Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

A Spotlight on the Role of Radiomics and Machine-Learning Applications in the Management of Intracranial Meningiomas: A New Perspective in Neuro-Oncology: A Review

Background: In recent decades, the application of machine learning technologies to medical imaging has opened up new perspectives in neuro-oncology, in the so-called radiomics field. Radiomics offer new insight into glioma, aiding in clinical decision-making and patients’ prognosis evaluation. Although meningiomas represent the most common primary CNS tumor and the majority of them are benign and slow-growing tumors, a minor part of them show a more aggressive behavior with an increased proliferation rate and a tendency to recur. Therefore, their treatment may represent a challenge. Methods: According to PRISMA guidelines, a systematic literature review was performed. We included selected articles (meta-analysis, review, retrospective study, and case–control study) concerning the application of radiomics method in the preoperative diagnostic and prognostic algorithm, and planning for intracranial meningiomas. We also analyzed the contribution of radiomics in differentiating meningiomas from other CNS tumors with similar radiological features. Results: In the first research stage, 273 papers were identified. After a careful screening according to inclusion/exclusion criteria, 39 articles were included in this systematic review. Conclusions: Several preoperative features have been identified to increase preoperative intracranial meningioma assessment for guiding decision-making processes. The development of valid and reliable non-invasive diagnostic and prognostic modalities could have a significant clinical impact on meningioma treatment

Surgical Back Risk Syndrome and Spinal Cord Stimulation: Better Safe Than Sorry

Background: Recurrent and chronic low back pain, caused by degenerative lumbar spondylosis, commonly affects elderly patients, even those with no previous low back surgery. These patients, like those affected by failed back surgery syndrome (FBSS), may become unresponsive to medical conservative treatment and their quality of life could be easily compromised. Moreover, general comorbidities, obesity, and other typical conditions of the elderly may make surgery under general anesthesia riskier than the natural history of the disease. These patients could be considered affected by surgical back risk syndrome (SBRS). Methods: In this article, we report our preliminary observational prospective study on the role of spinal cord stimulation (SCS) in 3 groups of patients: the FBSS group, the SBRS group, and the "other" group. Selection criteria, treatment modality, and outcomes for each patient group are described and discussed. Moreover, a potentially useful diagnostic and therapeutic flowchart on the management options for lumbar back diseases is discussed. Results: The FBSS group included 25 patients, the SBRS group included 10 patients, and the other group included 3 patients. In 22/25 patients with FBSS (88% of the total), the implantation of a definitive neurostimulator was successful. In almost all patients in both the SBRS and the other groups, the implantation of a definitive neurostimulator was successful. Conclusions: In our opinion, SCS could be considered as a valid alternative treatment not only in selected patients affected by FBSS but also in selected patients affected by SBRS, in whom back surgery under general anesthesia may be challenging and overcome the potential benefit of the surgery itself. SBRS could be considered a new disease entity to be managed through SCS

Diffuse idiopathic skeletal hyperostosis: A functional enemy of vertebral stability – Case series and surgical consideration of craniovertebral junction involvement

Context: Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier's syndrome may reduce vertebral mobility, thus affecting the stability of adjacent vertebral segments and promoting spinal stenosis, vertebral dislocation, and unstable fracture secondary to low-energy trauma. Aims: This study aimed to contribute with a case series of three patients affected by DISH undergone surgery with occipitocervical fixation for craniovertebral junction (CVJ) instability since the poor literature about CVJ instability and surgery in patients affected by DISH. Settings and Design: This was a multicentric case series. Subjects and Methods: Literature about CVJ instability and surgery in patients affected by DISH is poor. Thus, we present a case series of three patients affected by DISH, who underwent surgery with occipitocervical fixation with different clinical and radiological patterns. Results: CVJ represents one of the most mobile joints of the spine and is at greater risk for instability. Moreover, instability itself may act as primum movens for several degenerative conditions such as cervical spondylosis, ossification of the posterior longitudinal ligament, and cervical deformities. On the contrary, DISH itself may worsen CVJ instability because of subaxial spine stiffness. In case of DISH, the rigid unit formed by several ossified vertebral bodies acts as a long lever arm, increasing the forces applied to the hypermobile CVJ and reducing the dynamic buffer capability of ossified spine. On the other hand, vertebral instability increases the odds of fractures. In such cases, CVJ posterior instrumentation and fusion is an effective and feasible surgical technique, aimed to restore vertebral stability and to halt the progression of spinal stenosis. Conclusions: Due to the altered dynamics cervical spine along with the possible comorbidities, treatment indication and surgery for patients affected by DISH must be tailored case by case

Correlation between “Snake-Eyes” Sign and Role of Surgery with a Focus on Postoperative Outcome: A Systematic Review

(1) Background: The “snake-eyes” sign represents a unique finding characterized by bilateral hyperintense symmetric, circular, or ovoid foci on T2-weighted MRI sequences in the anterior horn cells of the spinal cord. There are conflicting opinions as some authors affirm that it does not affect the prognosis of cervical myelopathy while other papers emphasize the opposite, stating how the “snake-eyes” sign constitutes an irreversible lesion and a predictor of poor prognosis. This systematic review evaluates the correlation between the “snake-eyes” sign and the prognosis of cervical myelopathy after surgery including anterior and/or posterior approaches; (2) Methods: A systematic literature review was conducted following the PRISMA statement and a total of seven papers were included; (3) Results: A total of 419 patients were evaluated, with a mean age of 55.72 ± 14.38 years. After surgery, 26.01% of patients experienced a significant clinical improvement, while in 61.81%, there was no significant improvement. In particular, 144 of 196 patients (73.5%) treated through an anterior approach and 114 of 223 (51.1%) that underwent a posterior approach, did not present a significant improvement. Furthermore, in 12.17% of patients, the postoperative outcome was not reported, leading to a high risk of bias in the assessment of the prognostic significance of the “snake-eyes” appearance; (4) Conclusions: The “snake-eyes” sign is usually considered as an unfavorable predictive marker for myelopathic surgical patients, but the pathophysiology is still unclear, and the results have not yet reached unified levels of evidence

Burden of Surgical Treatment for the Management of Cervical Myelopathy in Mucopolysaccharidoses: A Systematic Review

Mucopolysaccharidoses (MPSs) are a rare group of heterogeneous genetic and metabolic disorders, caused by loss of functions of several enzymes that are involved in glycosaminoglycan catabolism. Their progressive accumulations in cells, tissues, and consequently, organs lead to several clinical manifestations, such as musculoskeletal involvement. Indeed, the most common manifestation in the central nervous system is represented by cervical spinal stenosis due to bony alterations or dural thickening. Cervical involvement can commonly cause myelopathy and instability exerting severe symptoms. A prompt diagnosis and treatment of the aforementioned conditions is mandatory to ensure a better quality of life in patients with such debilitating disorders. Nevertheless, a clear consensus about their management (i.e., surgical or not) is still lacking, leading to an inevitable delay. This review aims to investigate and discuss the main causes of myelopathy in patients with mucopolysaccharidoses, available therapeutic strategies, and the impact and role of surgery on the neurological outcome

The Impact of Single-Level ACDF on Neural Foramen and Disc Height of Surgical and Adjacent Cervical Segments: A Case-Series Radiological Analysis

Background: ACDF has become one of the established procedures for the surgical treatment of symptomatic cervical spondylosis, showing excellent clinical results and effective improvements in neural functions and neck pain relief. The main purpose of ACDF is neural decompression, and it is considered by some authors as an indirect result of the intervertebral distraction and cage insertion and the consequent restoration of the disc space and foramen height. Methods: Radiological data from 28 patients who underwent single-level ACDF were retrospectively collected and evaluated. For neural foramen evaluation, antero-posterior (A-P) and cranio-caudal (C-C) diameters were manually calculated; for intervertebral disc height the anterior, centrum and posterior measurement were calculated. All measurements were performed at surgical and adjacent (above and below) segments. NRS, NDI and also the mJOA and Nurick scale were collected for clinical examination and complete evaluation of patients’ postoperative outcome. Results: The intervertebral disc height in all its measurements, in addition to the height (C-C diameter) of the foramen (both right and left) increase at the surgical segment when comparing pre and postop results (p < 0.001, and p = 0.033 and p = 0.001). NRS and NDI radiculopathy scores showed improved results from pre- to post-op evaluation (p < 0.001), and a negative statistical correlation with the improved disc height at the surgical level. Conclusions: The restoration of posterior disc height through cage insertion appears to be effective in increasing foraminal height in patients with symptomatic preoperative cervical foraminal stenosis

Updated Systematic Review on the Role of Brain Invasion in Intracranial Meningiomas: What, When, Why?

Several recent studies are providing increasing insights into reliable markers to improve the diagnostic and prognostic assessment of meningioma patients. The evidence of brain invasion (BI) signs and its associated variables has been focused on, and currently, scientific research is investing in the study of key aspects, different methods, and approaches to recognize and evaluate BI. This paradigm shift may have significant repercussions for the diagnostic, prognostic, and therapeutic approach to higher-grade meningioma, as long as the evidence of BI may influence patients’ prognosis and inclusion in clinical trials and indirectly impact adjuvant therapy. We intended to review the current knowledge about the impact of BI in meningioma in the most updated literature and explore the most recent implications on both clinical practice and trials and future directions. According to the PRISMA guidelines, systematic research in the most updated platform was performed in order to provide a complete overview of characteristics, preoperative applications, and potential implications of BI in meningiomas. Nineteen articles were included in the present paper and analyzed according to specific research areas. The detection of brain invasion could represent a crucial factor in meningioma patients’ management, and research is flourishing and promising