Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Prophylactic pectoralis major flap to compensate for increased risk of pharyngocutaneous fistula in laryngectomy patients with low skeletal muscle mass (PECTORALIS): study protocol for a randomized controlled trial.

BACKGROUND: Total laryngectomy (TL) is a surgical procedure commonly performed on patients with advanced laryngeal or hypopharyngeal carcinoma. One of the most common postoperative complications following TL is the development of a pharyngocutaneous fistula (PCF), characterized by a communication between the neopharynx and the skin. PCF can lead to extended hospital stays, delayed oral feeding, and compromised quality of life. The use of a myofascial pectoralis major flap (PMMF) as an onlay technique during pharyngeal closure has shown potential in reducing PCF rates in high risk patients for development of PCF such as patients undergoing TL after chemoradiation and low skeletal muscle mass (SMM). Its impact on various functional outcomes, such as shoulder and neck function, swallowing function, and voice quality, remains less explored. This study aims to investigate the effectiveness of PMMF in reducing PCF rates in patients with low SMM and its potential consequences on patient well-being. METHODS: This multicenter study adopts a randomized clinical trial (RCT) design and is funded by the Dutch Cancer Society. Eligible patients for TL, aged ≥ 18 years, mentally competent, and proficient in Dutch, will be enrolled. One hundred and twenty eight patients with low SMM will be centrally randomized to receive TL with or without PMMF, while those without low SMM will undergo standard TL. Primary outcome measurement involves assessing PCF rates within 30 days post-TL. Secondary objectives include evaluating quality of life, shoulder and neck function, swallowing function, and voice quality using standardized questionnaires and functional tests. Data will be collected through electronic patient records. DISCUSSION: This study's significance lies in its exploration of the potential benefits of using PMMF as an onlay technique during pharyngeal closure to reduce PCF rates in TL patients with low SMM. By assessing various functional outcomes, the study aims to provide a comprehensive understanding of the impact of PMMF deployment. The anticipated results will contribute valuable insights into optimizing surgical techniques to enhance patient outcomes and inform future treatment strategies for TL patients. TRIAL REGISTRATION: NL8605, registered on 11-05-2020; International Clinical Trials Registry Platform (ICTRP).

Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands.

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10-20) vs. 59 days (95% CI 23-98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). CONCLUSION:  Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. WHAT IS KNOWN: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. WHAT IS NEW: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

Key Considerations in the Health Technology Assessment of Advanced Therapy Medicinal Products in Scotland, The Netherlands, and England.

OBJECTIVES: Advanced therapy medicinal products (ATMPs) are highly innovative therapies. Their costs and uncertain value claims have raised concerns among health technology assessment (HTA) bodies and payers. Little is known about how underlying considerations in HTA of ATMPs shape assessment and reimbursement recommendations. We aim to identify and assess key considerations that played a role in HTA of ATMPs underlying reimbursement recommendations. METHODS: A review of HTA reports was conducted of all authorized ATMPs in Scotland, The Netherlands, and England. Considerations were extracted and categorized into EUnetHTA Core Model domains. Per jurisdiction, considerations were aggregated and key considerations identified (defined as occurring in >1/assessment per jurisdiction). A narrative analysis was conducted comparing key considerations between jurisdictions and different reimbursement recommendations. RESULTS: We identified 15 ATMPs and 18 HTA reports. In The Netherlands and England most key considerations were identified in clinical effectiveness (EFF) and cost- and economic effectiveness (ECO) domains. In Scotland, the social aspects domain yielded most key considerations, followed by ECO and EFF. More uncertainty in evidence and assessment outcomes was accepted when orphan or end-of-life criteria were applied. A higher percentage of considerations supporting recommendations were identified for products with positive recommendations compared with restricted and negative recommendations. CONCLUSIONS: This is the first empirical review of HTA's using the EUnetHTA Core Model to identify and structure key considerations retrospectively. It provides insights in supporting and opposing considerations for reimbursement of individual products and differences between jurisdictions. Besides the EFF and ECO domain, the social, ethical, and legal domains seem to bear considerable weight in assessment of ATMPs.

Diagnostic accuracy of Ara h 2 for detecting peanut allergy in children.

BACKGROUND: Specific IgE to Ara h 2 is a diagnostic test for peanut allergy which may reduce the need for double-blind placebo-controlled food challenges (DBPCFC); however, guidance for using Ara h 2 in place of DBPCFCs has not been validated. OBJECTIVE: To prospectively evaluate 1) diagnostic accuracy of previously published Ara h 2 cut-off levels to diagnose peanut allergy in children and 2) costs. METHODS: A consecutive series of 150 children age 3.5 to 18 years was evaluated in secondary and tertiary settings in the Netherlands. sIgE to Ara h 2 was the index test, and oral peanut ingestion was the reference test. Oral peanut ingestion was home or supervised introduction for Ara h 2 ≤ 0.1, DBPCFC for 0.1-5.0 and open food challenge for ≥5.0. Costs were calculated using financial healthcare data. RESULTS: A conclusive reference test was performed in 113 children (75%). Sixty-four children (57%) had peanut allergy, as confirmed by a DBPCFC (27/47) or an open challenge (37/50). Forty-nine children (43%) were considered peanut-tolerant after peanut introduction (19/19), a DBPCFC (20/47) or an open challenge (10/50). Area under the curve for Ara h 2 was 0.94 (95% CI 0.90-0.98). The diagnostic flow chart correctly classified 26/26 (100%; 84-100) of children with Ara h 2 ≤ 0.1 as peanut-tolerant and 34/35 (97%; 83-100) of children with Ara h 2 ≥ 5.0 as peanut-allergic. At a cut-off of ≤0.1 and ≥5.0, a sensitivity of respectively 100% (93-100) and 53% (38-67) was observed and a specificity of 53% (38-67) and 98% (87-100). Mean annual costs of the flow chart were estimated as €320-€636 per patient lower than following national allergy guidelines. CONCLUSIONS: In this diagnostic accuracy study, which did not take into account pretest probability, we have validated previously published Ara h 2 cut-off levels which are associated with peanut tolerance and allergy.

Estimation of manufacturing development costs of cell-based therapies: a feasibility study.

BACKGROUND AIMS: Cell-based therapies (CBTs) provide opportunities to treat rare and high-burden diseases. Manufacturing development of these innovative products is said to be complex and costly. However, little research is available providing insight into resource use and cost drivers. Therefore, this study aimed to assess the feasibility of estimating the cost of manufacturing development of two cell-based therapy case studies using a CBT cost framework specifically designed for small-scale cell-based therapies. METHODS: A retrospective costing study was conducted in which the cost of developing an adoptive immunotherapy of Epstein-Barr virus-specific cytotoxic T lymphocytes (CTLs) and a pluripotent stem cell (PSC) master cell bank was estimated. Manufacturing development was defined as products advancing from technology readiness level 3 to 6. The study was conducted in a Scottish facility. Development steps were recreated via developer focus groups. Data were collected from facility administrative and financial records and developer interviews. RESULTS: Application of the manufacturing cost framework to retrospectively estimate the manufacturing design cost of two case studies in one Scottish facility appeared feasible. Manufacturing development cost was estimated at £1,201,016 for CTLs and £494,456 for PSCs. Most costs were accrued in the facility domain (56% and 51%), followed by personnel (20% and 32%), materials (19% and 15%) and equipment (4% and 2%). CONCLUSIONS: Based on this study, it seems feasible to retrospectively estimate resources consumed in manufacturing development of cell-based therapies. This fosters inclusion of cost in the formulation and dissemination of best practices to facilitate early and sustainable patient access and inform future cost-conscious manufacturing design decisions.

Cost and impact of early diagnosis in primary immunodeficiency disease: A literature review.

BACKGROUND: New, innovative, costly diagnostic methods for patients with primary immunodeficiencies (PID) demand upfront insight into their potential cost savings and added value for individual patients. As such, high quality, comparable economic evaluations are of utmost importance to enable informed decisions. The objective of this review was therefore to create an extensive overview of current costing studies and potential cost savings of early diagnosis in primary immunodeficiency disease. METHODS: A literature search in PubMed was conducted and studies involving any form of costing study in the field of PIDs were included. Of the included studies, study characteristics, cost parameters and benefits of early diagnosis were extracted and outlined in separate tables. RESULTS: Twenty two studies met the inclusion criteria and were included in the review. The papers were categorized according to their subject: neonatal screening for severe combined immunodeficiency (SCID), Ig replacement therapies and studies reporting on costs of general or specific PIDs. Within and between these groups variability in reported costing characteristics was observed. In studies that reported cost savings pre- and post-diagnosis, cost savings ranged from 6500 to 108,463 USD of total costs per patient. CONCLUSION: This literature review shows that, regardless of what aspect of PIDs has been studied, in nearly all cases early diagnosis reduces health care consumption and leads to better health outcomes for patients with PIDs. We found considerable variability in costing characteristics of economic evaluations of PID patients, which hampers the comparability of outcomes. More effort is needed to create uniformity and define cost parameters in economic evaluations in the field of PIDs, facilitating further prospective research to extensively assess the benefits of early diagnosis.

What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings.

BACKGROUND AIMS: Recent technical and clinical advances with cell-based therapies (CBTs) hold great promise in the treatment of patients with rare diseases and those with high unmet medical need. Currently the majority of CBTs are developed and manufactured in specialized academic facilities. Due to small scale, unique characteristics and specific supply chain, CBT manufacturing is considered costly compared to more conventional medicinal products. As a result, biomedical researchers and clinicians are increasingly faced with cost considerations in CBT development. The objective of this research was to develop a costing framework and methodology for academic and other small-scale facilities that manufacture cell-based therapies. METHODS: We conducted an international multi-center costing study in four facilities in Europe using eight CBTs as case studies. This study includes costs from cell or tissue procurement to release of final product for clinical use. First, via interviews with research scientists, clinicians, biomedical scientists, pharmacists and technicians, we designed a high-level costing framework. Next, we developed a more detailed uniform methodology to allocate cost items. Costs were divided into steps (tissue procurement, manufacturing and fill-finish). The steps were each subdivided into cost categories (materials, equipment, personnel and facility), and each category was broken down into facility running (fixed) costs and operational (variable) costs. The methodology was tested via the case studies and validated in developer interviews. Costs are expressed in 2018 euros (€). RESULTS: The framework and methodology were applicable across facilities and proved sensitive to differences in product and facility characteristics. Case study cost estimates ranged between €23 033 and €190 799 Euros per batch, with batch yield varying between 1 and 88 doses. The cost estimations revealed hidden costs to developers and provided insights into cost drivers to help design manufacturing best practices. CONCLUSIONS: This framework and methodology provide step-by-step guidance to estimate manufacturing costs specifically for cell-based therapies manufactured in academic and other small-scale enterprises. The framework and methodology can be used to inform and plan cost-conscious strategies for CBTs.

A Review of Methodological Considerations for Economic Evaluations of Gene Therapies and Their Application in Literature.

OBJECTIVES: To identify methodological considerations discussed in literature addressing economic evaluations (EEs) of gene therapies (GTs). Additionally, we assessed if these considerations are applied in published GT EEs to increase understanding and explore impact. METHODS: First a peer-reviewed literature review was performed to identify research addressing methodological considerations of GT EEs until August 2019. Identified considerations were grouped in themes using thematic content analysis. A second literature search was conducted in which we identified published evaluations. The EE quality of reporting was assessed using Consolidated Health Economic Evaluation Reporting Standards. RESULTS: The first literature search yielded 13 articles discussing methodological considerations. The second search provided 12 EEs. Considerations identified were payment models, definition of perspectives, addressing uncertainty, data extrapolation, discount rates, novel value elements, and use of indirect and surrogate endpoints. All EEs scored satisfactory to good according to Consolidated Health Economic Evaluation Reporting Standards. Regarding methodological application, we found 1 methodological element (payment models) was applied in 2 base cases. Scenarios explored alternative perspectives, survival assumptions, and extrapolation methods in 10 EEs. CONCLUSIONS: Although EE quality of reporting was considered good, their informativeness for health technology assessment and decision makers seemed limited owing to many uncertainties. We suggest accepted EE methods can broadly be applied to GTs, but few elements may need adjustment. Further research and multi-stakeholder consensus is needed to determine appropriateness and application of individual methodological considerations. For now, we recommend including scenario analyses to explore impact of methodological choices and (clinical) uncertainties. This study contributes to better understanding of perceived appropriate evaluation of GTs and informs best modeling practices.

Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies: a Systematic Review.

BACKGROUND: As the application of next generation sequencing (NGS) is moving to earlier stages in the diagnostic pipeline for primary immunodeficiencies (PIDs), re-evaluation of its effectiveness is required. The aim of this study is to systematically review the diagnostic yield of NGS in PIDs. METHODS: PubMed and Embase databases were searched for relevant studies. Studies were eligible when describing the use of NGS in patients that had previously been diagnosed with PID on clinical and/or laboratory findings. Relevant data on study characteristics, technological performance and diagnostic yield were extracted. RESULTS: Fourteen studies were eligible for data extraction. Six studies described patient populations from specific PID subcategories. The remaining studies included patients with unsorted PIDs. The studies were based on populations from Italy, Iran, Turkey, Thailand, the Netherlands, Norway, Saudi Arabia, Sweden, the UK, and the USA. Eight studies used an array-based targeted gene panel, four used WES in combination with a PID filter, and two used both techniques. The mean reported reading depth ranged from 98 to 1337 times. Five studies described the sensitivity of the applied techniques, ranging from 83 to 100%, whereas specificity ranged from 45 to 99.9%. The percentage of patients who were genetically diagnosed ranged from 15 to 79%. Several studies described clinical implications of the genetic findings. DISCUSSION: NGS has the ability to contribute significantly to the identification of molecular mechanisms in PID patients. The diagnostic yield highly depends on population and on the technical circumstances under which NGS is employed. Further research is needed to determine the exact diagnostic yield and clinical implications of NGS in patients with PID.

DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

BACKGROUND: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. METHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. FINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. INTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. FUNDING: Dutch Cancer Society.

RELEASE-HF study: a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands.

INTRODUCTION: Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-)effective. METHODS AND ANALYSIS: The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation - Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible. TRIAL REGISTRATION NUMBER: NCT05654961.

Paving the path for implementation of clinical genomic sequencing globally: Are we ready?

Despite the emerging evidence in recent years, successful implementation of clinical genomic sequencing (CGS) remains limited and is challenged by a range of barriers. These include a lack of standardized practices, limited economic assessments for specific indications, limited meaningful patient engagement in health policy decision-making, and the associated costs and resource demand for implementation. Although CGS is gradually becoming more available and accessible worldwide, large variations and disparities remain, and reflections on the lessons learned for successful implementation are sparse. In this commentary, members of the Global Economics and Evaluation of Clinical Genomics Sequencing Working Group (GEECS) describe the global landscape of CGS in the context of health economics and policy and propose evidence-based solutions to address existing and future barriers to CGS implementation. The topics discussed are reflected as two overarching themes: (1) system readiness for CGS and (2) evidence, assessments, and approval processes. These themes highlight the need for health economics, public health, and infrastructure and operational considerations; a robust patient- and family-centered evidence base on CGS outcomes; and a comprehensive, collaborative, interdisciplinary approach.

Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in the netherlands.

AIMS: Recent trials have shown that low-dose colchicine (0.5 mg once daily) reduces major cardiovascular events in patients with acute and chronic coronary syndromes. We aimed to estimate the cost-effectiveness of low-dose colchicine therapy in patients with chronic coronary disease when added to standard background therapy. METHODS AND RESULTS: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, costs and quality of life obtained from the Low-dose Colchicine 2 (LoDoCo2) trial, as well as meta-analyses and public sources. In this trial, Low-dose colchicine was added to standard of care and compared to placebo. The main outcomes were cardiovascular events including myocardial infarction, stroke and coronary revascularisation, quality-adjusted life-year (QALY), the cost per QALY gained (incremental cost-effectiveness ratio), and net monetary benefit. In the model, low-dose colchicine therapy yielded 0.04 additional QALYs compared with standard of care at an incremental cost of €455 from a societal perspective and €729 from a healthcare perspective, resulting in a cost per QALY gained of €12,176/QALY from a societal perspective and €19,499/QALY from a healthcare perspective. Net monetary benefit was €1,414 from a societal perspective and €1,140 from a healthcare perspective. Low-dose colchicine has a 96% and 94% chance of being cost effective, from respectively a societal and healthcare perspective when using a willingness to pay of €50,000/QALY. Net monetary benefit would decrease below zero when annual low-dose colchicine costs would exceed an annual cost of €221 per patient. CONCLUSION: Adding low-dose colchicine to standard of care in patients with chronic coronary disease is cost-effective according to commonly accepted thresholds in Europe and Australia and compares favourably in cost-effectiveness to other drugs used in chronic coronary disease.

Toward Transplantation of Liver Organoids: From Biology and Ethics to Cost-effective Therapy.

Liver disease is a common cause of morbidity and mortality, and many patients would benefit from liver transplantation. However, because of a shortage of suitable donor livers, even of those patients who are placed on the donor liver waiting list, many do not survive the waiting time for transplantation. Therefore, alternative treatments for end-stage liver disease need to be explored. Recent advances in organoid technology might serve as a solution to overcome the donor liver shortage in the future. In this overview, we highlight the potential of organoid technology for cell therapy and tissue engineering approaches. Both organoid-based approaches could be used as treatment for end-stage liver disease patients. Additionally, organoid-based cell therapy can also be used to repair liver grafts ex vivo to increase the supply of transplantable liver tissue. The potential of both approaches to become clinically available is carefully assessed, including their clinical, ethical, and economic implications. We provide insight into what aspects should be considered further to allow alternatives to donor liver transplantation to be successfully clinically implemented.

Managing the Increasing Burden of Atrial Fibrillation through Integrated Care in Primary Care: A Cost-Effectiveness Analysis.

Introduction: Integrated care for patients with atrial fibrillation (AF) in primary care reduced mortality compared to usual care. We assessed the cost-effectiveness of this approach. Methods: Dutch primary care practices were randomised to provide integrated care for AF patients or usual care. A cost-effectiveness analysis was performed from a societal perspective with a 2-year time horizon to estimate incremental costs and Quality Adjusted Life Years (QALYs). A sensitivity analysis was performed, imputing missing questionnaires for a large group of usual care patients. Results: 522 patients from 15 intervention practices were compared to 425 patients from 11 usual care practices. No effect on QALYs was seen, while mean costs indicated a cost reduction between €865 (95% percentile interval (PI) -€5730 to €3641) and €1343 (95% PI -€6534 to €3109) per patient per 2 years. The cost-effectiveness probability ranged between 36% and 54%. In the sensitivity analysis, this increased to 95%-99%. Discussion: Results should be interpreted with caution due to missing information for a large proportion of usual care patients. Conclusion: The higher costs from extra primary care consultations were likely outweighed by cost reductions for other resources, yet this study doesn't give sufficient clarity on the cost-effectiveness of integrated AF care.

Dual hormone fully closed loop in type 1 diabetes: a randomised trial in the Netherlands - study protocol.

INTRODUCTION: The management of type 1 diabetes (T1DM) has undergone significant advancements with the availability of novel technologies, notably continuous and flash glucose monitoring (CGM and FGM, respectively) and hybrid closed loop (HCL) therapy. The dual hormone fully closed loop (DHFCL) approach with insulin and glucagon infusion has shown promising effects in small studies on glycaemic regulation and quality of life in T1DM. METHODS AND ANALYSIS: The Dual Hormone Fully Closed Loop for Type 1 Diabetes (DARE) study is a non-commercial 12-month open-label, two-arm randomised parallel-group trial. The primary aim of this study is to determine the long-term effects on glycaemic control, patient-reported outcome measurements and cost-effectiveness of the DHFCL compared with usual care, that is, HCL or treatment with multiple daily insulin injections+FGM/CGM. We will include 240 adult patients with T1DM in 14 hospitals in the Netherlands. Individuals will be randomised 1:1 to the DHFCL or continuation of their current care. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Medical Research Ethics Committee NedMec, Utrecht, the Netherlands. Findings will be disseminated through peer-reviewed publications and presentations at local, national and international conferences. TRIAL REGISTRATION NUMBER: NCT05669547.

Low dose cisplatin weekly versus high dose cisplatin every three weeks in primary chemoradiotherapy in head and neck cancer patients with low skeletal muscle mass: The CISLOW-study protocol.

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness.

Home telemonitoring versus hospital care in complicated pregnancies in the Netherlands: a randomised, controlled non-inferiority trial (HoTeL).

BACKGROUND: Women with complicated pregnancies often require hospital admission. Telemonitoring at home is a promising alternative that fulfils a worldwide need in obstetric health care. Moreover, the COVID-19 pandemic has accelerated the transformation to digital care. The aim of this study was to evaluate safety, clinical effectiveness, patient satisfaction, and costs of home telemonitoring against hospital care in complicated pregnancies. METHODS: We did a multicentre, randomised, controlled, non-inferiority trial in six hospitals (four general teaching hospitals and two university hospitals) in the Netherlands (located in Utrecht, Amsterdam, and Groningen). Women aged 18 years and older with singleton pregnancies (>26 weeks gestation) requiring monitoring for pre-eclampsia, fetal growth restriction, fetal anomaly, preterm rupture of membranes, reduced fetal movements, or history of fetal death were included in the study. Participants were randomly assigned to either hospital admission or telemonitoring in (1:1), stratified for the six diagnoses for inclusion and the six centres of inclusion, using block randomisation (block sizes of four and six). When assigned to telemonitoring, participants went home with devices for cardiotocography and blood pressure measurements and had daily contact with their care providers after digitally sending their home measurements. When assigned to hospital admission, participants received care as usual on the ward until the postpartum period. The primary outcome was a composite of adverse perinatal outcomes assessed after delivery, including mortality; an Apgar score below 7 after 5 min or an umbilical arterial pH at birth below 7·05; maternal morbidity; admission of the newborn to the neonatal intensive care unit; and rate of caesarean section. The primary outcome was assessed in the intention-to-treat population. The non-inferiority margin for the primary outcome was a 10% absolute increase in composite primary endpoint based on baseline 20% incidence. The study was registered at the Dutch Trial Registration (NL5888) and is now closed to new participants. FINDINGS: From Dec 1, 2016, to Nov 30, 2019, 201 pregnant women were randomly assigned to an intervention procedure. 101 women were allocated to the telemonitoring group and 100 to the hospital admission group. One participant in the telemonitoring group withdrew consent before the intervention was initiated, and 100 participants were analysed for the primary outcome. In the hospital admission group, four participants did not receive the allocated intervention because they did not accept hospital admission. 100 participants in each group were analysed for the primary outcome according to the intention-to-treat principal. No participants were lost to follow-up. The primary outcome occurred in 31 (31%) of 100 participants in the telemonitoring group and in 40 (40%) of 100 participants in the hospital admission group. Adjusted for centre of inclusion, diagnosis, and nulliparity, the risk difference in primary outcome between both groups was 10·3% (95% CI -22·4 to 2·2) lower in the telemonitoring group, below the pre-defined non-inferiority margin of 10% absolute increase. A similar distribution for each of the individual components within the composite primary outcome was seen between groups. Five serious adverse events were reported: one neonatal death in the hospital admission group, in addition to one intra-uterine fetal death, two neonatal deaths, and one case of eclampsia in the telemonitoring group, all unrelated to the study. INTERPRETATION: This non-inferiority trial shows the first evidence that telemonitoring might be as safe as hospital admission for monitoring complicated pregnancies. FUNDING: Stichting Achmea Gezondheidszorg and ICT Healthcare Technology Solutions.

Cost-effectiveness of Laparoscopic vs Open Gastrectomy for Gastric Cancer: An Economic Evaluation Alongside a Randomized Clinical Trial.

Importance: Laparoscopic gastrectomy is rapidly being adopted worldwide as an alternative to open gastrectomy to treat gastric cancer. However, laparoscopic gastrectomy might be more expensive as a result of longer operating times and more expensive surgical materials. To date, the cost-effectiveness of both procedures has not been prospectively evaluated in a randomized clinical trial. Objective: To evaluate the cost-effectiveness of laparoscopic compared with open gastrectomy. Design, Setting, and Participants: In this multicenter randomized clinical trial of patients undergoing total or distal gastrectomy in 10 Dutch tertiary referral centers, cost-effectiveness data were collected alongside a multicenter randomized clinical trial on laparoscopic vs open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). A modified societal perspective and 1-year time horizon were used. Costs were calculated on the individual patient level by using hospital registry data and medical consumption and productivity loss questionnaires. The unit costs of laparoscopic and open gastrectomy were calculated bottom-up. Quality-adjusted life-years (QALYs) were calculated with the EuroQol 5-dimension questionnaire, in which a value of 0 indicates death and 1 indicates perfect health. Missing questionnaire data were imputed with multiple imputation. Bootstrapping was performed to estimate the uncertainty surrounding the cost-effectiveness. The study was conducted from March 17, 2015, to August 20, 2018. Data analyses were performed between September 1, 2020, and November 17, 2021. Interventions: Laparoscopic vs open gastrectomy. Main Outcomes and Measures: Evaluations in this cost-effectiveness analysis included total costs and QALYs. Results: Between 2015 and 2018, 227 patients were included. Mean (SD) age was 67.5 (11.7) years, and 140 were male (61.7%). Unit costs for initial surgery were calculated to be €8124 (US $8087) for laparoscopic total gastrectomy, €7353 (US $7320) for laparoscopic distal gastrectomy, €6584 (US $6554) for open total gastrectomy, and €5893 (US $5866) for open distal gastrectomy. Mean total costs after 1-year follow-up were €26 084 (US $25 965) in the laparoscopic group and €25 332 (US $25 216) in the open group (difference, €752 [US $749; 3.0%]). Mean (SD) QALY contributions during 1 year were 0.665 (0.298) in the laparoscopic group and 0.686 (0.288) in the open group (difference, -0.021). Bootstrapping showed that these differences between treatment groups were relatively small compared with the uncertainty of the analysis. Conclusions and Relevance: Although the laparoscopic gastrectomy itself was more expensive, after 1-year follow-up, results suggest that differences in both total costs and effectiveness were limited between laparoscopic and open gastrectomy. These results support centers' choosing, based on their own preference, whether to (de)implement laparoscopic gastrectomy as an alternative to open gastrectomy.