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Context: Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). The definition of predictive factors of survival is incomplete., Objective: To identify pre- and posttreatment survival predictors in a real-life cohort of RR-DTC treated with lenvatinib., Design: Multicenter, retrospective, cohort study., Setting: 3 Italian thyroid cancer referral centers., Participants: 55 RR-DTC treated with lenvatinib., Main Outcome Measures: Progression-free survival (PFS) and overall survival (OS)., Results: Lenvatinib was the first-line kinase-inhibitor in 96.4% of subjects. Median follow-up was 48 months. Median PFS and OS were 26 [95% confidence interval (CI) 19.06-32.93] and 70 months (95% CI 36-111.99), respectively. Pretreatment setting: Eastern Cooperative Oncology Group (ECOG) performance status was independently related to PFS [P < .001; hazard ratio (HR) 18.82; 95% CI 3.65-97.08: score 0-1 as reference] and OS (P = .001; HR 6.20; 95% CI 2.11-18.20; score 0-1 as reference); radioactive iodine (RAI) avidity was independently related to PFS (P = .047; HR 3.74; 95% CI 1.01-13.76; avid disease as reference). Patients with good ECOG status (0-1) and RAI-avid disease obtained objective response in 100% of cases and achieved a median PFS of 45 months without any death upon a median follow-up of 81 months. Posttreatment setting: the best radiological response independently predicted PFS (P = .001; HR 4.6; 95% CI 1.89-11.18; partial/complete response as reference) and OS (P = .013; HR 2.94; 95% CI 1.25-6.89; partial/complete response as reference)., Conclusion: RR-DTC with good performance status and RAI-avid disease obtains the highest clinical benefit from lenvatinib. After treatment initiation, objective response was the only independent survival predictor., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: The utility of thyroglobulin (Tg) in the follow-up of differentiated thyroid cancer (DTC) patients has been well-documented. Although third-generation immunoassays have improved accuracy, limitations persist (interfering anti-Tg antibodies and measurement variability). Evolving treatment strategies require a reevaluation of Tg thresholds for optimal patient management., Objective: To assess the performance of serum Tg testing in two populations: patients receiving total thyroidectomy and radioiodine remnant ablation (RRA), or treated with thyroidectomy alone., Design: Prospective observational study. Setting. Centers contributing to the Italian Thyroid Cancer Observatory (ITCO) database., Patients: We included 540 patients with 5 years of follow-up and negative anti-Tg antibodies., Interventions: Serum Tg levels assessed at 1-year follow-up visit., Main Outcome Measure: Detection of structural disease within 5 years of follow-up., Results: After excluding 26 patients with structural disease detected at any time point, the median Tg did not differ between patients treated with or without radioiodine. Data-driven Tg thresholds were established based on the 97th percentile of Tg levels in disease-free individuals: 1.97 ng/mL for patients undergoing thyroidectomy alone (lower than proposed by the MSKCC protocol and ESMO Guidelines, yet demonstrating good predictive ability, with a negative predictive value (NPV) of 98%) and 0.84 ng/mL for patients receiving post-surgical RRA. High sensitivity and NPV supported the potential of these thresholds in excluding structural disease., Conclusions: This real-world study provides evidence for the continued reliability of 1-year serum Tg levels. The data-driven Tg thresholds proposed offer valuable insights for clinical decision-making in patients undergoing total thyroidectomy with or without RRA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes., (© 2024 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Liquid biopsy is a minimally invasive diagnostic tool for identification of tumor-related mutations in circulating cell-free DNA (cfDNA). The aim of this study was to investigate feasibility, sensitivity, and specificity of non-invasive prenatal test (NIPT) for identification of chromosomal abnormalities in cfDNA from a total of 77 consecutive patients with non-Hodgkin B-cell lymphomas, Hodgkin lymphoma (HL), or plasma cell dyscrasia. In this case series, half of patients had at least one alteration, more frequently in chromosome 6 (23.1%), chromosome 9 (20.5%), and chromosomes 3 and 18 (16.7%), with losses of chromosome 6 and gains of chromosome 7 negatively impacting on overall survival (OS), with a 5-year OS of 26.9% and a median OS of 14.6 months, respectively (P = 0.0009 and P = 0.0004). Moreover, B-cell lymphomas had the highest NIPT positivity, especially those with aggressive lymphomas, while patients with plasma cell dyscrasia with extramedullary disease had a higher NIPT positivity compared to conventional cytogenetics analysis and a worse outcome. Therefore, we proposed a NIPT-based liquid biopsy a complementary minimally invasive tool for chromosomal abnormality detection in hematological malignancies. However, prospective studies on larger cohorts are needed to validate clinical utility of NIPT-based liquid biopsy in routinely clinical practice., (© 2024. The Author(s).)

Purpose/methods: The determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated., Results: The samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients., Conclusion: This study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine., (© 2023. The Author(s).)

SARS-CoV-2 and its variants cause CoronaVIrus Disease 19 (COVID-19), a pandemic disease. Hematological malignancies increase susceptibility to severe COVID-19 due to immunosuppression. Anti-SARS-CoV-2 neutralizing antibodies protect against severe COVID-19. This retrospective real-life study aimed to evaluate seropositivity and neutralizing antibody rates against SARS-CoV-2 and its Omicron BA.1 variant in hematological patients. A total of 106 patients with different hematologic malignancies, who have mostly received three or more vaccine doses (73%), were included in this study. Serum was collected between May and June 2022. The primary endpoint was anti-SARS-CoV-2 antibody response against ancestral (wild type; wt) and Omicron BA.1 virus, defined as a neutralizing antibody titer ≥ 1:10. Adequate neutralizing antibody response was observed in 75 (71%) and 87 (82%) of patients for wt and Omicron BA.1 variants, respectively.However, patients with B-cell lymphoproliferative disorders and/or those treated with anti-CD20 monoclonal antibodies in the prior 12 months showed a lower seropositivity rate compared to other patients against both Omicron BA.1 variant (73% vs 91%; P = 0.02) and wt virus (64% vs 78%; P = 0.16). Our real-life experience confirmed that full vaccination against SARS-CoV-2 induces adequate neutralizing antibody protection for both the wt virus and Omicron BA.1 variants, even in hematological frail patients. However, protective measures should be maintained in hematological patients, especially those with B-cell lymphoproliferative diseases treated with anti-CD20 monoclonal antibodies, because these subjects could have a reduced neutralizing antibody production., (© 2023. The Author(s).)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor ( p  < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients ( p  = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p  = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p  = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p  = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Context: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features., Objective: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors., Methods: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction., Results: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis., Conclusion: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bisphenol A (BPA) is a widespread thyroid disruptor, but evidence about an association with thyroid cancer is weak. Excess body weight is a risk factor for thyroid cancer and affects activity of endocrine disruptors. Aim of the study was to investigate the association between BPA exposure and thyroid cancer, verifying the effect modification related to body weight. We performed a multicentre, cross-sectional study including consecutive patients referring for nodular goiter. The quantitative determination of BPA in serum samples was performed through high performance liquid chromatography system, coupled in tandem with ultraviolet and fluorescence detection. Ninety-six patients were included: 55 benign nodules, 41 thyroid cancers, 28 normal weight, and 68 overweight/obese. BPA was detected in 79 subjects. In the overall study population and in the group with BMI<25 kg/m 2 BPA exposure was not significantly correlated to thyroid cancer (p = 0.08 and 0.759, respectively). In the group with BMI≥25 kg/m 2 , BPA-exposed subjects showed significantly higher risk of malignancy (OR: 5.3, p = 0.028). At multivariate analysis, such association was independent of smoking, alcohol consumption, occupational exposure, and phthalates exposure (p = 0.021 and 0.016, respectively), but was lost after adjustment for the presence of metabolic syndrome (p = 0.089). In overweight/obese subjects, BPA exposure was significantly associated with higher thyroid stimulating hormone levels. Our study suggests that BPA exposure is a risk factor for thyroid cancer in overweight/obese subjects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Access to assistive technologies (ATs) is a human right for people with disabilities, but there are a range of barriers, including lack of adequate information. This review aimed to explore the implications of information asymmetry on the delivery of AT and to investigate if there are effective and equitable ways of providing AT brokerage services to people needing AT., Design: Scoping review., Data Sources: EBSCO Medline, EBSCO Cinahl, Academic Search Ultimate, Business Source Ultimate, Proquest Central, Scopus, Web of Science, PsychINFO, EconLit and JSTOR were searched through 18 July 2021., Eligibility Criteria: Intervention and observational studies and articles directly related to information asymmetry and brokerage in the context of AT were included. In addition, a scan of web-based resources and services was undertaken., Data Extraction and Synthesis: Four authors independently screened the articles for inclusion and performed a narrative synthesis., Results: Thirty-three articles were identified. The narrative synthesis showed that: (1) AT users want access to impartial information sources; (2) users want to be involved in AT selection; (3) users benefit from access to demonstration sites; (4) users want access to training and ongoing support in their use of AT; and (5) users want access to information on new and emerging technologies. Access to information and user engagement, we produced better outcomes and satisfaction. Web-based repositories are valuable for user research and peer feedback, while demonstration sites address the need for expert advice, trial use of equipment, training and support in equipment use and maintenance., Conclusions: Access to impartial information brokerage is critical to optimise AT selection. The implications of information asymmetry include lower user satisfaction, equipment underutilisation or abandonment. Aspects such as access to demonstration sites and web-based resources were also important., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Harmonization of flow cytometry protocols from instrument settings to antibody panel and reagents is highly encouraged for inter-laboratory data comparison in both research and clinical settings, especially for minimal residual disease monitoring evaluation in hematological diseases across centers. Here, we described inter-intra instrument comparison of two standardized 10-color staining dried tubes for B- and T-cell lymphoproliferative disorder diagnosis and monitoring on two different flow cytometers, a Beckman Coulter NaviosEx and a Beckman Coulter DxFlex. A total of 47 consecutive patients were enrolled, and 39 of them were evaluable for further studies. We show highly comparable results between the two cytometers for cell frequency and fluorescence intensity signals for both standardized 10-color staining dried tubes. For this latter, fluorescence of each antibody and subject was normalized on the mean value obtained from the entire study cohort thus reducing the effects of biological variability and allowing comparison between instruments with different detector sensitivity. In summary, dried tubes were confirmed as an optimal standardized diagnostic tool, especially when associated with EuroFlow standardized procedures by minimizing technical and biological variability. However, data analysis is still operator-dependent, and more efforts are needed to develop automated or semi-automated software for flow cytometry data analysis for diagnostic purposes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

BACKGROUND: Patients receiving specialty medications have conditions that are often complex, high cost, and high need. Prompt treatment initiation is essential for the appropriate management of many conditions treated by specialty products. Improving the turnaround time (TAT) of specialty pharmacy prescriptions helps ensure patients receive the medication they need in the necessary time frame to optimize health outcomes. Despite a clinical justification for improved TAT, there is a gap in the literature describing what factors impact these times. OBJECTIVE: To determine factors that may influence specialty pharmacy TATs and to identify good practices that specialty pharmacies use to improve TAT. METHODS: This qualitative study used 4 focus groups with specialty pharmacy subject matter experts. Each focus group represented different specialty pharmacy types, including health system, payer-associated, retail chain, and independent specialty pharmacies. Attitudes, beliefs, and experiences regarding specialty pharmacy TAT were captured. Open-ended questions and prompts eliciting impediments, facilitators, and good practices associated with specialty pharmacy TAT were asked of participants. Data were analyzed thematically. RESULTS: Fifteen individuals participated across 4 focus groups: payer-associated (n = 4), independent (n = 3), health system (n = 5), and retail chain (n = 3) specialty pharmacies. Average TATs varied across specialty pharmacy type and by prescription type (clean vs intervention). Several interconnected themes were identified, including barriers with health benefits formulary management, prior authorization delays, differences in requirements between managed care organizations, and miscommunication with physicians, among others. Five subthemes were identified during the discussion of factors influencing TAT, including patient characteristics, pharmacy characteristics, provider characteristics, clinical situations, and health benefit design and formulary considerations. Pharmacy workflow improvements through technology integration are thought to improve TAT. In addition, participants noted facilitators including specialization among pharmacists and technicians in certain diseases, particularly hepatitis C and cancer. Some good practices included using patient financial advocates, technology integration, and a structured patient onboarding process, which were found to minimize delays caused by prior authorization, communication, and formularies. CONCLUSIONS: A multitude of factors impacting specialty pharmacy prescription TAT were identified. Multidisciplinary coordination between pharmacies, physicians, and managed care organizations is essential to ensure patients receive medications in the necessary time frame to optimize health outcomes. DISCLOSURES: This study was conducted with support from Pfizer.

Background: Current chronic lymphocytic leukemia (CLL) International Prognostic Index (IPI) stratifies patients based on clinical, molecular, and biochemical features; however, B-cell markers also influence CLL outcomes. Here, prognostic roles of CD11c, CD38, and CD49d were first evaluated, and then an immunophenotypic score was combined with CLL-IPI for risk stratification of CLL patients., Methods: A total of 171 CLL subjects were included, and surface marker expression was assessed by flow cytometry. Levels ≥30% were chosen as cut-off of positivity to a marker; then values of 1 (for CD11c and CD38) or 3 (for CD49d) were assigned and scores determined for each patient's clone immunophenotype., Results: CD49d positivity was significantly associated with simultaneous expression of CD11c and/or CD38, unmutated IGHV status, and higher β2-microglobulin levels compared to those with CD49d negativity. Moreover, CD49d + patients experienced a shorter progression-free survival and time to treatment. When the immunophenotypic score was combined with CLL-IPI, patients with high-risk immunophenotype had a significantly lower time-to-treatment regardless CLL-IPI., Conclusions: Our results suggested clinical utility of an integrated prognostic score for better risk stratification of CLL patients. These results require further validation in prospective larger studies., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Introduction: Lymph node (LN) fine needle aspiration cytology (FNAC) is a safe, quick, inexpensive, reliable, and minimally invasive technique for the diagnosis of lymphadenopathies. Recently, an international committee of experts proposed guidelines for the performance, classification, and reporting of LN-FNAC: the Sydney System. We set out to analyse the diagnostic performance of the Sydney System in a retrospective study., Methods: We retrieved 1458 LN-FNACs, reformulated the diagnoses according to the Sydney System, and compared them to the histological control where available (n = 551, 37.8%)., Results: The risk of malignancy for each of the five categories was 66.7% for inadequate/insufficient, 9.38% for benign (overall: 0.84%), 28.6% for atypical, 100% for suspicious and 99.8% for malignant. LN-FNAC showed a sensitivity of 97.94%, a specificity of 96.92%, a positive predictive value of 99.58%, and a negative predictive value of 86.30%., Conclusions: These data support the usage of LN-FNAC as an agile first-level technique in the diagnosis of lymphadenopathies. The Sydney System supports and enhances this role of LN-FNAC, and its adoption is encouraged. In negative cases, coupled with ancillary techniques, LN-FNAC can reassure the clinician regarding the benignity of a lymphadenopathy and indicate the need for clinical follow-up, which will catch possible false negatives. In positive cases, LN-FNAC can provide sufficient information, including predictive biomarkers, to initiate management and obviate the need for subsequent, more invasive procedures. Given its speed, minimal invasiveness, and low cost, LN-FNAC can be performed in most cases, even when more invasive techniques are not feasible., (© 2021 John Wiley & Sons Ltd.)

Objective: To determine the financial and non-financial costs of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan., Method: The population costs of ADHD in Australia were estimated for the financial year 2018 to 2019 using a prevalence approach to cost estimation across all ages. Financial (healthcare, productivity, education and justice systems, and deadweight losses) and non-financial costs were measured (Disability Adjusted Life Years (DALYs))., Results: The total social and economic cost of ADHD in 2018 to 2019 were US$12.76 billion (range US$8.40 billion to US$17.44 billion, with per person costs of US$15,664 per year). Productivity costs made up 81% of the total financial costs, followed by deadweight losses (11%), and health system costs (4%). Loss in terms of wellbeing was significant (US$5.31 billion)., Conclusion: There is a need to raise public awareness of the considerable socioeconomic impact and burden of ADHD in order to drive investment and policy decisions that improve identification and treatment of ADHD.

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p  = 0.65), tumor size >2 cm (OR 1.45, p  = 0.34), aggressive PTC histology (OR 0.55, p  = 0.15), and age at diagnosis (OR 0.90, p  = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p  = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients ( p  = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Study Objectives: To estimate economic cost of common sleep disorders in Australia for 2019-2020., Methods: Costs were estimated for obstructive sleep apnea (OSA), insomnia, and restless legs syndrome (RLS) using prevalence, financial, and nonfinancial data from national databases. These included: (1) financial costs associated with health care, informal care, productivity losses, non-medical accident costs, deadweight loss from taxation/welfare inefficiencies; and (2) nonfinancial costs associated with loss of well-being. They were expressed in U.S. dollars ($)., Results: Estimated overall cost of sleep disorders in Australia in 2019-2020 (population: 25.5 million) was $35.4 billion (OSA $13.1 billion; insomnia $13.3 billion, RLS $9.0 billion). Of this, the financial cost component was $10.0 billion, comprised of: health system costs $0.7 billion; productivity losses $7.7 billion; informal care $0.2 billion; other, mainly non-medical accident costs, $0.4 billion; and deadweight losses $1.0 billion. For moderate to severe OSA syndrome, insomnia unrelated to other conditions and RLS, financial costs represented $16,717, $21,982, and $16,624 per adult with the condition for the year, respectively. The nonfinancial cost was $25.4 billion., Conclusions: The economic costs associated with sleep disorders are substantial. The financial component of $10.0 billion is equivalent to 0.73% of Australian gross domestic product. The nonfinancial cost of $25.4 billion represents 3.2% of total Australian burden of disease for the year. Health system costs of these disorders are low relative to those associated with their consequences, suggesting greater expenditure on detection, treatment and prevention is warranted., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018., Methods: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups., Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time., Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Non-alcoholic steatohepatitis (NASH) - a progressive subset of non-alcoholic fatty liver disease (NAFLD) - is a chronic liver disease that can progress to advanced fibrosis, cirrhosis, and end-stage liver disease (ESLD) if left untreated. Early-stage NASH is usually asymptomatic, meaning a large proportion of the prevalent population are undiagnosed. Receiving a NASH diagnosis increases the probability that a patient will receive interventions for the purpose of managing their condition. The purpose of this study was to estimate the disease burden and economic impact of diagnosed NASH in the United Kingdom (UK) adult population in 2018., Methods: The socioeconomic burden of diagnosed NASH from a societal perspective was estimated using cost-of-illness methodology applying a prevalence approach. This involved estimating the number of adults with diagnosed NASH in the UK in a base period (2018) and the economic and wellbeing costs attributable to diagnosed NASH in that period. The analysis was based on a targeted review of the scientific literature, existing databases and consultation with clinical experts, health economists and patient groups., Results: Of the prevalent NASH population in the UK in 2018, an estimated 79.8% were not diagnosed. In particular, of the prevalent population in disease stages F0 to F2, only 2.0% (F0), 2.0% (F1) and 16.5% (F2), respectively, were diagnosed. Total economic costs of diagnosed NASH in the UK ranged from £2.3 billion (lower prevalence scenario, base probability of diagnosis scenario) to £4.2 billion (higher prevalence scenario, base probability of diagnosis scenario). In 2018, people with NASH in the UK were estimated to experience 94,094 to 174,564 disability-adjusted life years (DALYs) overall. Total wellbeing costs associated with NASH in 2018 were estimated to range between £5.6 to £10.5 billion., Conclusion: The prevention and appropriate management of adult NASH patients could result in reduced economic costs and improvements in wellbeing.

The kinase-inhibitors (KIs) sorafenib and lenvatinib demonstrated efficacy in iodine-refractory DTC upon phase III studies. However, evidence allowing a punctual balance of benefits and risks is poor. Furthermore, the lack of a direct comparison hampers to establish the proper sequence of administration. However, some insights may provided: a) indirect comparison between phase III trials showed milder toxicity for sorafenib, which should be preferred in case of cardiovascular comorbidities; b) prospective evidence of efficacy in KIs pre-treated patients is available only for lenvatinib, which should be used as second-line. Promising activity was found for the majority of other tested KIs, but no placebo-controlled trials are available. Emerging, but still early, frontiers include the restoration of iodine-sensitivity and the selective activity on pathogenic mutations. In conclusion, the use of KIs in iodine-refractory DTC is far from a structured therapeutic algorithm., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To estimate one-year costs of eating disorders in the United States (U.S.) from a societal perspective, including the costs to the U.S. health system, individual and family productivity costs, lost wellbeing, and other societal economic costs, by setting and payer. Findings will inform needed policy action to mitigate the impact of eating disorders in the U.S., Method: Costs of eating disorders were estimated using a bottom-up cost-of-illness methodology, based on the estimated one-year prevalence of eating disorders. Intangible costs of reduced wellbeing were also estimated using disability-adjusted life years., Results: Total economic costs associated with eating disorders were estimated to be $64.7 billion (95% CI: $63.5-$66.0 billion) in fiscal year 2018-2019, equivalent to $11,808 per affected person (95% CI: $11,754-$11,863 per affected person). Otherwise Specified Feeding or Eating Disorder accounted for 35% of total economic costs, followed by Binge Eating Disorder (30%), Bulimia Nervosa (18%) and Anorexia Nervosa (17%). The substantial reduction in wellbeing associated with eating disorders was further valued at $326.5 billion (95% CI: $316.8-$336.2 billion)., Discussion: The impact of eating disorders in the U.S. is substantial when considering both economic costs and reduced wellbeing (nearly $400 billion in fiscal year 2018-2019). Study findings underscore the urgency of identifying effective policy actions to reduce the impact of eating disorders, such as through primary prevention and screening to identify people with emerging or early eating disorders in primary care, schools, and workplaces and ensuring access to early evidence-based treatment., (© 2021 Wiley Periodicals LLC.)

Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients' age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4 + T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation., Competing Interests: Conflict of interest: The authors declare no conflicts of interest., (© 2021 Luca Pezzullo et al., published by De Gruyter.)

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and mortality after organ or hematopoietic stem cell transplantation (HSCT). Letermovir (LTV) is a novel antiviral agent approved for CMV prophylaxis after allogeneic transplantation. In this single-center real-world study, we evidenced the efficacy and safety of LTV for CMV prophylaxis in allogeneic HSCT recipients. A total of 133 consecutive patients who underwent autologous or allogeneic HSCT were included in the study, and a subgroup of 13 allogeneic HSCT recipients received CMV prophylaxis with LTV 240 mg/daily from day +7 to +100 (allo-LTV cohort). All patients in the allo-LTV cohort were at moderate or high risk of reactivation based on donor/recipient serology status, and 62% also received haploidentical HSCT and cyclophosphamide which further increased the CMV reactivation risk. CMV infection rate was also compared to that observed in allogeneic HSCT patients without CMV prophylaxis and autologous recipients who have the lowest reported CMV infection incidence and were used as a control cohort. In our experience, patients receiving LTV showed a significant decline in CMV reactivation incidence to similar rates described in autologous HSCT recipients (7.7% of allogeneic LTV-treated vs 68% of allogeneic recipients without prophylaxis vs 15% of autologous patients; p> 0.0001). The only patient in the allo-LTV cohort with CMV reactivation was a 25-year-old female with a diagnosis of very high-risk acute lymphoblastic leukemia who received a haploidentical HSCT after ex vivo T cell depletion. CMV reactivation occurred beyond LTV course, at +187 days from transplantation. In addition, we confirmed efficacy and safety of valganciclovir 450 mg/daily as pre-emptive therapy or for treatment of CMV disease in allogeneic and autologous HSCT recipients who experienced CMV reactivation even after LTV prophylaxis. However, further clinical trials in larger populations and longer follow-up are required to confirm our preliminary results.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis., Methods: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up., Results: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories., Conclusions: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class., (© 2019 American Cancer Society.)

Study Objectives: To determine cost-effectiveness of continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) in Australia for 2017-2018 to facilitate public health decision-making., Methods: Analysis was undertaken of direct per-person costs of CPAP therapy (according to 5-year care pathways), health system and other costs of OSA and its comorbidities averted by CPAP treatment (5-year adherence rate 56.7%) and incremental benefit of therapy (in terms of disability-adjusted life years [DALYs] averted) to determine cost-effectiveness of CPAP. This was expressed as the incremental cost-effectiveness ratio (= dollars per DALY averted). Direct costs of CPAP were estimated from government reimbursements for services and advertised equipment costs. Costs averted were calculated from both the health care system perspective (health system costs only) and societal perspective (health system plus other financial costs including informal care, productivity losses, nonmedical accident costs, deadweight taxation and welfare losses). These estimates of costs (expressed in US dollars) and DALYs averted were based on our recent analyses of costs of untreated OSA., Results: From the health care system perspective, estimated cost of CPAP therapy to treat OSA was $12 495 per DALY averted while from a societal perspective the effect was dominant (-$10 688 per DALY averted) meaning it costs more not to treat the problem than to treat it., Conclusions: These estimates suggest substantial community investment in measures to more systematically identify and treat OSA is justified. Apart from potential health and well-being benefits, it is financially prudent to do so., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objective: Fine needle cytology (FNC) is the first-line diagnostic method to determine the benign or malignant nature of thyroid nodules. The gray zone of cytological classifications remains, however, a crucial and challenging area for cytopathologists., Design, Patients and Measurements: In the present study, 141 thyroid cytological samples, with ultrasonographic suspicious features, have been prospectively analysed. Molecular analyses were performed by an innovative technology using two multiplex PCRs for the amplification of BRAF, N-H-K-RAS and RET exon genes. RNA samples were studied for RET/PTC1 and RET/PTC3 rearrangements by PCR amplification, and the conditions were set-up to study, with a single experiment, both wild-type PAX8 and PAX8/PPARɣ rearrangements. In total, 111 samples were examined for BRAF, N-H-KRAS and RET genes. An ultrasonographic, cytological and molecular correlation was also carried out in an attempt to suggest a possible way to manage the patients with thyroid nodules. Cyto-histological correlation was available in 115 cases, and it was used to verify the global diagnostic accuracy of this combined approach., Results: According to the histopathological diagnosis, FNC accuracy was 100% for TIR5 and metastases; 89% for TIR4; 84% for TIR3A and 58% for TIR3B. About 11% of the studied samples showed either RET-PTC1 or RET/PTC3 chromosomal rearrangements, and only one sample simultaneously presented RET/PTC1 and RET/PTC3 rearrangements. PAX8/PPARɣ rearrangement was found in 6% of the samples., Conclusions: A multidisciplinary approach to the thyroid is therefore necessary to develop innovative methods suitable for an improved diagnostic and prognostic definition of thyroid cancer., (© 2019 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objectives: To estimate the economic impact of delirium in the Australian population in 2016-2017, including financial costs, and its burden on health., Design, Setting and Participants: A cost of illness study was conducted for the Australian population in the 2016-2017 financial year. The prevalence of delirium in 2016-2017 was calculated to inform cost estimations. The costs estimated in this study also include dementia attributable to delirium., Main Outcome Measures: The total and per capita costs were analysed for three categories: health systems costs, other financial costs including productivity losses and informal care and cost associated with loss of well-being (burden of disease). Costs were expressed in 2016-2017 pound sterling (£) and Australian dollars ($A)., Results: There were an estimated 132 595 occurrences of delirium in 2016-2017, and more than 900 deaths were attributed to delirium in 2016-2017. Delirium causes an estimated 10.6% of dementia in Australia. The total costs of delirium in Australia were estimated to be £4.3 billion ($A8.8 billion) in 2016-2017, ranging between £2.6 billion ($A5.3 billion) and £5.9 billion ($A12.1 billion). The total estimated costs comprised financial costs of £1.7 billion and the value of healthy life lost of £2.5 billion. Dementia attributable to delirium accounted for £2.2 billion of the total cost of delirium., Conclusions: These findings highlight the substantial burden that delirium imposes on Australian society-both in terms of financial costs associated with health system expenditure and the increased need for residential aged care due to the functional and cognitive decline associated with delirium and dementia. To reduce the substantial well-being costs of delirium, further research should seek to better understand the potential pathways from an episode of delirium to subsequent mortality and reduced cognitive functioning outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi-center study enrolled 20 adult patients with intermediate- or high-risk primary MF, post- polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib-hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow-up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC., Methods: Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520., Results: Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5-52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0-21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%)., Conclusions: Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.

Study Objectives: To estimate the economic cost (financial and nonfinancial) of inadequate sleep in Australia for the 2016-2017 financial year and relate this to likely costs in similar economies., Methods: Analysis was undertaken using prevalence, financial, and nonfinancial cost data derived from national surveys and databases. Costs considered included the following: (1) financial costs associated with health care, informal care provided outside healthcare sector, productivity losses, nonmedical work and vehicle accident costs, deadweight loss through inefficiencies relating to lost taxation revenue and welfare payments; and (2) nonfinancial costs of loss of well-being. They were expressed in US dollars ($)., Results: The estimated overall cost of inadequate sleep in Australia in 2016-2017 (population: 24.8 million) was $45.21 billion. The financial cost component was $17.88 billion, comprised of as follows: direct health costs of $160 million for sleep disorders and $1.08 billion for associated conditions; productivity losses of $12.19 billion ($5.22 billion reduced employment, $0.61 billion premature death, $1.73 billion absenteeism, and $4.63 billion presenteeism); nonmedical accident costs of $2.48 billion; informal care costs of $0.41 billion; and deadweight loss of $1.56 billion. The nonfinancial cost of reduced well-being was $27.33 billion., Conclusions: The financial and nonfinancial costs associated with inadequate sleep are substantial. The estimated total financial cost of $17.88 billion represents 1.55 per cent of Australian gross domestic product. The estimated nonfinancial cost of $27.33 billion represents 4.6 per cent of the total Australian burden of disease for the year. These costs warrant substantial investment in preventive health measures to address the issue through education and regulation.

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent., Methods: Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field., Objective: The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

Thyroid nodules are very common, and their frequency is four to five times higher in women than in men. Most of them are benign, with only a very little percentage revealing a malignant neoplasm. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography and following fine-needle aspiration. Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. A standard diagnostic approach is represented by 'first-level' exams, consisting in neck ultrasonography and serum thyroid-stimulating hormone measurement, followed, only for nodules that are suspicious of malignancy, by 'second-level' exams, consisting of fine-needle aspiration and mutational test, which does detect particular DNA mutations present only in malignant cells. In this review, we will analyze the genetics of thyroid cancer and its heterogeneity, and we will briefly describe the current available diagnostic and therapeutic approaches.

Background: Heart conditions impose physical, social, financial and health-related quality of life limitations on individuals in Brazil., Objectives: This study assessed the economic burden of four main heart conditions in Brazil: hypertension, heart failure, myocardial infarction, and atrial fibrillation. In addition, the cost-effectiveness of telemedicine and structured telephone support for the management of heart failure was assessed., Methods: A standard cost of illness framework was used to assess the costs associated with the four conditions in 2015. The analysis assessed the prevalence of the four conditions and, in the case of myocardial infarction, also its incidence. It further assessed the conditions' associated expenditures on healthcare treatment, productivity losses from reduced employment, costs of providing formal and informal care, and lost wellbeing. The analysis was informed by a targeted literature review, data scan and modelling. All inputs and methods were validated by consulting 15 clinicians and other stakeholders in Brazil. The cost-effectiveness analysis was based on a meta-analysis and economic evaluation of post-discharge programs in patients with heart failure, assessed from the perspective of the Brazilian Unified Healthcare System (Sistema Unico de Saude)., Results: Myocardial infarction imposes the greatest financial cost (22.4 billion reais/6.9 billion USD), followed by heart failure (22.1 billion reais/6.8 billion USD), hypertension (8 billion reais/2.5 billion USD) and, finally, atrial fibrillation (3.9 billion reais/1.2 billion USD). Telemedicine and structured telephone support are cost-effective interventions for achieving improvements in the management of heart failure., Conclusions: Heart conditions impose substantial loss of wellbeing and financial costs in Brazil and should be a public health priority.

Purpose: To assess the role of clinical, biochemical, and morphological parameters, as added to cytology, for improving pre-surgical diagnosis of palpable thyroid nodules., Methods: Patients with a palpable thyroid nodule were eligible if surgical intervention was indicated after a positive or suspicious for malignancy FNAC (TIR 4-5 according to the 2007 Italian SIAPEC-IAP classification), or two inconclusive FNAC at a ≥3 months interval, or a negative FNAC associated with one or more risk factor. Reference standard was histological malignancy diagnosis. Likelihood ratios of malignancy, sensitivity, specificity, negative (NPV), and positive predictive value (PPV) were described. Multiple correspondence analysis (MCA) and logistic regression were applied., Results: Cancer was found in 433/902 (48%) patients. Considering TIR4-5 only as positive cytology, specificity, and PPV were high (94 and 91%) but sensitivity and NPV were low (61 and 72%); conversely, including TIR3 among positive, sensitivity and NPV were higher (88 and 82%) while specificity and PPV decreased (52 and 63%). Ultrasonographic size ≥3 cm was independently associated with benignity among TIR2 cases (OR of malignancy 0.37, 95% CI 0.18-0.78). In TIR3 cases the hard consistency of small nodules was associated with malignity (OR: 3.51, 95% CI 1.84-6.70, p < 0.001), while size alone, irrespective of consistency, was not diagnostically informative. No other significant association was found in TIR2 and TIR3., Conclusions: The combination of cytology with clinical and ultrasonographic parameters may improve diagnostic definition of palpable thyroid nodules. However, the need for innovative diagnostic tools is still high.

The Hyperparathyroidism with Jaw-Tumours syndrome is caused by mutations of the CDC73 gene: it has been suggested that early onset of the disease and high Ca 2+ levels may predict the presence of a CDC73 mutation. We searched for large deletions at the CDC73 locus in patients with: HPT-JT (nr 2), atypical adenoma (nr 7) or sporadic parathyroid carcinoma (nr 11) with a specific MLPA and qRT-PCR assays applied on DNA extracted from whole blood. A Medline search in database for all the papers reporting a CDC73 gene mutation, clinical/histological diagnosis, age at onset, Ca 2+ , PTH levels for familial/sporadic cases was conducted with the aim to possibly identify biochemical/clinical markers predictive, in first diagnosis, of the presence of a CDC73 gene mutation. A novel genomic deletion of the first 10 exons of the CDC73 gene was found in a 3-generation HPT-JT family, confirmed by SNP array analysis. A classification tree built on the published data, showed the highest probability of having a CDC73 mutation in subjects with age at the onset < 41.5 years (44/47 subjects, 93.6%, had the mutation). Whereas the lowest probability was found in subjects with age at the onset ≥ 41.5 years and Ca 2+ levels <13.96 mg/dL (7/20 subjects, 35.0%, had the mutation, odds ratio = 27.1, p < 0.001). We report a novel large genomic CDC73 gene deletion identified in an Italian HPT-JT family. Age at onset < 41.5 ys and Ca 2+ > 13.96 mg/dL are predictive for the presence of a CDC73 genetic lesion., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

Background: To quantify the economic impact of sight loss and blindness in the United Kingdom (UK) population, including direct and indirect costs, and its burden on health., Methods: Prevalence data on sight loss and blindness by condition, Census demographic data, data on indirect costs, and healthcare cost databases were used. Blindness was defined as best corrected visual acuity (BCVA) of < 6/60, and sight loss as BCVA < 6/12 to 6/60, in the better-seeing eye., Results: Sight loss and blindness from age-related macular degeneration (AMD), cataract, diabetic retinopathy, glaucoma and under-corrected refractive error are estimated to affect 1.93 (1.58 to 2.31) million people in the UK. Direct health care system costs were £3.0 billion, with inpatient and day care costs comprising £735 million (24.6%) and outpatient costs comprising £771 million (25.8%). Indirect costs amounted to £5.65 (5.12 to 6.22) billion. The value of the loss of healthy life associated with sight loss and blindness was estimated to be £19.5 (15.9 to 23.3) billion or £7.2 (5.9 to 8.6) billion, depending on the set of disability weights used. For comparison with other published results using 2004 disability weights and the 2008 estimates, the total economic cost of sight loss and blindness was estimated to be £28.1 (24.0 to 32.5) billion in 2013. Using 2010 disability weights, the estimated economic cost of sight loss and blindness was estimated to be £15.8 (13.5 to 18.3) billion in 2013., Conclusions: The large prevalence of sight loss and blindness in the UK population imposes significant costs on public funds, private expenditure, and health. Prevalence estimates relied on dated epidemiological studies and may not capture recent advances in treatment, highlighting the need for population-based studies that track the prevalence of sight-impairing eye conditions and treatment effects over time.

An ageing population and growing prevalence of chronic diseases including cardiovascular disease (CVD) and type 2 diabetes (T2D) are putting increased pressure on healthcare expenditure in Australia. A cost of illness analysis was conducted to assess the potential savings in healthcare expenditure and productivity costs associated with lower prevalence of CVD and T2D resulting from increased intake of cereal fibre. Modelling was undertaken for three levels of increased dietary fibre intake using cereal fibre: a 10% increase in total dietary fibre; an increase to the Adequate Intake; and an increase to the Suggested Dietary Target. Total healthcare expenditure and productivity cost savings associated with reduced CVD and T2D were calculated by gender, socioeconomic status, baseline dietary fibre intake, and population uptake. Total combined annual healthcare expenditure and productivity cost savings of AUD$17.8 million-$1.6 billion for CVD and AUD$18.2 million-$1.7 billion for T2D were calculated. Total savings were generally larger among adults of lower socioeconomic status and those with lower dietary fibre intakes. Given the substantial healthcare expenditure and productivity cost savings that could be realised through increases in cereal fibre, there is cause for the development of interventions and policies that encourage an increase in cereal fibre intake in Australia., Competing Interests: The authors declare no conflict of interest. Kellogg Australia had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.