The tumour-derived extracellular vesicle proteome varies by endometrial cancer histology and is confounded by an obesogenic environment.

Endometrial cancer, the most common gynaecological cancer worldwide, is closely linked to obesity and metabolic diseases, particularly in younger women. New circulating biomarkers have the potential to improve diagnosis and treatment selections, which could significantly improve outcomes. Our approach focuses on extracellular vesicle (EV) biomarker discovery by directly profiling the proteome of EVs enriched from frozen biobanked endometrial tumours. We analysed nine tissue samples to compare three clinical subgroups-low BMI (Body Mass Index) Endometrioid, high BMI Endometrioid, and Serous (any BMI)-identifying proteins related to histological subtype, BMI, and shared secreted proteins. Using collagenase digestion and size exclusion chromatography, we successfully enriched generous quantities of EVs (range 204.8-1291.0 µg protein: 1.38 × 1011-1.10 × 1012 particles), characterised by their size (∼150 nm), expression of EV markers (CD63/81), and proposed endometrial cancer markers (L1CAM, ANXA2). Mass spectrometry-based proteomic profiling identified 2075 proteins present in at least one of the 18 samples. Compared to cell lysates, EVs were successfully depleted for mitochondrial and blood proteins and enriched for common EV markers and large secreted proteins. Further analysis highlighted significant differences in EV protein profiles between the high BMI subgroup and others, underlining the impact of comorbidities on the EV secretome. Interestingly, proteins differentially abundant in tissue subgroups were largely not also differential in matched EVs. This research identified secreted proteins known to be involved in endometrial cancer pathophysiology and proposed novel diagnostic biomarkers (EIF6, MUC16, PROM1, SLC26A2).

Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification.

BACKGROUND: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis. OBJECTIVE: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers. DESIGN: Prospective observational cohort study. SETTING: Single-center, Leeds, United Kingdom. PARTICIPANTS: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred. MEASUREMENTS: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done. RESULTS: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years. LIMITATIONS: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability. CONCLUSION: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Leeds Biomedical Research Centre.

Mucinous ovarian carcinoma: A survey of practice in Australia and New Zealand.

BACKGROUND: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer with limited evidence to support clinical care. AIMS: We undertook a clinician survey to better understand current practice in treating MOC in Australia and New Zealand, and to determine any features associated with variation in care. In addition, we aimed to understand future research priorities. METHODS: A RedCap survey was distributed to clinician members of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Questions included respondent demographics, three case studies and future research priorities. Clinicians were asked questions specific to their speciality. RESULTS: Respondents (n = 47) were commonly experienced gynae-oncology specialists, most often surgical (38%) or medical (30%) oncologists. There was good consensus for surgical approaches for stage I disease; however, variation in practice was noted for advanced or recurrent MOC. Variation was also observed for medical oncologists; in early-stage disease there was no clear consensus on whether to offer chemotherapy, or which regimen to recommend. For advanced and recurrent disease a wide range of chemotherapy options was considered, with a trend away from an ovarian-type toward gastrointestinal (GI)-type regimens in advanced MOC. This practice was reflected in future research priorities, with 'Is a GI chemotherapy regimen better than an ovarian regimen?' the most highly ranked option, followed by 'Should stage 1C patients receive chemotherapy?' CONCLUSIONS: Although the number of respondents limited the analyses, it was clear that chemotherapy selection was a key point of divergence for medical oncologists. Future research is needed to establish well-evidenced guidelines for clinical care of MOC.

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-expansion stage of a multicentre, open-label, phase I trial.

BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Biomarkers During Recovery From AKI and Prediction of Long-term Reductions in Estimated GFR.

RATIONALE & OBJECTIVE: The effects of acute kidney injury (AKI) on long-term kidney function, cardiovascular disease, and mortality are well documented. We aimed to identify biomarkers for the estimation of risk of new or worsening chronic kidney disease (CKD) following AKI. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults from a single clinical center who experienced AKI between May 2013 and May 2016 and survived until 3 years after the hospitalization during which AKI occurred. Participants included those with and without preexisting CKD. PREDICTORS: Panel of 11 plasma biomarkers measured 3 months after hospitalization. OUTCOME: Kidney disease progression, defined as a≥25% decrease in estimated glomerular filtration rate (eGFR) combined with worsening CKD stage, assessed 3 years after the occurrence of AKI. ANALYTICAL APPROACH: Associations between biomarkers and kidney disease progression were evaluated in multivariable logistic regression models. Importance of predictor variables was assessed by constructing multiple decision trees, with penalized least absolute shrinkage and selection operator logistic regression for variable selection used to produce multivariable models. RESULTS: A total of 500 patients were studied. Soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, cystatin C, neutrophil gelatinase-associated lipocalin, 3-month eGFR, and urinary albumin-creatinine ratio were independently associated with kidney disease progression and were more important than AKI severity or duration. A multivariable model containing sTNFR1, sTNFR2, cystatin C, and eGFR discriminated between those with and without kidney disease progression (area under the curve, 0.79 [95% CI, 0.70-0.83]). Optimizing the cutoff point to maximize utility as a "rule-out" test to identify those at low risk increased the sensitivity of the model to 95% and its negative predictive value to 92%. LIMITATIONS: Lack of external validation cohort. Analyses limited to patients who survived for 3 years after AKI. Mixed population of patients with and without baseline CKD. CONCLUSIONS: A panel of plasma biomarkers measured 3 months after discharge from a hospitalization complicated by AKI provides a potential opportunity to identify patients who are at very low risk of incident or worsening CKD. Further study is required to determine its clinical utility through independent prospective validation.

Interobserver and intraobserver variability of RECIST assessment in ovarian cancer.

OBJECTIVES: Measurement of Response Evaluation Criteria In Solid Tumors (RECIST) relies on reproducible unidimensional tumor measurements. This study assessed intraobserver and interobserver variability of target lesion selection and measurement, according to RECIST version 1.1 in patients with ovarian cancer. METHODS: Eight international radiologists independently viewed 47 images demonstrating malignant lesions in patients with ovarian cancer and selected and measured lesions according to RECIST V.1.1 criteria. Thirteen images were viewed twice. Interobserver variability of selection and measurement were calculated for all images. Intraobserver variability of selection and measurement were calculated for images viewed twice. Lesions were classified according to their anatomical site as pulmonary, hepatic, pelvic mass, peritoneal, lymph nodal, or other. Lesion selection variability was assessed by calculating the reproducibility rate. Lesion measurement variability was assessed with the intra-class correlation coefficient. RESULTS: From 47 images, 82 distinct lesions were identified. For lesion selection, the interobserver and intraobserver reproducibility rates were high, at 0.91 and 0.93, respectively. Interobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass and other lesions. Intraobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass, hepatic, nodal, and other lesions. Selection reproducibility was lowest for peritoneal lesions (interobserver reproducibility rate 0.76 and intraobserver reproducibility rate 0.69). For lesion measurement, the overall interobserver and intraobserver intraclass correlation coefficients showed very good concordance of 0.84 and 0.94, respectively. Interobserver intraclass correlation coefficient showed very good concordance for hepatic, pulmonary, peritoneal, and other lesions, and ranged from 0.84 to 0.97, but only moderate concordance for lymph node lesions (0.58). Intraobserver intraclass correlation coefficient showed very good concordance for all lesions, ranging from 0.82 to 0.99. In total, 85% of total measurement variability resulted from interobserver measurement difference. CONCLUSIONS: Our study showed that while selection and measurement concordance were high, there was significant interobserver and intraobserver variability. Most resulted from interobserver variability. Compared with other lesions, peritoneal lesions had the lowest selection reproducibility, and lymph node lesions had the lowest measurement concordance. These factors need consideration to improve response assessment, especially as progression free survival remains the most common endpoint in phase III trials.

Research biopsies in patients with gynecologic cancers: patient-reported outcomes, perceptions, and preferences.

BACKGROUND: Despite the growing integration of mandatory biopsies for correlative endpoints within oncology clinical trials, there are sparse data on patient-reported outcomes, perceptions, and preferences. OBJECTIVE: This study aimed to prospectively assess the impact of research biopsies on the quality of life in patients with gynecologic cancer, evaluate patient-reported outcomes, and determine factors associated with patients' willingness to undergo sequential biopsies. STUDY DESIGN: We conducted a prospective study in patients with gynecologic malignancies undergoing research biopsies between 2015 and 2019 at Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02334761). Here, we report the results of the paper-based surveys performed before and 1 week after biopsy. Although the questionnaires each assessed the impact of anxiety using a modified version of the Hospital Anxiety and Depression Scale, the postbiopsy questionnaire specifically assessed the likelihood of future biopsies, postbiopsy symptoms, complications, and perceptions. RESULTS: A total of 129 patients were enrolled, of which 91 (70.5%) completed at least 1 questionnaire. These patients had either ovarian (89%; 81 of 91) or endometrial cancer (11%; 10 of 91). Of all biopsies taken, 75% were from the abdomen or pelvis (67 of 89). There was 1 clinician-reported complication, a perihepatic hematoma (1%). Pain during the biopsy and physical discomfort were experienced by 60.3% (41 of 68) and 61.8% (42 of 68), respectively. Embarrassment and loss of dignity were experienced by 13.2% (9 of 68) and 11.8% (8 of 68), respectively. Although the mean Hospital Anxiety and Depression Scale score was in the normal range before and after biopsy, there was a significant decline in the total score after the biopsy (prebiopsy, 5.3 [standard deviation, 4.7] vs postbiopsy, 3.7 [standard deviation, 4.5]; P=.005); 84% of subjects (58 of 69) stated that they would definitely or likely consent to another biopsy. There was no impact on patients' willingness for future biopsies based on Eastern Cooperative Oncology Group status, biopsy site, age, number of cores, and pain during the biopsy; however, subjects who reported feeling physically uncomfortable (odds ratio, 0.14; P=.005), embarrassed (odds ratio, 0.03; P=.004) or experienced loss of dignity (odds ratio, 0.05; P=.01) during the biopsy and those who experienced flu-like symptoms (odds ratio, 0.2; P=.018) or felt feverish (odds ratio, 0.2; P=.035) 1 week after biopsy, were less likely to undergo a sequential biopsy. Similarly, those with higher Hospital Anxiety and Depression Scale scores before biopsy (odds ratio, 0.83; P=.008) and after biopsy (odds ratio, 0.8; P=.003) were less likely to consent for another biopsy. CONCLUSION: Research biopsies were generally well accepted. Most patients (83%) were willing to undergo serial biopsies if necessary. Addressing the potentially modifiable psychosocial aspects of the procedure may improve the experience with research biopsies for patients with gynecologic cancers.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective, multicentre cross-sectional study of prevalence, nature and anaesthetists' approach to management.

BACKGROUND: We sought to define the prevalence and nature of patient-reported drug allergies, determine their impact on prescribing, and explore drug allergy knowledge and attitudes amongst anaesthetists. METHODS: We performed a prospective cross-sectional study in 213 UK hospitals in 2018. Elective surgical patients were interviewed, with a detailed allergy history taken in those self-reporting drug allergy. Anaesthetists completed a questionnaire concerning perioperative drug allergy. RESULTS: Of 21 219 patients included, 6214 (29.3 %) (95% confidence interval [CI]: 28.7-29.9) reported drug allergy. Antibiotics, NSAIDs, and opioids were the most frequently implicated agents. Of a total of 8755 reactions, 2462 (28.1%) (95% CI: 29.2-31.1) were categorised as high risk for representing genuine allergy after risk stratification. A history suggestive of chronic spontaneous urticaria significantly increased the risk of reporting drug allergy (odds ratio 2.68; 95% CI: 2.4-3; P<0.01). Of 4756 anaesthetists completing the questionnaire, 1473 (31%) (95% CI: 29.7-32.3) routinely discuss perioperative allergy risk with patients. Prescribing habits in the presence of drug allergy labels differ depending on the implicated agent. Most anaesthetists (4678/4697; 99.6%) (95% CI: 99.4-99.8) prescribe opioids when reactions are consistent with side-effects, although 2269/4697 (48%) (95% CI: 46.9-49.7) would avoid the specific opioid reported. CONCLUSIONS: Almost 30% of UK elective surgical patients report a history of drug allergies, but the majority of reported reactions are likely to be non-allergic reactions. Allergy labels can impact on perioperative prescribing through avoidance of important drugs and use of less effective alternatives. We highlight important knowledge gaps about drug allergy amongst anaesthetists, and the need for improved education around allergy.

ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer.

BACKGROUND: The optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population. PRIMARY OBJECTIVES: In women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA-MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)-blocking monoclonal antibody) versus rucaparib alone (ATHENA-COMBO). STUDY HYPOTHESIS: (1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone. TRIAL DESIGN: ATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA-MONO and ATHENA-COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA-MONO compares arm B with arm D to evaluate rucaparib monotherapy versus placebo, and ATHENA-COMBO evaluates arm A versus arm B to investigate the effects of rucaparib and nivolumab in combination versus rucaparib monotherapy. ATHENA-MONO and ATHENA-COMBO share a common treatment arm (arm B) but each comparison is independently powered. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients ≥18 years of age with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response after completion of cytoreductive surgery and initial platinum-based chemotherapy are enrolled. No other prior treatment for ovarian cancer, other than the frontline platinum regimen, is permitted. PRIMARY ENDPOINT: The primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1. SAMPLE SIZE: Approximately 1000 patients have been enrolled and randomized. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial completed accrual in 2020. While dependent on event rates, primary results of ATHENA-MONO are anticipated in early 2022 and results of ATHENA-COMBO are anticipated to mature at a later date. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (NCT03522246).

Occupational silica exposure in an Australian systemic sclerosis cohort.

OBJECTIVE: To determine the frequency of self-reported occupational exposure to silica in SSc patients enrolled in the Australian Scleroderma Cohort Study, and to compare the disease characteristics of the silica-exposed patients with those of the non-exposed patients. METHOD: Data collected over a 12-year period from 1670 SSc patients were analysed. We compared the demographic and clinical characteristics of those who reported occupational silica exposure with those who did not. A subgroup analysis of male patients was performed, as well as a multivariable analysis of correlates of silica exposure. RESULTS: Overall, 126 (7.5%) of the cohort reported occupational silica exposure. These individuals were more likely to be male (73 of 231, i.e. 31.6% males exposed) and to have worked in mining and construction industries. Those who reported silica exposure were younger at the onset of SSc skin involvement [odds ratio (OR) 0.9, P = 0.02], of male gender (OR 14.9, P < 0.001), have joint contractures (OR 1.8, P = 0.05) and have higher physical disability as defined by scleroderma HAQ (OR 1.4, P = 0.01). CONCLUSION: The highest percentage of silica exposure was found in males. These patients were more likely to have the presence of certain clinical manifestations and Scl-70 antibody, which is known to confer a poor prognosis. These findings support the association between occupational silica exposure and the subsequent development of SSc. Further investigation is required to describe the range of clinical manifestations and disease course, including prognosis and treatment response, in those diagnosed with occupationally induced SSc compared with idiopathic SSc.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective multicentre cross-sectional study of incidence, risks, and attitudes in penicillin de-labelling strategies.

BACKGROUND: Penicillin allergy is associated with a range of poor health outcomes. Allergy testing can be made simpler by using a direct drug provocation test in patients at low risk of genuine allergy. This approach could allow population-level 'de-labelling'. We sought to determine the incidence and nature of penicillin allergy labels in UK surgical patients and define patient and anaesthetist attitudes towards penicillin allergy testing. METHODS: A prospective cross-sectional questionnaire study was performed in 213 UK hospitals. 'Penicillin allergic' patients were interviewed and risk-stratified. Knowledge and attitudes around penicillin allergy were defined in patients and anaesthetists. RESULTS: Of 21 219 patients, 12% (n=2626) self-reported penicillin allergy; 27% reported low-risk histories potentially suitable for a direct drug provocation test; an additional 40% reported symptoms potentially suitable for a direct drug provocation test after more detailed assessment. Of 4798 anaesthetists, 40% claimed to administer penicillin routinely when they judged the label low risk. Only 47% of anaesthetists would be happy to administer penicillin to a patient previously de-labelled by an allergy specialist using a direct drug provocation test; perceived lack of support was the most common reason for not doing so. CONCLUSIONS: At least 27% of patients with a penicillin allergy label may be suitable for a direct drug provocation test. Anaesthetists demonstrated potentially unsafe prescribing in patients with penicillin allergy labels. More than half of anaesthetists lack confidence in the results of a direct drug provocation tests undertaken by a specialist. Our findings highlight significant barriers to the effective implementation of widespread de-labelling in surgical patients.

Repurposing Clinical Decision Support System Data to Measure Dosing Errors and Clinician-Level Quality of Care.

We aimed to develop and validate an instrument to detect hospital medication prescribing errors using repurposed clinical decision support system data. Despite significant efforts to eliminate medication prescribing errors, these events remain common in hospitals. Data from clinical decision support systems have not been used to identify prescribing errors as an instrument for physician-level performance. We evaluated medication order alerts generated by a knowledge-based electronic prescribing system occurring in one large academic medical center's acute care facilities for patient encounters between 2009 and 2012. We developed and validated an instrument to detect medication prescribing errors through a clinical expert panel consensus process to assess physician quality of care. Six medication prescribing alert categories were evaluated for inclusion, one of which - dose - was included in the algorithm to detect prescribing errors. The instrument was 93% sensitive (recall), 51% specific, 40% precise, 62% accurate, with an F1 score of 55%, positive predictive value of 96%, and a negative predictive value of 32%. Using repurposed electronic prescribing system data, dose alert overrides can be used to systematically detect medication prescribing errors occurring in an inpatient setting with high sensitivity.

Trials with proxy-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

AIMS: A proxy is someone other than a patient who reports a patient's outcomes as if they are the patient. Due to known discordance with patient reports, proxies are often not recommended in clinical trials; however, proxies may be needed in certain research contexts. We aimed to identify and describe trials registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) with proxy-reported endpoints. METHODS: ANZCTR was systematically searched from inception (2005) to 31 March 2017 for trials with proxy-reported endpoints. Primary and secondary endpoints for each trial retrieved by the search were individually coded (proxy-reported: yes/no), and trials with confirmed proxy-reported endpoints were included in the analysis. RESULTS: Of 13,666 registered trials, 469 (3.4%) included a proxy-reported endpoint (867 individual proxy-reported endpoints in total: 62% family member proxy, 22% health professional). Proxy endpoint inclusion did not significantly increase over time (r = 0.18, p = 0.59). Mental health (11.5%), stroke (10.3%) and neurological (8.3%) trials had the highest proportion of trials using proxies. Of the 469 trials, 123 (26.2%) studies involved paediatric patients. DISCUSSION: Proxy-reported endpoints are included in a small but notable number of studies, which may indicate other types of outcomes are used for patients unable to self-report, or that these patients are under-researched.

A Systematic Review of Health-Related Quality of Life Reporting in Ovarian Cancer Phase III Clinical Trials: Room to Improve.

BACKGROUND: Epithelial ovarian cancer (OC) remains a significant cause of morbidity and mortality for women worldwide. Patients may experience a multitude of disease- and treatment-related symptoms that can impact quality of life (QOL) and should be measured and reported in clinical trials. This systematic review investigated the adequacy of reporting of QOL in randomized phase III trials in OC in both the first-line and recurrent disease setting. MATERIALS AND METHODS: A systematic review of MEDLINE and EMBASE identified randomized clinical trials of systemic therapy in OC from 1980 to 2014. The adequacy of reporting QOL was evaluated with respect to adherence to established guidelines on reporting QOL in clinical trials and the recent recommendations on the inclusion of patient-reported outcomes in clinical trials from the Fifth Ovarian Cancer Consensus Conference. RESULTS: Of 3,247 abstracts, 35 studies, including 24,664 patients, met inclusion criteria. Twenty-two trials (63%) were in the first-line setting, with 13 (37%) in the recurrent setting. The inclusion of QOL assessments increased from 2% (1980s) to 62% (2010+). Quality of life was a co-primary endpoint in only one trial.Minimal clinically important differences in QOL were defined in eight trials (23%), with results included in the abstract in 37% and article in 86%. Compliance was reported in 26 trials (74%), with 13 trials (37%) reporting specifically how they dealt with missing data. Only seven trials reported the reasons for missing data (20%).Group results were published in 29 trials (83%), with 6 (17%) reporting individual patient results. Results were more commonly reported as a mean overall score (21 trials; 60%), with specific domain scores in only 9 trials (26%). No studies reported QOL beyond progression or included predefined context-specific endpoints based on objectives of treatment (i.e., palliation/cure/maintenance) and the patient population. Duration of benefit of palliative chemotherapy was reported in only one study. CONCLUSION: Inclusion and reporting of QOL as a trial endpoint has improved in phase III trials in OC, but there are still significant shortfalls that need to be addressed in future trials. IMPLICATIONS FOR PRACTICE: The impact of treatment on quality of life (QOL) is an important consideration in patients with ovarian cancer for whom treatment is often given with palliative intent. Both the disease and treatment impact a patient's QOL and require careful evaluation in clinical trials. Matching the QOL questions to the patient population of interest is critical. Similar rigor to that used to assess progression-based endpoints is essential to guide clinical decisions. This systematic review demonstrated that although the inclusion and reporting of QOL as a trial endpoint has improved in phase III trials there are still significant shortfalls that need to be addressed in future trials.

The role of inflammatory markers in assessment of disease activity in systemic sclerosis.

OBJECTIVES: The role of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the assessment of disease activity in systemic sclerosis (SSc) remains controversial. We sought to evaluate the relationship between clinical features of SSc and raised inflammatory markers and to determine if changes in ESR and CRP reflect changes in other disease features over time. METHODS: One thousand, five hundred and forty-five patients enrolled in the Australian Scleroderma Cohort Study were observed over a mean 3.52±2.91 years and assessed at 6,119 study visits. Generalised estimating equations were used to determine the relationship between ESR≥20mm/hr and CRP≥5mg/L and features of disease. The associations between change in inflammatory markers and change in skin scores and respiratory function tests were analysed. RESULTS: Overall, there was a significant association between raised ESR and forced vital capacity (FVC)<80% predicted, diffusing capacity of the lung (DLCO)<80% predicted, pulmonary arterial hypertension (PAH), body mass index (BMI), proximal muscle strength, anaemia, and hypocomplementaemia (p<0.05). Raised CRP was significantly associated with modified Rodnan Skin Score>20, FVC<80%, DLCO<80%, PAH, digital ulcers, BMI, synovitis, tendon friction rub, anaemia, and hypocomplementaemia (p<0.05). A significant deterioration in respiratory function tests (RFTs) was associated with a 2-fold increase in both ESR and CRP (p<0.05). CONCLUSIONS: Raised inflammatory markers are associated with pulmonary, cutaneous and musculoskeletal manifestations of SSc. Rising inflammatory markers are correlated with declining respiratory function tests. This suggests inflammatory markers have a role in the assessment of SSc disease activity.

Switching From Originator to Biosimilar Infliximab in Paediatric Inflammatory Bowel Disease Is Feasible and Uneventful.

The safety, clinical efficacy, and cost-effectiveness of biosimilar infliximab in adult inflammatory bowel disease (IBD) have now been extensively shown. Limited data have been collected in the paediatric setting. We report nationwide, prospective, clinical safety and effectiveness data for patients from all 3 Scottish paediatric inflammatory bowel disease networks switching from originator to biosimilar infliximab. Prospective clinical data were collected for 33 patients. Information was collected from electronic patient records, laboratory reports, and patient case notes. There were no clinically significant changes to disease activity, biomarkers, antidrug antibodies, or trough drug levels (P > 0.1) within a 12-month follow-up period; in addition, there were no significant adverse events reported. No infusion reactions were seen in the 264 infusions delivered. Switching from originator infliximab to the biosimilar (CT-P13) appears to be associated with neither an increase in infusion reactions nor significant loss of effectiveness in the short term.

Trials with patient-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

AIMS: It is important to understand the number, types and regions of trials that include patient-reported outcomes (PROs) to appreciate how patient experiences have been considered in studies of health and interventions. Twenty-seven percent of trials registered with ClinicalTrials.gov (2007-2013) included PROs; however, a regional breakdown was not provided and no reviews have been conducted of the Australia New Zealand Clinical Trials Registry (ANZCTR). We aimed to identify trials registered with ANZCTR with PRO endpoints and describe their characteristics. METHODS: ANZCTR was systematically searched from inception (2005) to 31 March 2017 for trials with PRO endpoints. Search terms included PRO measures listed in Patient-Reported Outcomes Quality of Life Instrument Database and Grid-Enabled Measures, as well as generic PRO terms (e.g. "quality of life" (QOL)). Trial endpoints were individually coded using an established framework to identify trials with PROs for the analysis. RESULTS: Of 13,666 registered trials, 6168 (45.1%) included a PRO. The proportion of studies including PROs increased between 2006 and 2016 (r = 0.74, p = 0.009). Among the 6168 trials, there were 17,961 individual PRO endpoints, including symptoms/functional outcomes/condition-specific QOL (65.6%), generic QOL (13.2%), patient-reported experiences (9.9%), patient-reported behaviours (7.9%). Mental health was the most common category (99.8% included PROs), followed by physical medicine/rehabilitation (65.6%), musculoskeletal (63.5%), public health (63.1%), and cancer (54.2%). DISCUSSION: Our findings suggest growing use of PROs in the assessment of health and interventions in ANZ. Our review identifies trial categories with limited patient-reported information and provides a basis for future work on the impact of PRO findings in clinical care.