Bamaquimast (F 10126)

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

The Genetic Landscape and Epidemiology of Phenylketonuria

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

Effectiveness of osteopathic interventions in chronic non-specific low back pain: A systematic review and meta-analysis

Background: Chronic low back pain (CLBP) is a frequent cause of disability and it represents a medical, social and economic burden globally. Therefore, we assessed effectiveness of osteopathic interventions in the management of NS-CLBP for pain and functional status.
Methods: A systematic review and meta-analysis were conducted. Findings were reported following the PRISMA statement. Six databases were searched for RCTs. Studies were independently assessed using a standardized form. Each article was assessed using the Cochrane risk of bias (RoB) tool. Effect size (ES) were calculated at post-treatment and at 12 weeks' follow up. We used GRADE to assess quality of evidence.
Results: 10 articles were included. Studies investigated osteopathic manipulative treatment (OMT, n = 6), myofascial release (MFR, n = 2), craniosacral treatment (CST, n = 1) and osteopathic visceral manipulation (OVM, n = 1). None of the study was completely judged at low RoB. Osteopathy revealed to be more effective than control interventions in pain reduction (ES: -0.59; 95% CI: -0.81, -0.36; P < 0.00,001) and in improving functional status (ES: -0.42; 95% 95% CI: -0.68, -0.15; P = 0.002). Moderate-quality evidence suggested that MFR is more effective than control treatments in pain reduction (ES: -0.69; 95% CI: -1.05, -0.33; P = 0.0002), even at follow-up (ES: -0.73; 95% CI: -1.09, -0.37; P < 0.0001). Low-quality evidence suggested superiority of OMT in pain reduction (ES: -0.57; 95% CI: -0.90, -0.25; P = 0.001) and in changing functional status (ES: -0.34; 95% CI: -0.65, -0.03; P = 0.001). Very low-quality evidence suggested that MFR is more effective than control interventions in functional improvements (ES: -0.73; 95% CI: -1.25, -0.21; P = 0.006).
Conclusion: Results strengthen evidence that osteopathy is effective in pain levels and functional status improvements in NS-CLBP patients. MFR reported better level of evidence for pain reduction if compared to other interventions. Further high-quality RCTs, comparing different osteopathic modalities, are recommended to produce better-quality evidence.

Molecular Imaging and Theragnostics of Thyroid Cancers

Molecular imaging plays an important role in the evaluation and management of different thyroid cancer histotypes. The existing risk stratification models can be refined, by incorporation of tumor-specific molecular markers that have theranostic power, to optimize patient-specific (individualized) treatment decisions. Molecular imaging with varying radioisotopes of iodine (i.e., ¹³¹I, ¹²³I, ¹²⁴I) is an indispensable component of dynamic and theragnostic risk stratification of differentiated carcinoma (DTC) while [¹⁸F]F-fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) helps in addressing disease aggressiveness, detects distant metastases, and risk-stratifies patients with radioiodine-refractory DTC, poorly differentiated and anaplastic thyroid cancers. For medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells, [¹⁸F]F-dihydroxyphenylalanine (6-[¹⁸F]FDOPA) PET/CT and/or [¹⁸F]FDG PET/CT can be used dependent on serum markers levels and kinetics. In addition to radioiodine therapy for DTC, some theragnostic approaches are promising for metastatic MTC as well. Moreover, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC while new theragnostic approaches showed promising preliminary results for advanced and aggressive forms of follicular-cell derived thyroid cancers (i.e., peptide receptor radiotherapy). In order to help clinicians put the role of molecular imaging into perspective, the appropriate role and emerging opportunities for molecular imaging and theragnostics in thyroid cancer are discussed in our present review.

Malignant Mesothelioma

Malignant mesothelioma (MM) is a rare and aggressive cancer, related to chronic inflammation and oxidative stress caused mainly by exposure to asbestos [...].