Clinical hypnosis can reduce lower urinary tract symptoms in individuals with chronic pain.

STUDY PURPOSE: Lower urinary tract symptoms (LUTS) can occur in chronic pain populations at high rates and drastically affect quality of life. Hypnosis is a nonpharmacological treatment used in chronic pain known to have beneficial implications to health outside of pain reduction. This study evaluated the potential for hypnosis to reduce LUTS in a sample of individuals with chronic pain, if baseline LUTS severity affected outcomes, and specific LUTS that may respond to hypnosis. METHODS: Sixty-four adults with chronic pain and LUTS at a level of detectable symptom change (American Urological Association Symptom Index, AUASI 3) participated in an 8-week group hypnosis protocol. Participants completed validated assessments of LUTS, pain, and overall functioning before, after, 3- and 6-months posttreatment. Linear mixed effects models assessed improvement in LUTS over time while accounting for known factors associated with outcome (e.g., age, gender). The interaction of baseline symptom severity and treatment assessed the potential effect of baseline symptoms on change scores. RESULTS: Participants experienced significant and meaningful improvements in LUTS following group hypnosis (p = 0.006). There was a significant interaction between baseline symptom severity and treatment (p < 0.001), such that those with severe symptoms experienced the most pronounced gains over time (e.g., an 8.8 point reduction). Gains increased over time for those with moderate and severe symptoms. Changes in LUT symptoms occurred independently of pain relief. CONCLUSIONS: This pilot study suggests hypnosis has the potential to drastically improve LUTS in individuals with chronic pain, even when pain reduction does not occur. Results provide initial evidence for the treatment potential of hypnosis in urologic pain (and possibly non-pain/benign) populations, with randomized trials needed for definitive outcomes.

Compensatory coping and depression in women with interstitial cystitis/bladder pain syndrome.

INTRODUCTION: Women with genitourinary pain, a hallmark symptom of interstitial cystitis/bladder pain syndrome (IC/BPS), are at a two- to four-fold risk for depression as compared to women without genitourinary pain. Despite the pervasive impact of IC/BPS on psychological health, there is a paucity of empirical research on understanding the relation between IC/BPS and psychological distress. It has been previously reported that women with overactive bladder use increased compensatory coping and these behaviors are associated with heightened anxiety and stress. However, it is unknown whether a similar pattern emerges in IC/BPS populations, as ICBPS and OAB share many similar urinary symptoms. The current study examined the relationship between compensatory coping behaviors and symptoms of psychological distress in a sample of women with IC/BPS to inform understanding of risk and potential mechanisms for intervention. METHOD: This was a secondary analysis of an observational cohort of women with bladder symptoms. Fifty-five adult women with IC/BPS completed validated assessments of genitourinary symptoms, emotional distress, and bladder coping behaviors. Five compensatory coping behaviors were summed to create a total Bladder Coping Score. Linear regression examined associations between individual coping behaviors, total compensatory coping scores, and other risk variables. RESULTS: Most (93%) participants reported use of at least one compensatory coping behavior. Age, education level, history of vaginal birth, and symptom severity were all associated with greater compensatory coping scores, and anxiety was not. Beyond the influence of symptom severity, higher levels of depression were significantly associated with higher compensatory coping scores. DISCUSSION: Greater compensatory coping was associated with increased depression but not anxiety, suggesting different profiles of coping and psychological distress may exist among different types of bladder dysfunction.

Understanding the patient experience of chronic kidney disease stages 2-3b: a qualitative interview study with Kidney Disease Quality of Life (KDQOL-36) debrief.

BACKGROUND: Qualitative patient interviews and patient-reported outcome instruments are important tools to understand the patient experience of disease. The aim of this study was to use patient interviews to identify concepts relevant and important to patients living with chronic kidney disease (CKD) stages 2-3b, develop a comprehensive conceptual model of the patient experience and debrief the Kidney Disease Quality of Life 36-item instrument (KDQOL-36) for patients with CKD stages 2-3b. METHODS: Concept elicitation interviews were conducted with patients with CKD stages 2-3b to identify signs/symptoms and impacts most relevant and important to patients (i.e., 'salient' concepts) and develop a conceptual model for the disease. Based on the salient concepts identified in the interviews, new items were proposed to supplement the KDQOL-36. Cognitive debriefing was performed to evaluate the KDQOL-36 and the additional items. RESULTS: A total of 31 patients were interviewed in this study (22 for concept elicitation and 15 for cognitive debriefing). The interviews identified 56 concepts (33 signs/symptoms and 23 impacts), 17 of which had not been identified in a previous literature review. Four signs/symptoms ('fatigue/lack of energy/tiredness', 'sleep problems', 'increased urination [including nocturia]' and 'swelling in legs/ankles/feet') and two impacts ('anxiety/worry' and 'general negative emotional/mental impact') were identified as salient. Of the salient signs/symptoms, three were not covered by the KDQOL-36 (sleep problems, increased urination and swelling in legs/ankles/feet) and were represented during cognitive debriefing interviews through four additional items (trouble falling asleep, trouble staying asleep, increased urination [including nocturia] and swelling in legs/ankles/feet) generated in the style of the KDQOL-36. All patients found the KDQOL-36 plus the four additional items relevant, and the majority found them clear. CONCLUSIONS: By identifying previously unknown concepts and augmenting the understanding of which are most important to patients, a comprehensive conceptual model was developed for patients who have CKD stages 2-3b. This study also demonstrates the suitability of the KDQOL-36 for patients who have CKD stages 2-3b and provides suggestions for how the instrument could be further developed to more comprehensively capture patient experience.

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions.

PURPOSE: The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored. METHODS: TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥ 10-point difference = clinically relevant). RESULTS: No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P = 0.034) when baseline was the reference, and for cough (HR 0.70; P = 0.009) and dyspnoea (HR 0.71; P = 0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P = 0.025) when baseline was the reference, and for cough (HR 0.70; P = 0.011), dyspnoea (HR 0.71; P = 0.003) and chest pain (HR 0.71; P = 0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms. CONCLUSION: This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125.

Living with heart failure: patient experiences and implications for physical activity and daily living.

AIMS: Heart failure (HF) substantially limits the ability of patients to engage in physical activities. A detailed understanding of how patients experience these limitations is required to develop valid and sensitive measures for use in clinical research. This qualitative study was designed to provide a thorough description of how HF patients experience physical activity limitations in their daily lives. METHODS AND RESULTS: Semi-structured interviews were conducted with 40 HF patients. Interview transcripts were coded with the aim of identifying key aspects of physical activity. Patients were divided between HF with preserved ejection fraction (n = 21, 52.5%) and HF with reduced ejection fraction (n = 19, 47.5%); the majority of patients were New York Heart Association Class II (n = 22, 52.5%) or Class III (n = 16, 40.0%). Relevant physical activity themes, including mobility and broader daily function areas, were identified. The most frequently reported mobility limitations involved difficulty walking (up a steep incline, up steps, and long distances), limited walking speed, difficulty standing for long periods of time, and difficulty carrying and lifting objects. These limitations were principally related to three HF symptoms: dyspnoea, tiredness/fatigue, and peripheral oedema. Patients adapted to their symptoms and related mobility limitations in several ways, including taking rests during an activity, doing an activity more slowly, and avoiding/refraining from an activity altogether. The broader daily function areas most commonly impacted by the mobility limitations were housework, exercising or playing sports, and going shopping. CONCLUSIONS: Heart failure patients report numerous physical activity limitations. These specific mobility and daily function areas can be measured using clinical outcome assessments (e.g. patient-reported outcomes and performance outcomes) in clinical trials and observational research. Accelerometry can be used to contribute to a holistic picture of patient functioning by passively collecting this type of data.

Willingness to report treatment-related symptoms of immunotherapy among patients with non-small cell lung cancer.

PURPOSE: Immunotherapy is an evolving therapeutic approach for non-small cell lung cancer (NSCLC). This study explored factors involved in patients' perceptions about reporting or not reporting treatment-related symptoms experienced while undergoing immunotherapy. METHODS: Patients receiving immunotherapy for NSCLC were recruited in the USA and Europe. Qualitative interviews were conducted to elicit treatment-related symptoms and explore patients' reasons and motivations for either reporting or not reporting these to their medical teams. Interviews were audio-recorded, transcribed, and coded for qualitative analysis. RESULTS: Sixty-six patients were interviewed (mean age: 62 years; 55% male; 91% with stage IV NSCLC). The most frequent symptoms that patients experienced but did not report were gastrointestinal (23% of patients), respiratory (17%), and energy related (12%). The most common reasons for not reporting symptoms included a perception that they were not severe enough, being unsure whether the experiences were side effects, and deciding that the experiences were expected and could be managed without assistance. Fear of having treatment discontinued was also mentioned but was not a prominent reason. The most common reasons for reporting symptoms were to ascertain if these were normal and expected, and to let the medical team know. Patients emphasized the importance of survival over treatment burden when balancing symptoms with treatment benefits. CONCLUSION: Patients have a range of reasons for not reporting their treatment-related symptoms when undergoing immunotherapy for NSCLC. Reasons are more strongly related to determination of the severity versus manageability of patients' experiences of symptoms than they are to the fear of having treatment discontinued.

How patients being treated for non-small cell lung cancer value treatment benefit despite side effects.

PURPOSE: To describe symptoms and side effects experienced by patients with advanced non-small cell lung cancer (NSCLC), assess how patients allocate sensations (i.e. symptoms or side effects) to either the disease or its treatment, and evaluate how patients balance side effects with treatment benefits. METHODS: Qualitative sub-studies were conducted as part of two clinical trials in patients treated for advanced NSCLC (AURA [NCT01802632]; ARCTIC [NCT02352948]). RESULTS: Interviews were conducted with 23 patients and 19 patients in the AURA and ARCTIC sub-studies, respectively. The most commonly experienced symptoms/side effects were respiratory (81% of patients), digestive (76%), pain and discomfort (76%), energy-related (71%), and sensory (62%). Patients identified a sensation as a treatment side effect if they had not experienced it before, if there was a temporal link between the sensation and receipt of treatment, and/or if their doctors consistently told or asked them about it in relation to side effects. Themes that emerged when patients talked about their cancer treatment and its side effects related to the serious nature of their advanced disease and their treatment expectations. Patients focused on treatment benefits, wanting a better quality of life, being hopeful, not really having a choice, and not thinking about side effects. CONCLUSIONS: In these two qualitative sub-studies, patients with advanced NSCLC valued the benefits of their treatment regardless of side effects that they experienced. Patients weighed their options against the seriousness of their disease and expressed their willingness to tolerate their side effects in return for receiving continued treatment benefits.

Development of a preliminary conceptual model of the patient experience of chronic kidney disease: a targeted literature review and analysis.

BACKGROUND: Patient-reported outcome (PRO) instruments should capture the experiences of disease and treatment that patients consider most important in order to inform patient-centred care and product development. The aim of this study was to develop a preliminary conceptual model of patient experience in chronic kidney disease (CKD) based on a targeted literature review and to characterize existing PRO instruments used in CKD. METHODS: PubMed, EMBASE and Cochrane databases and recent society meetings were searched for publications reporting signs/symptoms and life impacts of CKD. Concepts identified in the literature review were used to develop a preliminary conceptual model of patient experience of CKD, overall, and within patient subpopulations of differing CKD causes, severities and complications. PRO instruments, identified from PRO databases, CKD literature and CKD clinical trials, were assessed for content validity, psychometric strength and coverage of concepts in the literature review. RESULTS: In total, 100 publications met criteria for analysis; 56 signs/symptoms and 37 life impacts of CKD were identified from these sources. The most frequently mentioned signs/symptoms were pain/discomfort (57% of publications) and tiredness/low energy/lethargy/fatigue (42%); the most commonly reported life impacts were anxiety/depression (49%) and decrements in physical functioning (43%). Signs/symptoms and life impacts varied across the subpopulations and were more frequent at advanced CKD stages. The preliminary conceptual model grouped signs/symptoms into seven domains (pain/discomfort; energy/fatigue; sleep-related; gastrointestinal-related; urinary-related; skin-/hair-/nails-related; and other) and life impacts into six domains (psychological/emotional strain; cognitive impairment; dietary habit disruption; physical function decrements; interference with social relationships; and other). Eleven PRO instruments were considered to be promising for use in CKD; all had limitations. CONCLUSIONS: Although preliminary, the proposed conceptual model highlights key PROs for people with CKD and is intended to spur development of more tailored PRO instruments to assess these concepts.

Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer.

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Reduced Tumorigenicity of Mouse ES Cells and the Augmented Anti-Tumor Therapeutic Effects under Parg Deficiency.

PolyADP-ribosylation is a post-translational modification of proteins, and poly(ADP-ribose) (PAR) polymerase (PARP) family proteins synthesize PAR using NAD as a substrate. Poly(ADP-ribose) glycohydrolase (PARG) functions as the main enzyme for the degradation of PAR. In this study, we investigated the effects of Parg deficiency on tumorigenesis and therapeutic efficacy of DNA damaging agents, using mouse ES cell-derived tumor models. To examine the effects of Parg deficiency on tumorigenesis, Parg+/+ and Parg-/- ES cells were subcutaneously injected into nude mice. The results showed that Parg deficiency delays early onset of tumorigenesis from ES cells. All the tumors were phenotypically similar to teratocarcinoma and microscopic findings indicated that differentiation spectrum was similar between the Parg genotypes. The augmented anti-tumor therapeutic effects of X-irradiation were observed under Parg deficiency. These results suggest that Parg deficiency suppresses early stages of tumorigenesis and that Parg inhibition, in combination with DNA damaging agents, may efficiently control tumor growth in particular types of germ cell tumors.

Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small-cell lung cancer.

BACKGROUND: In the FLAURA trial, osimertinib demonstrated superior progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial therapy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported outcomes from FLAURA are discussed here. METHODS: Patients (N = 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized treatment discontinuation were assessed using a mixed-effects model. A ≥10-point change was considered clinically relevant. Odds of improvement and time to deterioration were investigated. QLQ-C30 functioning scores were assessed post hoc. RESULTS: Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference favoring osimertinib for chest pain was not clinically relevant (-6.84 vs -3.88; p = 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p = 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs -3.91; p = 0.005). CONCLUSIONS: Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. CLINICAL TRIAL REGISTRATION: NCT02296125.

Self-compassion in mindfulness-based stress reduction: An examination of prediction and mediation of intervention effects.

The current investigation sought to clarify mechanisms of treatment effects in mindfulness-based stress reduction (MBSR). Self-compassion and mindful awareness were assessed first as dispositional influences and then as mediators of outcome in unique models. One hundred thirty individuals participating in the 8-week MBSR intervention were recruited (73.08% female, mean age = 46.97, SD = 14.07). Measures of psychosocial well-being (Brief Stress Inventory [BSI], Perceived Stress Scale-10 [PSS]), mindful awareness (Mindful Awareness and Attention Scale [MAAS]), and self-compassion (Self-Compassion Scale [SCS]) were collected at preintervention and postintervention. Regression was conducted to examine the influence of baseline MAAS and SCS on change in PSS and BSI scores. Serial multiple mediator models were conducted separately with pre/postintervention BSI and PSS values as criterion, and preintervention/postintervention MAAS and SCS values as mediators. Higher levels of baseline self-compassion were predictive of greater reductions in PSS scores (ß = 0.16). Reductions in BSI scores were serially mediated by change in self-compassion both directly (MBSR → ΔSCS → ΔBSI ß = 0.06) and indirectly through mindful awareness (MBSR → ΔMAAS → ΔSCS → ΔBSI ß = 0.09). Results provide support for the role of self-compassion as both a predictor of treatment effect and a process through which MBSR operates. Mechanisms underlying MBSR effects appear to be unique to the outcome of interest.

Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study.

BACKGROUND: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs). METHODS: PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1-42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42. FINDINGS: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1-29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [-1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [-0·51 to 3·34]), chest pain (-3·1 [-4·57 to -1·60] vs -3·5 [-5·68 to -1·29]), fatigue (-3·0 [-4·53 to -1·50] vs -5·2 [-7·45 to -2·98]), appetite loss (-5·8 [-7·28 to -4·36] vs -7·0 [-9·17 to -4·87]), physical functioning (0·1 [-1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [-0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI -1·89 to 4·11), dyspnoea (1·6, -0·58 to 3·87), chest pain (0·4, -2·13 to 2·93), fatigue (2·2, -0·38 to 4·78), appetite loss (1·2, -1·27 to 3·67), physical functioning (-1·9, -3·91 to 0·15), or global health status or quality of life (0·8, -1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints. INTERPRETATION: Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. FUNDING: AstraZeneca.

Patient-reported symptoms possibly related to treatment with osimertinib or chemotherapy for advanced non-small cell lung cancer.

OBJECTIVES: In the AURA3 trial, individuals received osimertinib 80 mg once daily or chemotherapy for advanced non-small cell lung cancer. Here, we explore patient-reported symptoms possibly related to treatment. MATERIALS AND METHODS: AURA3 was an open-label, randomized phase III trial involving 419 patients. As part of the trial's exploratory objectives, individuals were asked to complete the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) electronically, first weekly for 18 weeks and then every 3 weeks for up to 57 weeks, subject to the availability of validated local-language versions (English, German, Japanese and Spanish versions were available). RESULTS: In total, 161 patients (38%; 102 receiving osimertinib, 59 receiving chemotherapy) provided data for PRO-CTCAE analyses (mean age: 64 years; 63% women). Diarrhea was reported more commonly with osimertinib than with chemotherapy, and was mostly graded as occurring rarely or occasionally. Decreased appetite was reported less commonly with osimertinib than with chemotherapy. The proportion of patients reporting nausea changed little from baseline with osimertinib and increased with chemotherapy. Few patients reported vomiting. Both nausea and vomiting were generally graded as mild in severity. Fatigue was reported less commonly with osimertinib than with chemotherapy, and was mostly graded as mild or moderate. Of patients reporting fatigue, the proportion grading it as interfering at least 'somewhat' with their usual or daily activities was lower with osimertinib than with chemotherapy. CONCLUSION: Symptoms were generally mild and not frequent, with some differences in symptom patterns between the two treatment groups. The results support and complement the AURA3 trial data and give insight into patients' experience with treatment.

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop.

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.

Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial.

Purpose Capturing patient-reported outcome data is important for evaluating the overall clinical benefits of new cancer therapeutics. We assessed self-reported symptoms of advanced non-small-cell lung cancer in patients treated with osimertinib or chemotherapy in the AURA3 phase III trial. Patients and Methods Patients completed the European Organisation for Research and Treatment of Cancer 13-item Quality of Life Questionnaire-Lung Cancer Module (EORTC QLQ-LC13) questionnaire on disease-specific symptoms and the EORTC 30-item Core Quality of Life Questionnaire (EORTC QLC-C30) on general cancer symptoms, functioning, global health status/quality of life. We assessed differences between treatments in time to deterioration of individual symptoms and odds of improvement (a deterioration or improvement was defined as a change in score from baseline of ≥ 10). Hazard ratios (HRs) were calculated using a log-rank test stratified by ethnicity; odds ratios (ORs) were assessed using logistic regression adjusted for ethnicity. Results At baseline, the questionnaires were completed by 82% to 88% of patients, and 30% to 70% had individual key symptoms. Time to deterioration was longer with osimertinib than with chemotherapy for cough (HR, 0.74; 95% CI, 0.53 to 1.05), chest pain (HR, 0.52; 95% CI, 0.37 to 0.73), and dyspnea (HR, 0.42; 95% CI, 0.31 to 0.58). The proportion of symptomatic patients with improvement in global health status/quality of life was higher with osimertinib (80 [37%] of 215) than with chemotherapy (23 [22%] of 105; OR, 2.11; 95% CI, 1.24 to 3.67; P = .007). Proportions were also higher for appetite loss (OR, 2.50; 95% CI, 1.31 to 4.84) and fatigue (OR, 1.96; 95% CI, 1.20 to 3.22). Conclusion Time to deterioration of key symptoms was longer with osimertinib than with chemotherapy, and a higher proportion of patients had improvement in global health status/quality of life, demonstrating improved patient outcomes with osimertinib.

Development and Validation of the AFImpact: An Atrial Fibrillation-Specific Measure of Patient-Reported Health-Related Quality of Life.

BACKGROUND: Improvement in health-related quality of life is a key therapeutic goal of disease management in atrial fibrillation (AF). OBJECTIVES: To describe the development of the AFImpact, an AF-specific health-related quality-of-life patient-reported outcome measure. METHODS: Development and validation of the AFImpact comprised a qualitative stage, consisting of a literature review and concept elicitation interviews (91 patients with AF), item generation, and cognitive debriefing (30 patients with AF), and a quantitative stage, consisting of evaluation of the instrument's psychometric properties (313 patients with AF). Preliminary responsiveness to change was assessed in 118 patients undergoing cardioversion. RESULTS: On the basis of the literature review and concept elicitation interviews, 75 items were generated. Factor analyses guided a reduction to 18 items. Three domains were confirmed: vitality (7 items), emotional distress (8 items), and sleep (3 items). The 18-item AFImpact demonstrated high item convergent and discriminant validity. Cronbach α coefficients showed high internal consistency reliability. Test-retest reliability of individual items in stable patients (n = 33) was satisfactory, with intraclass correlation coefficients ranging from 0.61 to 0.86. All three AFImpact domain scores differentiated patients who reported different levels of overall health, thereby supporting known-groups validity. Scores for each item improved after cardioversion, with effect sizes ranging from -0.19 to -0.65. CONCLUSIONS: Psychometric evaluations support the reliability and validity of the AFImpact as a patient-reported outcome instrument to measure the impact of AF, with preliminary results in patients undergoing cardioversion supporting responsiveness to change.

Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes.

Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV-GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies.