<i>ABCB1</i> (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

BACKGROUND: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood. METHODS: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, western blotting and immunohistochemical analysis and ABCB1 activity assessed by the Vybrant and P-glycoprotein-Glo assays. RESULTS: Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. Resistance correlated with increased ABCB1 expression and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes. CONCLUSIONS: We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug-resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Evaluation of the Content Validity of the COVID-19 Symptoms Daily Diary

Jennifer Dine,1 Yanfen Guan,2 Mirline Milien,1 Claire Ervin,1 Dana D Byrne,2 Michelle L Brown,2 Carisa De Anda,2 Josephine M Norquist2 1RTI Health Solutions, Research Triangle Park, Durham, NC, USA; 2Merck & Co., Inc., Rahway, NJ, USACorrespondence: Jennifer Dine, Patient-Centered Outcomes Assessment, RTI Health Solutions, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC, 27709, USA, Email [email protected]: The COVID-19 Symptoms Daily Diary (CSDD) is a patient-reported outcome measure designed to assess the severity of core COVID-19 symptoms in clinical trials. The preliminary version of the CSDD was developed based on regulatory guidance and the hallmark COVID-19 symptoms identified by the CDC. This study aimed to evaluate CSDD content validity, to determine whether it is fit for the purpose of supporting efficacy endpoints in clinical trials of treatments for COVID-19. This research also sought to evaluate the appropriateness of a newly developed Pre–COVID-19 Symptoms Questionnaire.Methods: A targeted literature review was completed to evaluate the relevance of concepts included in the diary and to identify any important symptoms that may have been missing. Hybrid (concept elicitation and cognitive debriefing) semistructured qualitative interviews were then conducted across 3 iterative rounds with 30 adults in the United States recently diagnosed with COVID-19.Results: The CSDD included concepts that were most frequently reported by interview participants, including those identified as most bothersome and most important to treat. During cognitive debriefing, participants described the diary concepts as salient and reported the instructions, recall period, and response options as clear and appropriate. Only 2 of 15 CSDD items were modified across 3 interview rounds; specifically, definitions for the vomiting and diarrhea frequency items were clarified for consistent interpretation and response. Interview participants also reported general ease in understanding and responding to the Pre–COVID-19 questionnaire, with feedback resulting in only minor changes to the reference period and instructions.Conclusion: The findings of the current study provide strong evidence for the content validity of the CSDD and the appropriateness of each of the items assessed. This rigorous evaluation (aligned with regulatory guidance) indicates that the CSDD is fit for the purpose of supporting efficacy endpoints in planned clinical trials evaluating medications for COVID-19 treatment.Keywords: patient-reported outcome measures, COVID-19, qualitative, symptom burde

Would loss to follow-up bias the outcome evaluation of patients operated for degenerative disorders of the lumbar spine?: A study of responding and non-responding cohort participants from a clinical spine surgery registry

Loss to follow-up may bias the outcome assessments of clinical registries. In this study, we wanted to determine whether outcomes were different in responding and non-responding patients who were included in a clinical spine surgery registry, at two years of follow-up. In addition, we wanted to identify risk factors for failure to respond. 633 patients who were operated for degenerative disorders of the lumbar spine were followed for 2 years using a local clinical spine registry. Those who did not attend the clinic and those who did not answer a postal questionnaire—for whom 2 years of outcome data were missing—and who would be lost to follow-up according to the standard procedures of the registry protocols, were defined as non-respondents. They were traced and interviewed by telephone. Outcome measures were: improvement in health-related quality of life (EQ-5D), leg pain, and back pain; and also general state of health, employment status, and perceived benefits of the operation. We found no statistically significant differences in outcome between respondents (78% of the patients) and nonrespondents (22%). Receipt of postal questionnaires (not being summoned for a follow-up visit) was the strongest risk factor for failure to respond. Forgetfulness appeared to be an important cause. Older patients and those who had complications were more likely to respond. Interpretation A loss to follow-up of 22% would not bias conclusions about overall treatment effects and, importantly, there were no indications of worse outcomes in non-respondents

Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items

The use of global health items permits an efficient way of gathering general perceptions of health. These items provide useful summary information about health and are predictive of health care utilization and subsequent mortality. Analyses of 10 self-reported global health items obtained from an internet survey as part of the Patient-Reported Outcome Measurement Information System (PROMIS) project. We derived summary scores from the global health items. We estimated the associations of the summary scores with the EQ-5D index score and the PROMIS physical function, pain, fatigue, emotional distress, and social health domain scores. Exploratory and confirmatory factor analyses supported a two-factor model. Global physical health (GPH; 4 items on overall physical health, physical function, pain, and fatigue) and global mental health (GMH; 4 items on quality of life, mental health, satisfaction with social activities, and emotional problems) scales were created. The scales had internal consistency reliability coefficients of 0.81 and 0.86, respectively. GPH correlated more strongly with the EQ-5D than did GMH (r = 0.76 vs. 0.59). GPH correlated most strongly with pain impact (r = −0.75) whereas GMH correlated most strongly with depressive symptoms (r = −0.71). Two dimensions representing physical and mental health underlie the global health items in PROMIS. These global health scales can be used to efficiently summarize physical and mental health in patient-reported outcome studies

Patient-centred measurement in ophthalmology – a paradigm shift

Ophthalmologists and researchers in ophthalmology understand what a rapidly evolving field ophthalmology is, and that to conduct good research it is essential to use the latest and best methods. In outcomes research, one modern initiative has been to conduct holistic measurement of outcomes inclusive of the patient's point of view; patient-centred outcome. This, of course, means including a questionnaire. However, the irony of trying to improve outcomes research by being inclusive of many measures is that the researcher may not be expert in all measures used. Certainly, few people conducting outcomes research in ophthalmology would claim to be questionnaire experts. Most tend to be experts in their ophthalmic subspecialty and probably simply choose a popular questionnaire that appears to fit their needs and think little more about it. Perhaps, unlike our own field, we assume that the field of questionnaire research is relatively stable. This is far from the case. The measurement of patient-centred outcomes with questionnaires is a rapidly evolving field. Indeed, over the last few years a paradigm shift has occurred in patient-centred measurement

Fear of hypoglycaemia: defining a minimum clinically important difference in patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>To explore the concept of the Minimum Clinically Important Difference (MID) of the Worry Scale of the Hypoglycaemia Fear Survey (HFS-II) and to quantify the clinical importance of different types of patient-reported hypoglycaemia.</p> <p>Methods</p> <p>An observational study was conducted in Germany with 392 patients with type 2 diabetes mellitus treated with combinations of oral anti-hyperglycaemic agents. Patients completed the HFS-II, the Treatment Satisfaction Questionnaire for Medication (TSQM), and reported on severity of hypoglycaemia. Distribution- and anchor-based methods were used to determine MID. In turn, MID was used to determine if hypoglycaemia with or without need for assistance was clinically meaningful compared to having had no hypoglycaemia.</p> <p>Results</p> <p>112 patients (28.6%) reported hypoglycaemic episodes, with 15 patients (3.8%) reporting episodes that required assistance from others. Distribution- and anchor-based methods resulted in MID between 2.0 and 5.8 and 3.6 and 3.9 for the HFS-II, respectively. Patients who reported hypoglycaemia with (21.6) and without (12.1) need for assistance scored higher on the HFS-II (range 0 to 72) than patients who did not report hypoglycaemia (6.0).</p> <p>Conclusion</p> <p>We provide MID for HFS-II. Our findings indicate that the differences between having reported no hypoglycaemia, hypoglycaemia without need for assistance, and hypoglycaemia with need for assistance appear to be clinically important in patients with type 2 diabetes mellitus treated with oral anti-hyperglycaemic agents.</p

U.S. General Population Estimate for “Excellent” to “Poor” Self-Rated Health Item

BACKGROUND: The most commonly used self-reported health question asks people to rate their general health from excellent to poor. This is one of the Patient-Reported Outcomes Measurement Information System (PROMIS) global health items. Four other items are used for scoring on the PROMIS global physical health scale. Because the single item is used on the majority of large national health surveys in the U.S., it is useful to construct scores that can be compared to U.S. general population norms. OBJECTIVE: To estimate the PROMIS global physical health scale score from the responses to the single excellent to poor self-rated health question for use in public health surveillance, research, and clinical assessment. DESIGN: A cross-sectional survey of 21,133 individuals, weighted to be representative of the U.S. general population. PARTICIPANTS: The PROMIS items were administered via a Web-based survey to 19,601 persons in a national panel and 1,532 subjects from PROMIS research sites. The average age of individuals in the sample was 53 years, 52 % were female, 80 % were non-Hispanic white, and 19 % had a high school degree or lower level of education. MAIN OUTCOME MEASURES: PROMIS global physical health scale. KEY RESULTS: The product–moment correlation of the single item with the PROMIS global physical health scale score was 0.81. The estimated scale score based on responses to the single item ranged from 29 (poor self-rated health, 2.1 SDs worse than the general population mean) to 62 (excellent self-rated health, 1.2 SDs better than the general population mean) on a T-score metric (mean of 50). CONCLUSIONS: This item can be used to estimate scores for the PROMIS global physical health scale for use in monitoring population health and achieving public health objectives. The item may also be used for individual assessment, but its reliability (0.52) is lower than that of the PROMIS global health scale (0.81)