were summarised. Costs for European five (EU5) countries (France, Germany, Italy, Spain and UK) were calculated and patients with high and low current seizure burden compared. Direct healthcare costs and out-of-pocket costs were calculated using literature reported health service costs and participant reported costs, respectively. RESULTS: Direct annual costs of management of non-seizure-related symptoms ($7929) contributed to approximately 50% of all costs (including medication). Excluding medication, non-seizure-related costs dominated costs of care. Cost for patients with high seizure burden were higher for seizure-related healthcare use and physiotherapy, but lower for other therapies. Most (80%) caregivers reported an influence on their career choices and 28% of those in work had missed over three working days in the past four weeks for emergency or routine needs of their child. Caregivers had little free time, relied on family members for support and respite, and experienced emotional stress and uncertainty about their child's future healthcare needs. CONCLUSION: Families caring for a DS patient manage considerable social and financial impacts. Total direct costs of DS patients (excluding drugs) are driven by non-seizure-related healthcare use and high seizure burden is associated with higher healthcare costs.

Modelling the Survival Outcomes of Immuno-Oncology Drugs in Economic Evaluations: A Systematic Approach to Data Analysis and Extrapolation.

BACKGROUND: New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival. OBJECTIVES: Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy. METHODS: The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab. RESULTS: Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan-Meier (K-M) curve. RCS estimates fit the K-M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony. CONCLUSIONS: RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost-effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens.