Editorial Commentary: Evidence for Patch Augmentation of Rotator Cuff Repair Is Weak.

Rotator cuff repair has a substantial failure rate despite various attempts to improve outcome and prevent a retear. Patch augmentation is an intuitively appealing approach to seek to reduce failure rate and improve outcomes for patients. Two main augmentation approaches are used: "on-lay" and "bridging." The literature is heterogeneous, and the best approach is uncertain. The evidence on patch augmentation for rotator cuff repair is both disparate and weak. Large randomized trials and registry data are required to move the field, ensure patient safety, and avoid wasting precious resources.

Cellular characterisation of advanced osteoarthritis knee synovium.

OBJECTIVES: Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores. METHODS: Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected. RESULTS: The proportion of immune cells in OA synovium varied between patients (8-38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45-PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer. CONCLUSIONS: There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.

Serious adverse event rates and reoperation after arthroscopic shoulder surgery: population based cohort study.

OBJECTIVE: To provide clinicians and patients with accurate risk estimates of serious adverse events after common elective shoulder arthroscopic procedures, including reoperation within one year. DESIGN: Population based cohort study. SETTING: Hospital Episode Statistics for NHS England, including civil registration mortality data from the Office for National Statistics. PARTICIPANTS: 288 250 arthroscopic shoulder procedures performed in 261 248 patients aged ≥16 years between 1 April 2009 and 31 March 2017. Elective procedures were grouped into subacromial decompression, rotator cuff repair, acromioclavicular joint excision, glenohumeral stabilisation, and frozen shoulder release. MAIN OUTCOME MEASURES: The primary outcomes were rates of serious adverse events (mortality, pulmonary embolism, pneumonia, myocardial infarction, acute kidney injury, stroke, and urinary tract infection) requiring inpatient care within 90 days post-surgery. Secondary outcomes were specific adverse event rates at 90 days, and reoperations (including for deep infection) within one year. RESULTS: The overall rate of complications within 90 days after arthroscopic shoulder surgery (including reoperation) was low at 1.2% (95% confidence interval 1.2% to 1.3%), with one in 81 patients at risk, and varied according to type of procedure, from 0.6% (0.5% to 0.8%) for glenohumeral stabilisation to 1.7% (1.5% to 1.8%) for frozen shoulder release. After adjustment for age, comorbidities, and sex, no effect of procedure type was observed. Pneumonia was the most common adverse event (0.3%, 0.3% to 0.4%), with one in 303 patients at risk. Pulmonary embolic events were rare, at 0.1% (0.1% to 0.1%), with one in 1428 patients at risk. At one year, the overall rate for reoperation was 3.8% (3.8% to 3.9%), with one in 26 patients at risk, ranging from 2.7% (2.5% to 3.0%) for glenohumeral stabilisation to 5.7% (5.4% to 6.1%) for frozen shoulder release. The overall rate of further surgery for deep infection was low, at 0.1% (0.1% to 0.1%), with one in 1111 patients at risk, but was higher after rotator cuff repair (0.2%, 0.2% to 0.2%), with one in 526 patients at risk. Over the study period the number of arthroscopic shoulder procedures increased, except for subacromial decompression, which decreased. CONCLUSIONS: The findings of this study suggest that risks of serious adverse events associated with common shoulder arthroscopy procedures are low. Nevertheless, serious complications do occur, and include the risk of reoperation in one in 26 patients within one year. STUDY REGISTRATION: Clinical. TRIALS: gov NCT03573765.

Findings from the patch augmented rotator cuff surgery (PARCS) feasibility study.

BACKGROUND: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The patch augmented rotator cuff surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. METHODS: A mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society's (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. RESULTS: The BESS surgeons' survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting. CONCLUSIONS: Randomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.

Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro.

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.

Patch augmentation surgery for rotator cuff repair: the PARCS mixed-methods feasibility study.

BACKGROUND: A rotator cuff tear is a common, disabling shoulder problem. Symptoms may include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a need to improve the outcome of rotator cuff surgery, and the use of patch augmentation (on-lay or bridging) to provide support to the healing process and improve patient outcomes holds promise. Patches have been made using different materials (e.g. human/animal skin or tissue and synthetic materials) and processes (e.g. woven or mesh). OBJECTIVES: The aim of the Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study was to determine the design of a definitive randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. DESIGN: A mixed-methods feasibility study of a randomised controlled trial. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library databases were searched between April 2006 and August 2018. METHODS: The project involved six stages: a systematic review of clinical evidence, a survey of the British Elbow and Shoulder Society's surgical membership, a survey of surgeon triallists, focus groups and interviews with stakeholders, a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. The various stakeholders (including patients, surgeons and industry representatives) were involved in stages 2-6. RESULTS: The systematic review comprised 52 studies; only 15 were comparative and, of these, 11 were observational (search conducted in August 2018). These studies were typically small (median number of participants 26, range 5-152 participants). There was some evidence to support the use of patches, although most comparative studies were at a serious risk of bias. Little to no published clinical evidence was available for a number of patches in clinical use. The membership survey of British Elbow and Shoulder surgeons [105 (21%) responses received] identified a variety of patches in use. Twenty-four surgeons (77%) completed the triallist survey relating to trial design. Four focus groups were conducted, involving 24 stakeholders. Differing views were held on a number of aspects of trial design, including the appropriate patient population (e.g. patient age) to participate. Agreement on the key research questions and the outline of two potential randomised controlled trials were achieved through the Delphi study [29 (67%)] and the consensus meeting that 22 participants attended. LIMITATIONS: The main limitation was that the findings were influenced by the participants, who are not necessarily representative of the views of the relevant stakeholder groups. CONCLUSION: The need for further clinical studies was clear, particularly given the range and number of different patches available. FUTURE WORK: Randomised comparisons of on-lay patch use for completed rotator cuff repairs and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. These elements are included in the trial designs proposed in this study. STUDY REGISTRATION: The systematic review is registered as PROSPERO CRD42017057908. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 13. See the NIHR Journals Library website for further project information.

Shoulder muscles and tendons allow us to move our arms to carry out daily activities, work and play sports. Disease and injury of these tendons can cause significant long-term disability. Early treatment of these tendon problems usually involves painkillers, injections and physiotherapy. However, many patients whose symptoms do not improve may need surgery to repair these tendons. Unfortunately, around 40% of surgical tendon repairs fail within 12 months. As such, these operations need to be improved. A promising approach is to use a patch to support the repair while the tendon heals; this patch is often used in a similar way to a plaster. However, it is not yet clear whether or not using a patch improves patient health and, if so, whether or not it makes enough of a difference to justify the additional cost to the NHS. A scientific study called a randomised controlled trial is needed to fairly assess the value of surgery with a patch in people requiring a tendon repair. This study must be carefully designed so that it is acceptable to patients and surgeons, among others, and feasible to run. We conducted a multistage study to explore whether or not a potential trial design could be achieved. We searched the scientific literature for previous research that had studied using patches for repairing shoulder tendons. We surveyed shoulder surgeons, including those who had previously been involved shoulder randomised controlled trials. We conducted four focus groups with stakeholders. Initial agreement on the best way to run a randomised controlled trial of patches in shoulder surgery was achieved using online questionnaires. Finally, we held a 2-day meeting to scrutinise the study findings and the relevant issues. Two potential studies were recommended, as was the need for closer monitoring of patch safety.

Use of implantable meshes for augmented rotator cuff repair: a systematic review and meta-analysis.

OBJECTIVE: To appraise studies reporting on clinical effectiveness and safety of surgical meshes used to augment rotator cuff repairs (RCRs). DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase and Cochrane databases were searched between April 2006 and April 2020. ELIGIBILITY CRITERIA: All studies evaluating adults (≥18 years) undergoing RCR were considered. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction and quality appraisal were conducted by two independent reviewers. Meta-analysis was conducted using a random-effects models if ≥2 comparative studies reported the same outcome measure. Risk of bias assessment was undertaken for randomised (RoB2, Cochrane) and comparative studies (ROBINS-I, Cochrane). RESULTS: We included 60 studies, consisting of 7 randomised controlled trials, 13 observational comparative studies and 40 observational case series. All comparative studies reported on shoulder-specific functional outcome scores, 18 on the radiographic occurrence of re-tear and 14 on pain score metrics. All studies contained some risk of bias.Compared with non-augmented repair, a small improvement in shoulder-specific function or pain scores was observed for synthetic patches with a mean improvement of 6.7 points on the University of California Los Angles (UCLA) shoulder score (95% CI 0.1 to 13.4) and 0.46 point reduction on the Visual Analogue Scale (95% CI -0.74 to -0.17), respectively. A reduced likelihood of radiologically observed re-tear was observed for synthetic (risk ratio (RR) 0.41, 95% CI 0.27 to 0.61) and allograft (RR 0.34, 95% CI 0.18 to 0.65) patches. A total of 49 studies reported on the occurrence of complications. Slightly higher crude complication rates were observed following patch-augmented repair (2.1%) than standard repair (1.6%). CONCLUSIONS: While several studies suggest a decreased failure rate and small improvements in shoulder function and pain following augmented RCR, a paucity of rigorous clinical evaluation, for both effectiveness and safety, prevents firm recommendations. PROSPERO REGISTRATION NUMBER: CRD42017057908.

Systematic review of the surgical management of rotator cuff repair with an augmentative patch: a feasibility study protocol.

BACKGROUND: Shoulder pain is a common problem in the general population and is responsible for prolonged periods of disability, loss of productivity, absence from work and inability to carry out household activities. Rotator cuff problems account for up to 70% of shoulder pain problems and are the third most prevalent musculoskeletal disorder after those occurring in the lower back and neck. Rotator cuff surgery has high failure rates (25-50% within 12 months), and as a result, there is a pressing need to improve the outcome of rotator cuff surgery. Patch augmented surgery for rotator cuff repairs has recently been developed and is increasingly being used within the UK National Health Service. Patch augmented surgery could lead to a dramatic improvement in patient and surgical outcomes, but its clinical and cost effectiveness needs rigorous evaluation. The existing evidence on the use of patches may be at risk of bias as currently only a small number of single-centre comparative studies appear to have been carried out. Additionally, it is unclear for which patches a clinical study (comparative and non-comparative) has been conducted. This paper outlines the protocol for a systematic review intended to summarise the best available clinical evidence and will indicate what further research is required. METHODS: Electronic databases (Medline, Embase and Cochrane) will be systematically searched between April 2006 and the present day for relevant publications using a specified search strategy, which can be adapted for the use in multiple electronic databases, and inclusion criteria. Screening of both titles and abstracts will be done by two independent reviewers with any discrepancies resolved by a third independent reviewer. Data extraction will include information regarding the type of participants, type of intervention and outcomes including but not limited to shoulder-specific function and pain scores, patch-related adverse events and type of study. The results will be summarised in a narrative review where qualitative analysis is not possible. DISCUSSION: This review aims to collate the current evidence base regarding the use of patches to augment rotator cuff repair. The results of this review will help to develop, using consensus methods, the design of a definitive randomised trial assessing the clinical and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and is feasible. SYSTEMATIC REVIEW REGISTRATION: CRD42017057908.

Validation of the updated ArthroS simulator: face and construct validity of a passive haptic virtual reality simulator with novel performance metrics.

PURPOSE: To assess the construct and face validity of ArthroS, a passive haptic VR simulator. A secondary aim was to evaluate the novel performance metrics produced by this simulator. METHODS: Two groups of 30 participants, each divided into novice, intermediate or expert based on arthroscopic experience, completed three separate tasks on either the knee or shoulder module of the simulator. Performance was recorded using 12 automatically generated performance metrics and video footage of the arthroscopic procedures. The videos were blindly assessed using a validated global rating scale (GRS). Participants completed a survey about the simulator's realism and training utility. RESULTS: This new simulator demonstrated construct validity of its tasks when evaluated against a GRS (p ≤ 0.003 in all cases). Regarding it's automatically generated performance metrics, established outputs such as time taken (p ≤ 0.001) and instrument path length (p ≤ 0.007) also demonstrated good construct validity. However, two-thirds of the proposed 'novel metrics' the simulator reports could not distinguish participants based on arthroscopic experience. Face validity assessment rated the simulator as a realistic and useful tool for trainees, but the passive haptic feedback (a key feature of this simulator) is rated as less realistic. CONCLUSION: The ArthroS simulator has good task construct validity based on established objective outputs, but some of the novel performance metrics could not distinguish between surgical experience. The passive haptic feedback of the simulator also needs improvement. If simulators could offer automated and validated performance feedback, this would facilitate improvements in the delivery of training by allowing trainees to practise and self-assess.

A survey on beliefs and attitudes of trainee surgeons towards placebo.

BACKGROUND: The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons. METHODS: An invitation to participate in an online survey was sent to all the email addresses in the members' database of the British Orthopaedic Trainees Association (BOTA). RESULTS: All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial. CONCLUSIONS: The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity.

Which Global Rating Scale? A Comparison of the ASSET, BAKSSS, and IGARS for the Assessment of Simulated Arthroscopic Skills.

BACKGROUND: With the move to competency-based models of surgical training, a number of assessment methods have been developed. Of these, global rating scales have emerged as popular tools, and several are specific to the assessment of arthroscopic skills. Our aim was to determine which one of a group of commonly used global rating scales demonstrated superiority in the assessment of simulated arthroscopic skills. METHODS: Sixty-three individuals of varying surgical experience performed a number of arthroscopic tasks on a virtual reality simulator (VirtaMed ArthroS). Performance was blindly assessed by two observers using three commonly used global rating scales used to assess simulated skills. Performance was also assessed by validated objective motion analysis. RESULTS: All of the global rating scales demonstrated construct validity, with significant differences between each skill level and each arthroscopic task (p < 0.002, Mann-Whitney U test). Interrater reliability was excellent for each global rating scale. Correlations of global rating scale ratings with motion analysis were high and strong for each global rating scale when correlated with time taken (Spearman rho, -0.95 to -0.76; p < 0.001), and correlation with total path length was significant and moderately strong (Spearman rho, -0.94 to -0.64; p < 0.001). CONCLUSIONS: No single global rating scale demonstrated superiority as an assessment tool. CLINICAL RELEVANCE: For these commonly used arthroscopic global rating scales, none was particularly superior and any one score could therefore be used. Agreement on using a single score seems sensible, and it would seem unnecessary to develop further scales with the same domains for these purposes.

Sacral insufficiency fractures: a case of mistaken identity.

INTRODUCTION: Sacral insufficiency fractures are an important cause of lower back pain in the elderly. Clinically and radiologically, they must be distinguished from osseous metastases, which frequently coexist. To date, no case report has comprehensively explored the full range of diagnostic hurdles and potential pitfalls. CASE PRESENTATION: We report the case of a 70-year-old Caucasian female who presented to our services with a short history of progressive back pain without any history of trauma. A prior history of breast cancer was noted. Bone scintigraphy was initially reported as consistent with metastatic sacral deposits. Further characterization with magnetic resonance imaging and computed tomography revealed bilateral insufficiency fractures of the sacral alar. The patient responded well to conservative management. CONCLUSION: To avoid misdiagnosis, particularly in those who are also at risk of osseous metastases, sacral insufficiency fractures must always be considered as a cause of lower back pain.

The stromal cell antigen CD248 (endosialin) is expressed on naive CD8+ human T cells and regulates proliferation.

CD248 (endosialin) is a transmembrane glycoprotein that is dynamically expressed on pericytes and fibroblasts during tissue development, tumour neovascularization and inflammation. Its role in tissue remodelling is associated with increased stromal cell proliferation and migration. We show that CD248 is also uniquely expressed by human, but not mouse (C57BL/6), CD8(+) naive T cells. CD248 is found only on CD8(+) CCR7(+) CD11a(low) naive T cells and on CD8 single-positive T cells in the thymus. Transfection of the CD248 negative T-cell line MOLT-4 with CD248 cDNA surprisingly reduced cell proliferation. Knock-down of CD248 on naive CD8 T cells increased cell proliferation. These data demonstrate opposing functions for CD248 on haematopoietic (CD8(+)) versus stromal cells and suggests that CD248 helps to maintain naive CD8(+) human T cells in a quiescent state.

Plasma cell-free DNA in ovarian cancer: an independent prognostic biomarker.

BACKGROUND: Cell-free DNA reflects both normal and tumor-derived DNA released into the circulation through cellular necrosis and apoptosis. The authors sought to determine the role of preoperative total plasma cell-free DNA levels in predicting clinical outcome in patients with ovarian cancer. METHODS: After institutional review board consent, DNA was extracted from plasma of 164 women with invasive epithelial ovarian carcinoma (EOC), 49 with benign ovarian neoplasms, and 75 age-matched controls. The samples were randomly divided into training (n = 144) and validation (n = 144) sets. Quantification of cell-free DNA was performed using real-time polymerase chain reaction for beta-globin, and the number of genome equivalents (GE) per milliliter of plasma was determined. Cell-free DNA was correlated with clinicopathologic parameters. RESULTS: The training and validation sets were similar in terms of demographic features. In the training set, EOC patients had a median preoperative cell-free DNA level of 10,113 GE/mL, compared with patients with benign ovarian neoplasms (median, 2365 GE/mL; P < .0001) and controls (median, 1912 GE/mL, P < .0001). Cell-free DNA >22,000 GE/mL was significantly associated with decreased patient survival (P < .001). After adjusting for other clinical variables, preoperative cell-free DNA >22,000 GE/mL was an independent predictor (P = .02) for disease-specific survival. Analysis of the validation set confirmed significantly higher cell-free DNA levels in EOC (median, 13,672 GE/mL) and that cell-free DNA >22,000 GE/mL was associated with a 2.83-fold increased risk of death from disease (P < .001). CONCLUSIONS: Preoperative plasma total cell-free DNA levels are significantly elevated in patients with EOC. Elevated plasma cell-free DNA is an independent predictor for death from disease in ovarian cancer.