Using Real-World Data in the Health Technology Assessment of Pharmaceuticals: Strengths, Difficulties, and a Pragmatic Way Forward.

In the past decade, there have been increasing calls for greater use of real-world evidence (RWE) and data (RWD), with the explicit goal of enabling faster provision of effective medicines to patients in need. The push for decision makers to accept RWE is especially noticeable in the pursuit of regulatory approval, but RWE, particularly when used to estimate the relative effectiveness of interventions, is not always readily accepted by agencies responsible for reimbursement and pricing of new pharmaceuticals and, to a varying degree, is not accepted across jurisdictions. This lack of trust hampers the use of RWE despite a very large and growing literature base on the principles of how RWE should be used. In this article, we suggest an important part of the explanation of why this situation has arisen and make suggestions for its alleviation. Given that problems commonly arise that are particular to the question being asked and the data sources being used, general guidance on the principles of how to use RWD cannot cover all eventualities. Therefore, we are suggesting the creation of an archive, or repository, to record uses of RWD in support of decisions by funding bodies or their advisors. This article introduces a proposed, structured classification of decision types using RWE, around which evidence can be assembled in a curated source (RWD/RWE taxonomy) and thus facilitate judgments on when evidence is "good enough." This article is part of a series in a special issue of this journal that looks at the barriers to optimal use of RWE in health technology assessment and how to overcome them. We begin significantly to populate our "taxonomy" with examples in an accompanying article. We also propose recommendations for international standards of evaluating the acceptability of RWD governance practices.

The Real-World Evidence Workstream in EUreccA 2025: How the Task Was Addressed.

This is one of a series of articles that consider the barriers to optimal use of real-world evidence (RWE) in health technology assessment (HTA) as well as ways to overcome them. The work was carried out as part of EUreccA 2025 (European Initiative for New Reimbursement and Access Approaches 2025), in particular with the RWE workstream embodied within that collaboration. The starting premises of this workstream were as follows: (1) the acceptance of RWE by HTA agencies and payers in the assessment of drugs is suboptimal and variable between jurisdictions, and (2) if that were not the case, the path of new pharmaceuticals to patients could be quicker and less expensive. Elsewhere in this issue we set out the conclusions we had reached in the EUreccA RWE workstream. In this article, we set out the methodology used to conduct the totality of the EureccA 2025 RWE workstream effort, which led us to those conclusions. The main results, strengths, and limitations of the individual parts are discussed further in separate articles in this supplement. Through scoping work, we generated 4 key topics within which to identify and address the barriers to optimal RWE use in HTA. Through pragmatic literature searches, stakeholder engagement, and case studies, we suggest ways in which the problems identified may be addressed as a contribution to progress in this area.

Across-Country Variations of Real-World Data and Evidence for Drugs: A 5-European-Country Study.

OBJECTIVES: This study aimed to describe the role of real-world data (RWD) and real-world evidence (RWE) in health technology assessment (HTA) in 5 European countries and to identify the hurdles to the acceptance of RWE and suggest directions toward its more effective use. METHODS: Authors from France, Germany, Italy, and Sweden used a common template to extract evidence. For England, the Cancer Drugs Fund was described and analyzed as a particular model for the use of RWD to provide evidence for coverage decisions and managed entry agreements. RESULTS: In all countries except Germany, HTA bodies acknowledged the relevance of RWD/RWE to address postlaunch uncertainties. In Germany, evidence from randomized controlled trials remains the gold standard, and evidence based on RWD is generally rejected. Multiple sources of RWD exist, but the quality, the immediate relevance of existing sources, and their interoperability limit their adaptation to the specifics of a given drug. This leads to skepticism about the validity of the evidence. Timing is also a key issue: the production of evidence may not be synchronized with the HTA and pricing bodies' agendas. The Cancer Drugs Fund case emphasizes that a strong partnership among all stakeholders and a pragmatic use of existing data, alongside clinical evidence provided by companies, are key success factors. CONCLUSIONS: A continuous investment in national health information systems is a key issue for providing valid RWE. Processes and aids to guide the acceptability and usage of RWE derived from pairing between sources and questions are essential.

Data Governance for Real-World Data Management: A Proposal for a Checklist to Support Decision Making.

OBJECTIVES: Real-world data (RWD) and real-world evidence (RWE) can provide extensive information on healthcare for use in health technology assessment and decision making. Nevertheless, there is a lack of consensus surrounding the appropriate data governance (DG) practices for RWD/RWE. Data sharing is also a large concern, especially considering evolving data protection regulations. Our objective is to propose recommendations for international standards of evaluating the acceptability of RWD governance practices. METHODS: After reviewing the literature, we created a checklist targeting DG practices for RWD/RWE. We then carried out a 3-round Delphi panel, including European policy makers, health technology assessment experts, and hospital managers. The consensus for each statement was measured and the checklist adjusted accordingly. RESULTS: The literature review identified the main topics regarding RWD/RWE DG practices: data privacy and security, data management and linkage, data access management, and the generation and use of RWE. Members of the Delphi panel (21 experts/25 invited) were presented a total of 24 statements related to each of the topics. Experts demonstrated a progressive level of consensus and importance ratings in all topics and to most statements. We suggest a refined checklist in which the statements rated less important or with less consensus have been removed. CONCLUSIONS: This study suggests how the DG of RWD/RWE could be qualitatively evaluated. We propose checklists that could be used by all RWD/RWE users to help ensure the quality and integrity of RWD/RWE governance and complement data protection law.

Structure and Content of a Taxonomy to Support the Use of Real-World Evidence by Health Technology Assessment Practitioners and Healthcare Decision Makers.

This is one of a series of articles that consider the barriers to optimal use of real-world evidence (RWE) in health technology assessment and how to overcome them. The work was performed as part of EUreccA 2025, in particular with the RWE workstream embodied within that collaboration. Elsewhere in this issue we described the reasoning and process that led us to develop practical tools to support RWE use, including this taxonomy and explained the methods used to do so. The taxonomy classifies questions that are typically addressed using real-world data in health technology assessment and the data sources typically used to address these questions. In this article, we describe the taxonomy itself. For as many of the pairings as possible, we have provided links to advice and methods on how to address the associated question using those data. We have also provided links to examples of RWE use in practical decision making to answer the questions posed. Our work is not complete, but we believe it is sufficient to demonstrate the value of such a taxonomy and information source if it is completed and curated as a "wiki" by the community that would use it.

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.

Primary superficial Ewing sarcoma: A unique entity? A case report including novel findings of ELF3 and TNFRSF14 copy number loss.

Primary superficial Ewing sarcoma (psES) cases are exceedingly rare, with fewer than 150 cases reported in the literature. Small case series have suggested differences between psES and Ewing sarcoma (ES) of bone or deep soft tissues: psES appears to have a more indolent course and a higher 5-year overall survival rate. PsES is more common in older adolescent females as opposed to younger males in their peak growth velocity years in bone or deep soft tissue ES. We present a case report of a 17-year-old female with a relatively static nodule on her left thigh for 4 years. Morphologic, immunohistochemical, and molecular evaluations confirmed ES. Patient underwent a gross-total resection and a shortened course of adjuvant chemotherapy without radiation. Cancer gene panel testing found three gene abnormalities (in addition to EWSR1-FLI1 fusion): CCND1 copy number gain, ELF3 copy number loss, and TNFRSF14 copy number loss. To our knowledge, this is the first published case report of psES to include genomic sequencing and the first to report ELF3 and TNFRSF14 abnormalities in ES. Larger series of psES cases with genomic profiling are needed to elucidate a possible genetic etiology for its more indolent clinical course and favorable outcomes.

CD56+ immune cell infiltration and MICA are decreased in breast lobules with fibrocystic changes.

PURPOSE: While the role of natural killer (NK) cells in breast cancer therapy has been investigated, little information is known about NK cell function and presence in nonmalignant and premalignant breast tissue. Here, we investigate and quantify NK cell marker CD56 and activating ligand MICA in breast tissue with benign breast disease. METHODS: Serial tissue sections from 88 subjects, 44 with benign breast disease (BBD) who remained cancer-free, and 44 with BBD who later developed cancer, were stained with H&E, anti-MICA, and anti-CD56. Up to ten representative lobules were identified on each section. Using digital image analysis, MICA and CD56 densities were determined for each lobule, reported as percent of pixels in the lobule that registered as stained by each antibody. Analyses were performed on a per-subject and per-lobule basis. RESULTS: Per-subject multivariate analyses showed associations of CD56 and MICA with age: CD56 was increased in older subjects (p = 0.03), while MICA was increased in younger subjects (p = 0.005). Per-lobule analyses showed that CD56 and MICA levels were both decreased in lobules with fibrocystic change, with median levels of CD56 and MICA staining, respectively, at 0.31 and 7.0% in fibrocystic lobules compared to 0.76 and 12.2% in lobules without fibrocystic change (p < 0.001 for each). Among fibrocystic lobules, proliferative/atypical lobules showed significantly lower expression compared to nonproliferative lobules for MICA (p = 0.02) but not for CD56 (p = 0.80). CONCLUSION: Levels of CD56+ NK cells and activating ligand MICA were decreased in breast lobules with fibrocystic change, and MICA levels showed a significant stepwise decrease with increasing histopathologic abnormality. MICA levels were also significantly decreased in older subjects, who generally have higher risk of developing cancer. These findings advance a model in which MICA promotes cytotoxic activity in CD56+ NK cells to protect against tumorigenesis in breast lobules, and suggest further research is warranted.

CONTRIBUTION OF STAKEHOLDER ENGAGEMENT TO THE IMPACT OF A HEALTH TECHNOLOGY ASSESSMENT: AN IRISH CASE STUDY.

OBJECTIVES: The aim of this study was to illustrate the contribution of stakeholder engagement to the impact of health technology assessment (HTA) using an Irish HTA of a national public access defibrillation (PAD) program. BACKGROUND: In response to draft legislation that proposed a PAD program, the Minister for Health requested that Health Information and Quality Authority undertake an HTA to inform the design and implementation of a national PAD program and the necessary underpinning legislation. The draft legislation outlined a program requiring widespread installation and maintenance of automatic external defibrillators in specified premises. METHODS: Stakeholder engagement to optimize the impact of the HTA included one-to-one interviews with politicians, engagement with an Expert Advisory Group, public and targeted consultation, and positive media management. RESULTS: The HTA quantified the clinical benefits of the proposed PAD program as modest, identified that substantial costs would fall on small/medium businesses at a time of economic recession, and that none of the programs modeled were cost-effective. The Senator who proposed the Bill actively publicized the HTA process and its findings and encouraged participation in the public consultation. Participation of key stakeholders was important for the quality and acceptability of the HTA findings and advice. Media management promoted public engagement and understanding. The Bill did not progress. CONCLUSIONS: The HTA informed the decision not to progress with legislation for a national PAD program. Engagement was tailored to ensure that key stakeholders including politicians and the public were informed of the HTA process, the findings, and the advice, thereby maximizing acceptance. Appropriate stakeholder engagement optimizes the impact of HTA.

Clinical-effectiveness of self-management interventions in chronic obstructive pulmonary disease: An overview of reviews.

Self-management (SM) is defined as the provision of interventions to increase patients' skills and confidence, empowering the individual to take an active part in their disease management. There is uncertainty regarding the optimal format and the short- and long-term benefits of chronic obstructive pulmonary disease (COPD) SM interventions in adults. Therefore, a high-quality overview of reviews was updated to examine their clinical effectiveness. Sixteen reviews were identified, interventions were broadly classified as education or action plans, complex interventions with an SM focus, pulmonary rehabilitation (PR), telehealth and outreach nursing. Systematic review and meta-analysis quality and the risk of bias of underlying primary studies were assessed. Strong evidence was found that PR is associated with significant improvements in health-related quality of life (HRQoL). Limited to moderate evidence for complex interventions (SM focus) with limited evidence for education, action plans, telehealth interventions and outreach nursing for HRQoL was found. There was strong evidence that education is associated with a significant reduction in COPD-related hospital admissions, moderate to strong evidence that telehealth interventions and moderate evidence that complex interventions (SM focus) are associated with reduced health care utilization. These findings from a large body of evidence suggesting that SM, through education or as a component of PR, confers significant health gains in people with COPD in terms of HRQoL. SM supported by telehealth confers significant reductions in healthcare utilization, including hospitalization and emergency department visits.

Accuracy and precision of minimally-invasive cardiac output monitoring in children: a systematic review and meta-analysis.

Several minimally-invasive technologies are available for cardiac output (CO) measurement in children, but the accuracy and precision of these devices have not yet been evaluated in a systematic review and meta-analysis. We conducted a comprehensive search of the medical literature in PubMed, Cochrane Library of Clinical Trials, Scopus, and Web of Science from its inception to June 2014 assessing the accuracy and precision of all minimally-invasive CO monitoring systems used in children when compared with CO monitoring reference methods. Pooled mean bias, standard deviation, and mean percentage error of included studies were calculated using a random-effects model. The inter-study heterogeneity was also assessed using an I(2) statistic. A total of 20 studies (624 patients) were included. The overall random-effects pooled bias, and mean percentage error were 0.13 ± 0.44 l min(-1) and 29.1 %, respectively. Significant inter-study heterogeneity was detected (P < 0.0001, I(2) = 98.3 %). In the sub-analysis regarding the device, electrical cardiometry showed the smallest bias (-0.03 l min(-1)) and lowest percentage error (23.6 %). Significant residual heterogeneity remained after conducting sensitivity and subgroup analyses based on the various study characteristics. By meta-regression analysis, we found no independent effects of study characteristics on weighted mean difference between reference and tested methods. Although the pooled bias was small, the mean pooled percentage error was in the gray zone of clinical applicability. In the sub-group analysis, electrical cardiometry was the device that provided the most accurate measurement. However, a high heterogeneity between studies was found, likely due to a wide range of study characteristics.

Developments in our understanding of the genetic basis of birth defects.

Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects.

Immune cell quantitation in normal breast tissue lobules with and without lobulitis.

While the immune microenvironment has been investigated in breast cancers, little is known about its role in non-malignant breast tissues. Here we quantify and localize cellular immune components in normal breast tissue lobules, with and without visible immune infiltrates (lobulitis). Up to ten representative lobules each in eleven normal breast tissue samples were assessed for B cells (CD20), cytotoxic T cells (CD8), helper T cells (CD4), dendritic cells (CD11c), leukocytes (CD45), and monocytes/macrophages (CD68). Using digital image analysis, immune cell densities were measured and compared between lobules with/without lobulitis. 109 lobules in 11 normal breast tissue samples were evaluated; 31 with lobulitis and 78 without. Immune cells showed consistent patterns in all normal samples, predominantly localized to lobules rather than stroma. Regardless of lobulitis status, most lobules demonstrated CD8+, CD11c+, CD45+, and CD68+ cells, with lower densities of CD4+ and CD20+ cells. Both CD11c+ and CD8+ cells were consistently and intimately associated with the basal aspect of lobule epithelium. Significantly higher densities of CD4+, CD8+, CD20+, and CD45+ cells were observed in lobules with lobulitis. In contrast, densities of monocytes/macrophages and dendritic cells did not vary with lobulitis. In normal breast tissue, myeloid and lymphoid cells are present and localized to lobules, with cytotoxic T and dendritic cells directly integrated with epithelium. Lobules with lobulitis have significantly more adaptive immune (B and T) cells, but no increase in dendritic cells or monocytes/macrophages. These findings indicate an active and dynamic mucosal immune system in normal breast tissue.

Accuracy of continuous noninvasive hemoglobin monitoring: a systematic review and meta-analysis.

BACKGROUND: Noninvasive hemoglobin (Hb) monitoring devices are available in the clinical setting, but their accuracy and precision against central laboratory Hb measurements have not been evaluated in a systematic review and meta-analysis. METHODS: We conducted a comprehensive search of the literature (2005 to August 2013) with PubMed, Web of Science and the Cochrane Library, reviewed references of retrieved articles, and contacted manufactures to identify studies assessing the accuracy of noninvasive Hb monitoring against central laboratory Hb measurements. Two independent reviewers assessed the quality of studies using recommendations for reporting guidelines and quality criteria for method comparison studies. Pooled mean difference and standard deviation (SD) (95% limits of agreement) across studies were calculated using the random-effects model. Heterogeneity was assessed using the I statistic. RESULTS: A total of 32 studies (4425 subjects, median sample size of 44, ranged from 10 to 569 patients per study) were included in this meta-analysis. The overall pooled random-effects mean difference (noninvasive-central laboratory) and SD were 0.10 ± 1.37 g/dL (-2.59 to 2.80 g/dL, I = 95.9% for mean difference and 95.0% for SD). In subgroup analysis, pooled mean difference and SD were 0.39 ± 1.32 g/dL (-2.21 to 2.98 g/dL, I = 93.0%, 71.4%) in 13 studies conducted in the perioperative setting and were -0.51 ± 1.59 g/dL (-3.63 to 2.62 g/dL, I = 83.7%, 96.4%) in 5 studies performed in the intensive care unit setting. CONCLUSIONS: Although the mean difference between noninvasive Hb and central laboratory measurements was small, the wide limits of agreement mean clinicians should be cautious when making clinical decisions based on these devices.

Using prediction intervals from random-effects meta-analyses in an economic model.

OBJECTIVES: When incorporating treatment effect estimates derived from a random-effect meta-analysis it is tempting to use the confidence bounds to determine the potential range of treatment effect. However, prediction intervals reflect the potential effect of a technology rather than the more narrowly defined average treatment effect. Using a case study of robot-assisted radical prostatectomy, this study investigates the impact on a cost-utility analysis of using clinical effectiveness derived from random-effects meta-analyses presented as confidence bounds and prediction intervals, respectively. METHODS: To determine the cost-utility of robot-assisted prostatectomy, an economic model was developed. The clinical effectiveness of robot-assisted surgery compared with open and conventional laparoscopic surgery was estimated using meta-analysis of peer-reviewed publications. Assuming treatment effect would vary across studies due to both sampling variability and differences between surgical teams, random-effects meta-analysis was used to pool effect estimates. RESULTS: Using the confidence bounds approach the mean and median ICER was €24,193 and €26,731/QALY (95%CI: €13,752 to €68,861/QALY), respectively. The prediction interval approach produced an equivalent mean and median ICER of €26,920 and €26,643/QALY (95%CI: -€135,244 to €239,166/QALY), respectively. Using prediction intervals, there is a probability of 0.042 that robot-assisted surgery will result in a net reduction in QALYs. CONCLUSIONS: Using prediction intervals rather than confidence bounds does not affect the point estimate of the treatment effect. In meta-analyses with significant heterogeneity, the use of prediction intervals will produce wider ranges of treatment effect, and hence result in greater uncertainty, but a better reflection of the effect of the technology.

Robot-assisted radical prostatectomy compared with open and laparoscopic approaches: a systematic review and meta-analysis.

Medline and Embase were searched for studies comparing robot-assisted radical prostatectomy with open prostatectomy and conventional laparoscopic prostatectomy. Random effects meta-analysis was used to calculate a pooled estimate of effect. The 95% prediction intervals are also reported. One randomized study and 50 observational studies were identified. The results show that compared with open surgery, robot-assisted surgery is associated with fewer positive surgical margins for pT2 tumors (relative risk 0.63, 95% confidence interval 0.49-0.81, P < 0.001) and improved outcomes for sexual function at 12 months (relative risk 1.60, 95% confidence interval 1.33-1.93, P = <0.001), and, to a lesser extent, urinary function at 12 months (relative risk 1.06, 95% confidence interval 1.02-1.11, P < 0.01). Compared with conventional laparoscopic prostatectomy, robot-assisted surgery is associated with a slight increase in urinary function at 12 months (relative risk 1.09, 95% confidence interval 1.02 to 1.17, P = 0.013). The overall methodological quality of the included studies was low, with high levels of heterogeneity. The use of prediction intervals as an aid to decision making in regard to the introduction of this technology is examined. Clinically significant improvements in positive surgical margins rates for pT2 tumors and sexual function at 12 months associated with robot-assisted surgery in comparison with open surgery should be interpreted with caution given the limitations of the evidence. Differences between robot-assisted and conventional laparoscopic surgery are minimal.

Duloxetine for Postoperative Pain Control Following Knee or Hip Replacement: A Systematic Review and Meta-Analysis.

Background: Duloxetine is a Food and Drug Administration-approved selective norepinephrine reuptake inhibitor for treating depression, anxiety, fibromyalgia, and neuropathic and chronic musculoskeletal pain. This meta-analysis aims to evaluate the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty. Methods: A literature search was performed, identifying randomized controlled trials investigating duloxetine for pain management after total hip and total knee arthroplasty. Data from the visual analog scale (VAS) for pain during movement and at rest were extracted for postoperative days (PODs) 1, 3, 7, and 14, as well as postoperative week 6 and postoperative month 3. Opioid use data were obtained at 24, 48 and 72 hours. All data were analyzed using inverse variance with random effects and presented as weighted mean difference. Results: Eight unique studies were identified and included, 7 of which were analyzed quantitatively. Duloxetine decreased postoperative opioid consumption at 48 and 72 hours. For VAS for pain at rest, significantly reduced pain was reported by duloxetine-treated patients at POD 3, POD 7, and postoperative week 6. For VAS for pain at movement, significantly reduced pain was reported by duloxetine-treated patients at POD1, POD 3, POD 7, POD 14, postoperative week 6, and postoperative month 3. Conclusions: Duloxetine appears to decrease postoperative pain and opioid consumption following total joint arthroplasty. However, definitive conclusions are limited by small sample size and study heterogeneity. While there is a need for follow-up studies to determine the optimal dose, duration, and patient population, strong preliminary data provide robust support for future large-scale efficacy studies.

Cost-effectiveness of prion filtration of red blood cells to reduce the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease in the Republic of Ireland.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a rare, progressive fatal noninflammatory neurodegenerative disease. Ireland has the second highest rate of vCJD in the world with an ongoing risk of vCJD transmission through blood transfusion. Prion-removing filters have been developed to reduce the risk of vCJD transmission. This study aimed to evaluate the cost-effectiveness of implementing a policy of prion filtration of red blood cells (RBCs) in the Republic of Ireland. STUDY DESIGN AND METHODS: A cost-effectiveness model was developed to simulate the likelihood of RBC recipients developing clinical vCJD as a result of being transfused with infected RBCs. Model variables were collected from published literature and expert opinion. Costs were estimated based on the processing changes required to implement prion filtration. RESULTS: In the absence of prion filtration, it is estimated that two individuals will develop clinical vCJD arising from RBC transfusions over a 10-year time horizon. The discounted life-years lost will be 18.5 years. With prion filtration, there will be no deaths or life-years lost. The discounted cost of universal prion filtration is €68.2 million over 10 years with a corresponding incremental cost-effectiveness ratio of €3.7 million per life-year gained. In 25.3% of simulations there were no deaths from vCJD infection through infected blood transfusions, irrespective of prion filtration. CONCLUSION: Prion filtration is considered not cost-effective by traditional measures. Although numerous non-cost-effective blood safety strategies have been implemented in the past, consideration should be given to the most efficient use of finite resources in transfusion medicine.

Prognostic Factors and Outcomes of De Novo Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVE: To review overall survival (OS), recurrence patterns, and prognostic factors of de novo sinonasal squamous cell carcinoma (DN-SCC). DATA SOURCES: PubMed, Scopus, OVID Medline, and Cochrane databases from 2006 to December 23, 2020. REVIEW METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Articles were required to report either recurrence patterns or survival outcomes of adults with DN-SCC. Case reports, books, reviews, meta-analyses, and database studies were all excluded. RESULTS: Forty-one studies reported on survival or recurrence outcomes. The aggregate 5-year OS was 54.5% (range, 18%-75%) from 35 studies (n = 1903). Patients undergoing open surgery were more likely to receive radiation therapy and present at an advanced stage compared to those receiving endoscopic surgery (all P < .001). Advanced T stage, presence of cervical nodal metastases, maxillary sinus primary site, and negative human papillomavirus (HPV) status were all correlated with significantly worse 5-year OS. Direct meta-analysis of 8 studies demonstrated patients with surgery were more likely to be alive at 5 years compared to those who did not receive surgery (odds ratio, 2.26; 95% CI, 1.48-3.47; P < .001). Recurrence was reported in 628 of 1471 patients from 26 studies (42.7%) with an aggregate 5-year locoregional control rate of 67.1% (range, 50.4%-93.3%). CONCLUSION: This systematic review and meta-analysis suggests that the 5-year OS rate for DN-SCC may approach 54.5% and recurrence rate approaches 42.7%. In addition, various tumor characteristics including advanced T stage, positive nodal status, maxillary sinus origin, and negative HPV status are all associated with decreased survival.

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance.

Folate receptor alpha (FRα), encoded by folate receptor 1 (adult) gene, has emerged as a cancer biomarker and potential therapeutic target. In addition, its expression in tumors may offer prognostic information. The aim of this study was to assess the prognostic value of FRα expression and other common molecular markers in resected liver metastases from colorectal cancer. To maximize potential biological differences, we selected two groups of patients with markedly different outcomes as study subjects. Immunohistochemical analysis of FRα expression and other common markers (thymidylate synthase, p53, p27, BCL2, ki67, MLH1, MSH2 and MGMT) on tissue microarrays was carried out on samples from 160 patients; 56 patients survived at least 10 years following liver resection, and 104 died within 2 years of surgery. These markers were evaluated and compared with standard clinical predictors of outcome including a previously validated clinical risk score. Our results showed that in addition to known clinical risk factors, FRα positivity was significantly associated with the early death group (32% compared with 13%; P=0.03). None of the other common molecular markers were differentially expressed between the two groups. On multivariate analysis, clinical risk score, margin status and FRα expression were independently associated with outcome. Specific multivariate comparisons confirmed that FRα expression was associated with outcome independent of the clinical risk score and margin. These data demonstrate that FRα expression is present in a subset of resected hepatic colorectal cancer metastases, and this marker is independently associated with survival after hepatic resection. The prognostic value of FRα expression and the utility of FRα-targeted therapies in stage-IV colorectal cancer patients deserve further exploration.