Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.     

Development and content validity of new patient-reported outcome questionnaires to assess the signs and symptoms and impact of atopic dermatitis: the Atopic Dermatitis Symptom Scale (ADerm-SS) and the Atopic Dermatitis Impact Scale (ADerm-IS)

Objectives: Atopic dermatitis (AD) is a chronic, relapsing skin condition, with signs and symptoms that impact patients’ lives and are best measured from the patient perspective. Therefore, there is a need for AD-specific questionnaires that are consistent with Food and Drug Administration guidance and best measurement practices, assessing sign and symptom severity and associated impacts, to support treatment efficacy in regulated trials. The objectives were to develop patient-reported outcome (PRO) questionnaires assessing sign and symptom severity, as well as impacts of moderate-to-severe adult AD.

Methods: A targeted literature review and meetings with clinical experts (dermatologists) were conducted to identify AD-related sign, symptom, and impact concepts. Results were harmonized and used to construct two draft PRO questionnaires: the Atopic Dermatitis Symptom Scale (ADerm-SS; 11 items) and the Atopic Dermatitis Impact Scale (ADerm-IS; 10 items). The content validity and questionnaire content were evaluated via qualitative concept elicitation/cognitive debriefing interviews with adult patients with moderate-to-severe AD.

Results: From the literature (n?=?13 articles), 13 sign and symptom and 43 impact concepts were identified, while 21 sign and symptom and 48 impacts were elicited from experts (n?=?3). During the patient interviews (n?=?15), 19 sign and symptom and 41 impact concepts were reported, the majority of which were evaluated by the ADerm-SS and ADerm-IS, thus substantiating the content of both questionnaires. Additionally, patients interpreted both questionnaires as intended by the developers.

Conclusions: The ADerm-SS and ADerm-IS can be regarded as content-valid PRO questionnaires for moderate-to-severe AD.     

Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized,Double-Blind,Placebo-Controlled Study

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial ({"type":"clinical-trial","attrs":{"text":"NCT02207946","term_id":"NCT02207946"}}NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p = 0.003) and Week 8 (p = 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p = 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.     

Social Phobia Among Depressed Individuals Entering Residential Rehabilitation Programmes: Prevalence and Correlates

Social phobia commonly co-occurs with substance use disorders and depression; however, the prevalence and correlates of social phobia among individuals with both of these disorders remain unknown. Interviews were conducted with 120 individuals entering residential rehabilitation for substance use treatment, who endorsed criteria for major depression and were recruited to a randomised controlled trial. Nearly three quarters (72.5%) of the sample met diagnostic criteria for social phobia. These individuals were more likely to report problematic drinking, more severe anxiety and depressive rumination, and lower distress tolerance, compared to individuals without social phobia. When examining the impact of applying diagnostic exclusion rules for social phobia among this cohort, results indicate that one third (32.2%) of those with social phobia specified their fear was related to a co-occurring mental health and/or substance use disorder. This group—who would not have met diagnostic criteria for social phobia if exclusion rules were strictly followed—experienced more severe depression, anxiety, depressive rumination, and repetitive negative thinking than those who did not make such attributions. The high prevalence and burden associated with social phobia among depressed substance users highlight the importance of screening for, assessing, and treating the disorder upon entry to treatment, irrespective of whether symptoms are related to other conditions.