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.

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.

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.

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.

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.

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.

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.

Which Applicant Factors Predict Success in Emergency Medicine Training Programs? A Scoping Review.

BACKGROUND: Program directors (PDs) in emergency medicine (EM) receive an abundance of applications for very few residency training spots. It is unclear which selection strategies will yield the most successful residents. Many authors have attempted to determine which items in an applicant's file predict future performance in EM. OBJECTIVES: The purpose of this scoping review is to examine the breadth of evidence related to the predictive value of selection factors for performance in EM residency. METHODS: The authors systematically searched four databases and websites for peer-reviewed and gray literature related to EM admissions published between 1992 and February 2019. Two reviewers screened titles and abstracts for articles that met the inclusion criteria, according to the scoping review study protocol. The authors included studies if they specifically examined selection factors and whether those factors predicted performance in EM residency training in the United States. RESULTS: After screening 23,243 records, the authors selected 60 for full review. From these, the authors selected 15 published manuscripts, one unpublished manuscript, and 11 abstracts for inclusion in the review. These studies examined the United States Medical Licensing Examination (USMLE), Standardized Letters of Evaluation, Medical Student Performance Evaluation, medical school attended, clerkship grades, membership in honor societies, and other less common factors and their association with future EM residency training performance. CONCLUSIONS: The USMLE was the most common factor studied. It unreliably predicts clinical performance, but more reliably predicts performance on licensing examinations. All other factors were less commonly studied and, similar to the USMLE, yielded mixed results.

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.

The Risk of Cancer from CT Scans and Other Sources of Low-Dose Radiation: A Critical Appraisal of Methodologic Quality.

INTRODUCTION: Concern exists that radiation exposure from computerized tomography (CT) will cause thousands of malignancies. Other experts share the same perspective regarding the risk from additional sources of low-dose ionizing radiation, such as the releases from Three Mile Island (1979; Pennsylvania USA) and Fukushima (2011; Okuma, Fukushima Prefecture, Japan) nuclear power plant disasters. If this premise is false, the fear of cancer leading patients and physicians to avoid CT scans and disaster responders to initiate forced evacuations is unfounded. STUDY OBJECTIVE: This investigation provides a quantitative evaluation of the methodologic quality of studies to determine the evidentiary strength supporting or refuting a causal relationship between low-dose radiation and cancer. It will assess the number of higher quality studies that support or question the role of low-dose radiation in oncogenesis. METHODS: This investigation is a systematic, methodologic review of articles published from 1975-2017 examining cancer risk from external low-dose x-ray and gamma radiation, defined as less than 200 millisievert (mSv). Following the PRISMA guidelines, the authors performed a search of the PubMed, Cochrane, Scopus, and Web of Science databases. Methodologies of selected articles were scored using the Newcastle Ottawa Scale (NOS) and a tool identifying 11 lower quality indicators. Manuscript methodologies were ranked as higher quality if they scored no lower than seven out of nine on the NOS and contained no more than two lower quality indicators. Investigators then characterized articles as supporting or not supporting a causal relationship between low-dose radiation and cancer. RESULTS: Investigators identified 4,382 articles for initial review. A total of 62 articles met all inclusion/exclusion criteria and were evaluated in this study. Quantitative evaluation of the manuscripts' methodologic strengths found 25 studies met higher quality criteria while 37 studies met lower quality criteria. Of the 25 studies with higher quality methods, 21 out of 25 did not support cancer induction by low-dose radiation (P = .0003). CONCLUSIONS: A clear preponderance of articles with higher quality methods found no increased risk of cancer from low-dose radiation. The evidence suggests that exposure to multiple CT scans and other sources of low-dose radiation with a cumulative dose up to 100 mSv (approximately 10 scans), and possibly as high as 200 mSv (approximately 20 scans), does not increase cancer risk.

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.

No Reduction in Surgical Site Infection Obtained with Post-Operative Antibiotics in Facial Fractures, Regardless of Duration or Anatomic Location: A Systematic Review and Meta-Analysis.

Background: We performed a systematic review of the literature on antibiotic prophylaxis practices in open reduction, and internal fixation of, facial fracture(s) (ORIFfx). We hypothesized that prolonged antibiotic prophylaxis (PAP) would not decrease the rate of surgical site infections (SSIs). Methods: We performed a systematic review of four databases: PubMed, CENTRAL, EMBase, and Web of Science, from inception through January 15, 2017. Three independent reviewers extracted fracture location (orbital, mid-face, mandible), antibiotic use, SSI incidence, and time from injury to surgery. Mantel-Haenszel and generalized estimating equations were carried out independently for each fracture zone. Results: Of the 587 articles identified, 54 underwent full-text review, yielding 27 studies that met our inclusion criteria. Of these, 16 studies (n = 2,316 patients) provided data for mandible fractures, four studies (n = 439) for mid-face fractures, and six studies (n = 377) for orbital fractures. Pooled analysis of each fracture type's SSI rate showed no statistically significant association with the odds ratio (OR) of developing an SSI. For mandible fractures treated with ORIFfx, the OR for an SSI after 24-72 hours of prophylaxis relative to <24 hours was 0.85 (95% confidence interval [CI] 0.62-1.17), whereas for >72 hours compared with <24 hours, the OR was 1.42 (95% CI) 0.96-2.11). For mid-face fractures, there was no improvement in SSI rate from PAP (OR 1.05; 95% CI 0.20-5.63). Conclusions: We did not demonstrate a lower rate of SSI associated with PAP for any ORIFfx repair. Post-operative antibiotics for >72 hours paradoxically may increase the SSI risk after mandible fracture repairs.

Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis.

OBJECTIVES: Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages. METHODS: First, we undertook to examine whether the folate receptor beta (FR-ß) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-ß monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis. RESULTS: Human tissue samples of rheumatoid arthritis, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-ß, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-ß accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-ß-positive macrophages upon treatment with an anti-FR-ß monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions. CONCLUSIONS: These data suggest that specific elimination of FR-ß-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-ß monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages.

Relation of Patent Foramen Ovale to Acute Mountain Sickness.

Over 50% of patients who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some patients are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (∼3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and 2-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15 of 24 (63%) compared with hikers without AMS 44 of 113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: odds ratio 4.15, 95% confidence intervals 1.14 to 15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in patients who plan to hike to high altitudes.

Scholarship in Emergency Medicine: A Primer for Junior Academics Part I: Writing and Publishing.

The landscape of scholarly writing, publishing, and university promotion can be complex and challenging. Mentorship may be limited. To be successful it is important to understand the key components of writing and publishing. In this article, we provide expert consensus recommendations on four key challenges faced by junior faculty: writing the paper; selecting contributors and the importance of authorship order; journal selection and indexing; and responding to critiques. After reviewing this paper, the reader should have an enhanced understanding of these challenges and strategies to successfully address them.

Measuring Scholarly Productivity: A Primer for Junior Faculty. Part III: Understanding Publication Metrics.

There are approximately 78 indexed journals in the specialty of emergency medicine (EM), making it challenging to determine which is the best option for junior faculty. This paper is the final component of a three-part series focused on guiding junior faculty to enhance their scholarly productivity. As an EM junior faculty's research career advances, the bibliometric tools and resources detailed in this paper should be considered when developing a publication submission strategy. The tenure and promotion decision process in many universities relies at least in part on these types of bibliometrics. This paper provides an understanding of new, alternative metrics that can be used to promote scientific progress in a transparent and timely manner.

Scholarship in Emergency Medicine: A Primer for Junior Academics: Part II: Promoting Your Career and Achieving Your Goals.

Scholarship is an important component of success for academic emergency physicians. Scholarship can take many forms, but all require careful planning. In this article, we provide expert consensus recommendations for improving junior faculty's scholarship in emergency medicine (EM). Specific focus is given to promoting your research career, obtaining additional training opportunities, networking in EM, and other strategies for strategically directing a long-term career in academic medicine.

Screening emergency department patients for opioid drug use: A qualitative systematic review.

INTRODUCTION: The opioid drug epidemic is a major public health concern and an economic burden in the United States. The purpose of this systematic review is to assess the reliability and validity of screening instruments used in emergency medicine settings to detect opioid use in patients and to assess psychometric data for each screening instrument. METHODS: PubMed/MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov were searched for articles published up to May 2018. The extracted articles were independently screened for eligibility by two reviewers. We extracted 1555 articles for initial screening and 95 articles were assessed for full-text eligibility. Six articles were extracted from the full-text assessment. RESULTS: Six instruments were identified from the final article list: Screener and Opioid Assessment for Patients with Pain - Revised; Drug Abuse Screening Test; Opioid Risk Tool; Current Opioid Misuse Measure; an Emergency Medicine Providers Clinician Assessment Questionnaire; and an Emergency Provider Impression Data Collection Form. Screening instrument characteristics, and reliability and validity data were extracted from the six studies. A meta-analysis was not conducted due to heterogeneity between the studies. CONCLUSIONS: There is a lack of validity and reliability evidence in all six articles; and sensitivity, specificity and predictive values varied between the different instruments. These instruments cannot be validated for use in emergency medicine settings. There is no clear evidence to state which screening instruments are appropriate for use in detecting opioid use disorders in emergency medicine patients. There is a need for brief, reliable, valid and feasible opioid use screening instruments in the emergency medicine setting.

Assessment of folate receptor alpha and beta expression in selection of lung and pancreatic cancer patients for receptor targeted therapies.

A number of folate receptor (FR) targeted small molecular drugs and monoclonal antibodies have been introduced into clinical trials to treat FR positive cancers. Because the therapeutic efficacy of these drugs depends prominently on the level of FR-α expression on the cancer cells, patients have been commonly selected for FR-targeted therapies based on the intensity of a folate-targeted radioimaging agent. Unfortunately, uptake of such imaging agents can be mediated by both major isoforms of the folate receptor, FR-α and FR-ß. Logically, if the FR positive cell population in a tumor mass is dominated by FR-ß positive macrophages, patients could be selected for therapy that have few FR-expressing cancer cells. Although several IHC studies have examined expression of either FR-α or FR-ß, no study to date has investigated expression of both FR-α and FR-ß in the same tumor mass. Herein, we utilize monoclonal antibodies specific for FR-α (mAb343) and FR-ß (m909) to query each isoform's expression in a range of cancers. We show that lung and pancreatic adenocarcinomas express the full spectrum of FR-α and FR-ß combinations with ~76% of lung adenocarcinomas expressing both FR-α and FR-ß while pancreatic cancers express primarily FR-ß. Thus, while folate-targeted imaging of lung cancer patients might accurately reflect the expression of FR-α on lung cancer cells, imaging of pancreatic cancer patients could mislead a physician into treating a nonresponding patient. Overall, these data suggest that an independent analysis of both FR-α and FR-ß should be obtained to predict the potential efficacy of a folate-targeted drug.

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.