Bridging and Validation of the Specific Graves Ophthalmopathy Quality of Life Questionnaire With Health State Utility Values.

OBJECTIVE: In thyroid eye disease (TED), inflammation and expansion of orbital muscle and periorbital fat result in diplopia and proptosis, severely impacting patient quality of life (QOL). The reported health state utility (HSU) scores, which are QOL measures, allow quantification of TED impact and improvement with therapies; however, no current QOL instrument has been validated with HSU scores for TED. Here, we used the disease-specific Graves Ophthalmopathy Quality of Life (GO-QOL) questionnaire and HSU scores to validate QOL impact. METHODS: The GO-QOL scores from patients in 2 randomized, masked, placebo-controlled teprotumumab trials (N=171) were compared with 6 HSU values based on severity of proptosis/diplopia in those studies. Patient GO-QOL and HSU scores were compared at baseline and after 6-month treatment via regression analyses. GO-QOL and HSU scores were correlated for validation and quantification of QOL impact by severity state and to estimate quality-adjusted life year improvement. RESULTS: GO-QOL scores were correlated with TED severity, indicating that worse severity was associated with lower (worse) GO-QOL scores. Less severe health states were represented by higher (better) GO-QOL scores. Importantly, GO-QOL scores were positively correlated with utility scores of the 6 health states, allowing for conversion of the GO-QOL scores to utility scores. A positive (improved) 0.013 utility change was found for each 1-point (positive) improvement in GO-QOL score produced by teprotumumab versus placebo. CONCLUSION: Patients with moderate-to-severe active TED health states demonstrate increasing TED severity associated with declining utility values and worsening GO-QOL scores. These results indicate that the GO-QOL scores can be used to bridge to the HSU scores for benefit quantification.

Defining ruxolitinib failure and transition to next-line therapy for patients with myelofibrosis: a modified Delphi panel consensus study.

Aim: To define ruxolitinib failure and develop parameters to guide transition to next-line therapy for patients with myelofibrosis. Methods: A modified Delphi panel with 14 hematologists-oncologists. Survey concepts included defining primary refractory status, loss of response, disease progression, intolerance and transition to next-line therapy. Results: Ruxolitinib failure may be defined as no improvement in symptoms or spleen size, progressive disease or ruxolitinib intolerance, following a maximally tolerated dose for ≥3 months. Loss of spleen response 1 month after initial response may prompt discontinuation. Lack of evidence to inform transition to next-line therapy was noted; tapering ruxolitinib should be considered according to ruxolitinib dose and patient characteristics. Conclusion: Expert consensus was provided on defining ruxolitinib failure and transition to next-line therapy as summarized in this position paper, which may support considerations in the development of future clinical practice guidelines.

People with myelofibrosis who receive treatment with ruxolitinib may need to stop treatment because it is not working or they cannot tolerate the side effects. There is little good scientific information available about how and when to stop ruxolitinib treatment, and how to move to another treatment after stopping ruxolitinib. A group of clinical experts in hematology and oncology followed a scientific process, called the Delphi method, to discuss this topic and to reach agreement on the most important aspects of this challenge. The experts agreed that ruxolitinib failure may be defined as having no improvement in symptoms or spleen size, progressive disease or ruxolitinib intolerance, after the patient was receiving the highest dose they could tolerate for ≥3 months. The results of this expert discussion may support patients and their healthcare providers making decisions in real life, and development of future clinical practice guidelines.

Expert Consensus on the Use of Teprotumumab for the Management of Thyroid Eye Disease Using a Modified-Delphi Approach.

BACKGROUND: Teprotumumab is the first treatment for thyroid eye disease (TED), a debilitating autoinflammatory condition, approved by the Food and Drug Administration in the United States, which reduces proptosis and improves quality of life. In the absence of guidelines, clinical recommendations were developed for using teprotumumab in patients with TED in the United States. METHODS: A 3-round modified-Delphi panel was conducted between October 2020 and February 2021 with experts in the management of patients with TED. Key areas regarding the use of teprotumumab were investigated, including eligible patient populations, concomitant treatments, and assessment of response and adverse events. This used 2 survey rounds via an online questionnaire, where statements were scored using 9-point Likert scales. Statements with conflict were included in the third round, involving a consensus meeting via videoconference. RESULTS: Consensus was obtained for all statements (n = 75); of which, 56% were revised to enable agreement of the group. The consensus meeting provided agreement regarding which populations should receive teprotumumab therapy, including all adult patients with TED with a clinical activity score of ≥4. Treatment with teprotumumab can also be considered for TED patients displaying the following characteristics: a CAS of <3, lid retraction of ≥2, and mild or early optic neuropathy with close clinical observation. Further recommendations included suitability of treatment for those beyond 16 months following the initial diagnosis of TED, low CAS concomitant treatment with steroids in some cases, retreatment for those who have relapses, and finally a recommendation to continue therapy for all 8 infusions despite the lack of response by the fourth infusion. CONCLUSIONS: This work constitutes the first consensus on guidelines for the use of teprotumumab. The modified Delphi approach involved physicians with significant experience with the clinical use of teprotumumab, and recommendations were based on current evidence.

Systematic Literature Review of the Epidemiology of Advanced Prostate Cancer and Associated Homologous Recombination Repair Gene Alterations.

PURPOSE: To characterize the global epidemiology of metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-resistant prostate cancer (mCRPC). Additionally, to assess the prevalence of homologous recombination repair gene alterations (HRRm) and their prognostic impact in advanced disease setting. MATERIALS AND METHODS: A systematic literature review of real-world evidence published from January 2009 through May 2019 was conducted to assess global epidemiology and clinical practice trends for mCSPC, nmCRPC, mCRPC and HRRm; 4,732 papers were systematically screened for inclusion. Ten conference proceedings from 2014 through 2019 were reviewed. RESULTS: Of the screened articles 22 relevant publications were identified for this paper. Six publications reported global epidemiology of advanced prostate cancer. The prevalence of nmCRPC was estimated as 1.1% to 12.3% of prostate cancer cases and for mCRPC 1.2% to 2.1% of prostate cancer cases. No mCSPC prevalence was captured. Sixteen publications investigated HRRm prevalence in advanced prostate cancer with the majority conducted in mCRPC assessed using next-generation sequencing of tissue and germline samples. In mCRPC, the highest prevalence HRRm in both germline (3.3%-6.0%) and somatic (5.0%-15.1%) was BRCA2. Five publications reported the prognostic impact of HRRm in advanced prostate cancer. CONCLUSIONS: Published real-world evidence quantifying the prevalence of advanced prostate cancer and HRRm beyond mCRPC is sparse. Published data on HRRm, specifically BRCA2, are consistent with published clinical trial data for poly (ADP-ribose) polymerase inhibitors in mCRPC. In mCRPC, real-world evidence suggests that patients with HRRm have different clinical outcomes to noncarriers. More data are needed to better understand real-world patient segmentation and clinical outcomes for biomarkers given increasing interest in profiling.

Assessing the impact and resource implications of contrast-enhanced ultrasound on workflow of patients with incidental focal liver lesions on the UK national health service.

Background: Focal liver lesions (FLL) are abnormal growths that require timely identification. Contrast-enhanced ultrasound (CEUS) is a cost-effective imaging modality for characterising FLL with similar sensitivity to computed tomography (CT) and magnetic resonance imaging (MRI). Despite being recommended by NICE, its adoption within the national health service (NHS) is limited due to low clinical demand, limited referral, and lack of knowledge. Purpose: To evaluate the impact of CEUS on patients with incidental FLL and assess the resource implications of introducing CEUS as a diagnostic service within the NHS. Material and methods: A patient flow review and cost-minimisation analysis were conducted. This involved a targeted literature review, NHS Trust stakeholder consultations, and development of a Microsoft Excel cost-minimisation model to explore potential value of CEUS use versus CT and MRI by episode. A scenario analysis of the base-case explored increasing CEUS use to 50% and 90%. A sensitivity analysis was performed to assess how changes in assumptions impacted the model and the resulting cost estimates. Results: The model, comparing a world with and without CEUS, showed that current use (base-case: 5%) resulted in cost savings of £224,790/year. The sensitivity analysis indicated that regardless of changes to the assumptions, CEUS still resulted in cost savings to the NHS. By increasing CEUS use to 50% and 90%, cost savings of up to £2,247,894/year and £4,046,208/year could be achieved, respectively. Conclusion: By standardising CEUS use for characterising FLL, substantial cost savings could be realised, whilst reducing wait times and expanding diagnostic capacity, thus preserving limited CT and MRI capacity for high-priority cases.

Utility Assessment of Moderate to Severe Thyroid Eye Disease Health States.

Importance: Thyroid eye disease (TED) results in varying degrees of proptosis and diplopia negatively affecting quality of life (QoL), producing possibly substantial visual changes, disfigurement, and disability. Objective: To determine the association of varying TED severities with QoL in a non-TED population by assessing health state utility scores. Design, Setting, and Participants: This qualitative study, conducted from April 20, 2020, to April 29, 2021, assessed health states for active, moderate-severe TED, and values were elicited using time trade-off methods. Six health states of varying severity were determined from 2 placebo-controlled clinical trials (171 patients with TED and clinical activity score ≥4, ±diplopia/proptosis) and refined using interviews with US patients with TED (n = 6). Each health state description was validated by interviews with additional TED patient advocates (n = 3) and physician experts (n = 3). Health state descriptions and a QOL questionnaire were piloted and administered to a general population. Visual analog scales (VASs) were also administered to detect concurrence of the findings. Main Outcomes and Measures: TED health state utility scores and whether they differ from one another were assessed using Shapiro-Wilk, Kruskal-Wallis, pairwise Wilcoxon rank sum, and paired t tests. Results: A total of 111 participants completed time trade-off interviews. The mean (SD) utility value was 0.44 (0.34). The lowest (worse) mean utility value was observed in the most severe disease state (constant diplopia/large proptosis) with 0.30 (95% CI, 0.24-0.36), followed by constant diplopia/small proptosis (0.34; 95% CI, 0.29-0.40), intermittent or inconstant diplopia/large proptosis (0.43; 95% CI, 0.36-0.49), no diplopia/large proptosis (0.46; 95% CI, 0.40-0.52), and intermittent or inconstant diplopia/small proptosis (0.52; 95% CI, 0.45-0.58). The highest (best) mean value, 0.60 (95% CI, 0.54-0.67), was observed for the least severe disease state (no diplopia/small proptosis). Conclusions and Relevance: These findings suggest that patients with active, moderate-severe TED may have substantial disutility, with increasing severity of proptosis/diplopia more likely to have detrimental associations with QoL. These health state scores may provide a baseline for determining QoL improvement in these TED health states (utility gains) treated with new therapies.

Epidemiology and costs of dengue in Thailand: A systematic literature review.

BACKGROUND: Dengue is the fastest-spreading vector-borne viral disease worldwide. In Thailand, dengue is endemic and is associated with a high socioeconomic burden. A systematic literature review was conducted to assess and describe the epidemiological and economic burden of dengue in Thailand. METHODS: Epidemiological and economic studies published in English and Thai between 2011-2019 and 2009-2019, respectively, were searched in MEDLINE, Embase, and Evidence-Based Medicines reviews databases. Reports published by the National Ministry of Public Health (MoPH) and other grey literature sources were also reviewed. Identified studies were screened according to predefined inclusion and exclusion criteria. Extracted data were descriptively summarised and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 155 publications were included in the review (39 journal articles and 116 grey literature). Overall, dengue incidence varied yearly, with the highest rates per 100,000 population in 2013 (dengue fever (DF) 136.6, dengue haemorrhagic fever (DHF) 100.9, dengue shock syndrome (DSS) 3.58) and 2015 (DF 133.1, DHF 87.4, DSS 2.14). Peak incidence coincided with the monsoon season, and annual mortality was highest for DSS, particularly in the age group 15-24-year-olds. The highest dengue incidence rates were reported in children (10-14-year-olds) and young adults (15-24-year-olds), irrespective of dengue case definition. Economic and societal burdens are extensive, with the average cost per case ranging from USD 41 to USD 261, total cost per year estimated at USD 440.3 million, and an average of 7.6 workdays lost for DHF and 6.6 days for DF. CONCLUSIONS: The epidemiological, economic, and societal burden of dengue in Thailand is high and underreported due to gaps in national surveillance data. The use of expansion factors (EFs) is recommended to understand the true incidence of dengue and cost-benefit of control measures. Furthermore, as dengue is often self-managed and underreported, lost school and workdays result in substantial underestimation of the true economic and societal burden of dengue. The implementation of integrated strategies, including vaccination, is critical to reduce the disease burden and may help alleviate health disparities and equity challenges posed by dengue.

Epidemiology and costs of dengue in Brazil: a systematic literature review.

OBJECTIVES: Dengue infection is a growing public health problem, with the number of reported cases increasing in the Americas and worldwide. This review characterized the epidemiological and economic burden of dengue in Brazil. METHODS: Embase, MEDLINE, evidence-based review databases, and gray literature sources were searched for published literature and surveillance reports on epidemiology (between 2000 and 2019) and costs (between 2009 and 2019) of dengue in Brazil. Studies were included if they reported data on incidence, seroprevalence, serotype distribution, expansion factors, hospitalization, mortality, or costs. Data were summarized descriptively and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 344 publications were included (167 peer-reviewed and 177 gray literature). Dengue outbreaks increased in incidence and frequency, with the highest incidence observed in 2015 at 807 cases per 100,000 population. Outbreaks were related to alternating predominant serotypes. Dengue was more frequent in young adults (aged 20-39 years) and in the Midwest. Cost and societal impacts are substantial and varied across regions, age, and public/private delivery of healthcare services. CONCLUSION: The burden of dengue in Brazil is increasing and likely underestimated. Therefore, developing and implementing new strategies, including vaccination, is essential to reduce the disease burden.

Epidemiology (2012-2019) and costs (2009-2019) of dengue in Malaysia: a systematic literature review.

OBJECTIVES: A systematic literature review was conducted to assess the epidemiology and economic burden of dengue in Malaysia. METHODS: Embase, MEDLINE, Evidence-Based Reviews databases, and gray literature sources were searched for English and Malay studies and surveillance reports on the epidemiology (between 2012 and 2019) and costs (between 2009 and 2019) of dengue in Malaysia. Independent screening of titles/abstracts, followed by full texts was performed using prespecified criteria. RESULTS: A total of 198 publications were included (55 peer-reviewed and 143 gray literature). Dengue incidence has been increasing in recent years, with 130,101 cases (dengue fever 129,578 cases; dengue hemorrhagic fever 523 cases) reported in 2019, which is the highest since 2012. All dengue virus serotypes co-circulated between 2004 and 2017, and major outbreaks occurred in a cyclical pattern, often associated with a change in the predominant circulating serotype. Economic impacts are substantial, including the societal impact of lost work (7.2-8.8 days) and school days (3.2-4.1 days) due to dengue. CONCLUSION: The rising incidence and high cost of dengue, coupled with overlapping diseases, will likely result in further pressures on the healthcare system. To appropriately mitigate and control dengue, it is critical to implement integrated strategies, including vaccination, to reduce the burden of dengue.

Understanding the Economic Burden of Treating Low-Grade Upper Tract Urothelial Cancer in the United States.

INTRODUCTION: Low grade upper tract urothelial cancer is an uncommon urothelial tumor for which treatment involves multiple ureteroscopic interventions and potentially radical nephroureterectomy. Given the burden of these procedures, there is growing interest in determining how the utilization, complications and morbidities associated with treatment contribute to the burden of care for upper tract urothelial cancer. The aim of this study was to conduct a systematic literature review to understand the economic burden of treating low grade upper tract urothelial cancer. METHODS: The systematic literature review captured publications from January 1, 2009 to March 11, 2019 in MEDLINE®, Embase®, Evidence-Based Medicine Reviews, PsycINFO and EconLit. Conference proceedings from 7 different conferences were also searched. RESULTS: We identified 15 studies that reported on the economic burden associated with treatment interventions in upper tract urothelial cancer. Treatment costs associated with radical nephroureterectomy were the greatest cost component contributing to expenditures including initial procedural costs (ranging from $11,793 to $23,235 per patient), readmission/retreatment costs ($31,697 per patient) and long-terms costs up to 5 years associated with end stage renal disease and chronic kidney disease ($41,474 to $385,464 per patient). Kidney-sparing management was identified as a cost saving alternative to radical nephroureterectomy, with $252,272 per patient saved through 5 years. CONCLUSIONS: The economic burden of low grade upper tract urothelial cancer is high due to costs incurred by patient comorbidities, multiple episodes of care and complications associated with radical nephroureterectomy. Therefore, there is a need for a paradigm shift towards cost-effective, minimally invasive, kidney-sparing treatments.

A structured literature review of interventions used in the management of nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) is a chronic, progressive disease, that can advance to fibrosis, cirrhosis, and hepatocellular carcinoma. Despite being a leading cause of liver transplantation, there are no approved pharmacological treatments. Our aim was to identify literature on management options in NASH. Our structured review of interventions treating NASH patients from English language publications between 1 January 2007 and 25 September 2017 elicited 48 eligible references. Lifestyle management was identified as the mainstay of NASH therapy. Vitamin E and pioglitazone reported reductions in steatosis; however, although recommended for some, no therapies are indicated in NASH. Multiple investigational treatments reported efficacy in mild-to-moderate fibrosis in Phase II/III NASH trials. Lifestyle management, although the focus of clinical guidelines, is insufficient for patients progressing to advanced fibrosis. With no clear guidelines for patients requiring interventions beyond lifestyle modification, long-term outcomes data are needed, particularly in patients with moderate-to-severe fibrosis.