Administering selected subscales of patient-reported outcome questionnaires to reduce patient burden and increase relevance: a position statement on a modular approach.

Patient-reported outcome (PRO) questionnaires considered in this paper contain multiple subscales, although not all subscales are equally relevant for administration in all target patient populations. A group of measurement experts, developers, license holders, and other scientific-, regulatory-, payer-, and patient-focused stakeholders participated in a panel to discuss the benefits and challenges of a modular approach, defined here as administering a subset of subscales out of a multi-scaled PRO measure. This paper supports the position that it is acceptable, and sometimes preferable, to take a modular approach when administering PRO questionnaires, provided that certain conditions have been met and a rigorous selection process performed. Based on the experiences and perspectives of all stakeholders, using a modular approach can reduce patient burden and increase the relevancy of the items administered, and thereby improve measurement precision and eliminate wasted data without sacrificing the scientific validity and utility of the instrument. The panelists agreed that implementing a modular approach is not expected to have a meaningful impact on item responses, subscale scores, variability, reliability, validity, and effect size estimates; however, collecting additional evidence for the impact of context may be desirable. It is also important to recognize that adequate rationale and evidence (e.g., of fit-for-purpose status and relevance to patients) and a robust consensus process that includes patient perspectives are required to inform selection of subscales, as in any other measurement circumstance, is expected. We believe that the considerations discussed within (content validity, administration context, and psychometric factors) are relevant across multiple therapeutic areas.

Association between duration of smoking abstinence before non-small-cell lung cancer diagnosis and survival: a retrospective, pooled analysis of cohort studies.

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.

Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in metastatic non-small cell lung cancer: CheckMate 9LA 2-year patient-reported outcomes.

BACKGROUND: In CheckMate 9LA (NCT03215706), first-line nivolumab plus ipilimumab with chemotherapy (2 cycles) significantly improved overall survival versus chemotherapy (4 cycles) in patients with metastatic non-small cell lung cancer and no known sensitising epidermal growth factor receptor/anaplastic lymphoma kinase alterations. We present exploratory patient-reported outcomes (PROs; minimum follow-up, 2 years). METHODS: In patients (N = 719) randomised 1:1 to nivolumab plus ipilimumab with chemotherapy or chemotherapy alone, disease-related symptom burden and health-related quality of life were assessed using the Lung Cancer Symptom Scale (LCSS) and 3-level EQ-5D (EQ-5D-3L). Treatment-phase changes in LCSS average symptom burden index (ASBI), LCSS three-item global index (3-IGI) and EQ-5D-3L visual analogue scale (VAS) and utility index (UI) over time were analysed descriptively and using mixed-effect model repeated measures. Time-to-deterioration/improvement analyses were conducted. RESULTS: Treatment-phase PRO questionnaire completion rates were >80%. Mean treatment-phase changes showed no deterioration from baseline in both arms for LCSS ASBI/3-IGI and EQ-5D-3L VAS/UI; however, minimally important differences were not met. Mixed-effect model repeated measures analyses showed overall reduction in symptom burden from baseline for both arms; changes from baseline for LCSS 3-IGI and EQ-5D-3L VAS/UI were numerically improved with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, but minimally important differences were not met. Nivolumab plus ipilimumab with chemotherapy delayed time-to-definitive-deterioration versus chemotherapy (LCSS ASBI: hazard ratio, 0.62 [95% confidence interval, 0.45-0.87]); results were similar across PRO measures. CONCLUSIONS: At 2-year minimum follow-up, first-line nivolumab plus ipilimumab with chemotherapy reduced the risk of definitive deterioration in disease-related symptom burden and health-related quality of life versus chemotherapy and maintained QoL in patients with metastatic non-small cell lung cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03215706.

Impact of Elotuzumab Plus Pomalidomide/Dexamethasone on Health-related Quality of Life for Patients With Relapsed/Refractory Multiple Myeloma: Final Data From the Phase 2 ELOQUENT-3 Trial.

Triplet regimens containing immunomodulatory drugs and proteasome inhibitors (PIs) have improved outcomes and extended survival for patients with relapsed/refractory multiple myeloma (RRMM). We evaluated updated health-related quality of life (HRQoL) findings from the phase 2 ELOQUENT-3 clinical trial (NCT02654132) after 4 years of treatment with elotuzumab plus pomalidomide and dexamethasone (EPd) and assessed the impact of the addition of elotuzumab on patients' HRQoL. HRQoL was assessed as an exploratory endpoint using the MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM), which evaluates symptom severity, symptom interference, and HRQoL, and the 3-level EQ-5D, a patient-reported measure of health utility and general health. Statistical analyses included descriptive responder, longitudinal mixed-model, and time-to-first-deterioration (TTD) analyses using prespecified minimally important differences and responder definitions. Of 117 randomized patients, 106 (EPd, n = 55; pomalidomide and dexamethasone [Pd], n = 51) were eligible for inclusion in HRQoL analyses. Completion rates at almost all on-treatment visits were ≥80%. The proportion of patients treated with EPd who improved or maintained stable HRQoL until cycle 13 ranged from 82% to 96% for MDASI-MM total symptom score and 64% to 85% for MDASI-MM symptom interference. Across measurements, there were no clinically meaningful differences in changes from baseline between treatment arms, and TTD was not significantly different for EPd versus Pd. In conclusion, HRQoL was not impacted by the addition of elotuzumab to Pd and did not significantly deteriorate in patients with RRMM previously treated with lenalidomide and a PI in ELOQUENT-3.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF©) and determination of a threshold score for moderate symptoms.

BACKGROUND: The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated. METHODS: The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted. RESULTS: A total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable (α > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire (p < 0.01). A biweekly ISM-SAF TSS from 21 to 28 begins to distinguish the moderately to severely symptomatic ISM/SSM patients from mildly symptomatic patients. CONCLUSION: The biweekly TSS of ISM-SAF was reliable, construct-valid, and able to distinguish among clinically distinct groups. A cut-off value of 28 is a conservative threshold that can be used for screening purposes in future clinical studies to identify patients with at least a moderate severity of ISM symptoms.

Gene-gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer.

BACKGROUND: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. AIM: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. METHODS: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. RESULTS: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13-1.27; p = 5.6 × 10-10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19-1.35; p = 1.0 × 10-12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. CONCLUSIONS: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data.

BACKGROUND: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. CONCLUSIONS: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Three-year follow-up and patient-reported outcomes from CheckMate 078: Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer.

OBJECTIVES: In the phase 3 CheckMate 078 study, nivolumab prolonged overall survival (OS) and showed a favorable safety profile versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer (aNSCLC). However, long-term efficacy, safety, and health-related quality of life findings with second-line nivolumab are very limited in Asian patients with previously treated aNSCLC. Here, we report updated clinical data and patient-reported outcomes (PROs) from the phase 3 CheckMate 078 trial with a 3-year minimum follow-up. MATERIALS AND METHODS: Patients with aNSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included objective response rate, progression-free survival, safety, and disease-related symptom deterioration assessed using the Lung Cancer Symptom Scale (LCSS) by Week 12. Additional PRO assessments were exploratory endpoints. RESULTS: At ≥ 37.3 months follow-up, 3-year OS rates were 19% with nivolumab and 12% with docetaxel; 30% and 0% of responders remained in response for ≥ 3 years, respectively. Incidence of treatment-related adverse events occurring after 2 years was lower than during the first 2 years. No new treatment-related deaths were reported. By Week 12 of treatment, rates of disease-related symptom deterioration were 32% with nivolumab and 47% with docetaxel. Completion rates for PRO questionnaires were ≥ 80% in both arms. Clinically meaningful and sustained improvements in LCSS Average Symptom Burden Index scores and delayed time to first symptom deterioration were observed with nivolumab against docetaxel. CONCLUSIONS: At 3 years, nivolumab continued to demonstrate survival benefit versus docetaxel, exhibiting improvements in disease-related symptoms and overall health status in a predominantly Chinese patient population with previously treated aNSCLC. No new safety signals were observed. These findings are similar to the global population.

Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF©.

BACKGROUND: Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis. METHODS: A review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated. RESULTS: For AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients. CONCLUSION: The AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients' perspective.

A Comparison of Generic and Condition-Specific Preference-Based Measures Using Data From Nivolumab Trials: EQ-5D-3L, Mapping to the EQ-5D-5L, and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions.

OBJECTIVES: There is growing interest in condition-specific preference measures, including the European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D). This research assessed the implications of using utility indices on the basis of the EQ-5D-3L, a mapping of EQ-5D-3L to the EQ-5D-5L, and the QLU-C10D, and compared their psychometric properties. METHODS: Data were taken from 8 phase 3 randomized controlled trials of nivolumab with or without ipilimumab for the treatment of solid tumors. Utilities for progression-related states were calculated using the UK and English value sets and incremental quality-adjusted life-years (QALYs) derived from established UK cost-effectiveness models. The psychometric properties of the utility indices were assessed using pooled trial data. RESULTS: Compared with the EQ-5D-3L index, the mapped EQ-5D-5L index yielded an average of 6% more and the QLU-C10D index an average of 2% fewer incremental QALYs for nivolumab versus comparators. All indices could differentiate between groups defined by performance status, cancer stage, or self-reported health status at baseline and detect meaningful changes in performance status, tumor response, health status, and quality of life over approximately 12 weeks of treatment. CONCLUSIONS: The lower QALY yield of the QLU-C10D was balanced by evidence of greater validity and responsiveness. Benefits gained from using the QLU-C10D may be apparent when treatments affect targeted symptoms and functional aspects, including sleep, bowel function, appetite, nausea, and fatigue. The observed differences in QALYs may not be sufficiently large to affect health technology assessment decisions.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients. METHODS: In PIONEER, a Phase 2 trial evaluating safety and efficacy of selective kinase inhibitor avapritinib in patients with ISM, the 12-item ISM-SAF was administered daily. Psychometric evaluation of score reliability, validity, and clinical interpretation was conducted using the trial data. RESULTS: Thirty-eight patients contributed to analyses (78.9% female; mean age = 49). Baseline internal consistency reliability (α) for bi-weekly TSS, GSS, and SSS was 0.86, 0.83, and 0.82, respectively. Test-retest reliability among patients exhibiting no change in Patient Global Impression of Symptom Severity (PGIS) between Baseline and Day 15 exceeded 0.74 universally. Construct validity and known-groups analysis showed moderate to strong ISM-SAF score correlation (r = 0.382-0.881) to supportive patient-reported questionnaires (e.g., PGIS and Mastocytosis Quality of Life Questionnaire) symptom and skin scores, and ability to distinguish among clinically unique groups. Correlations of ISM-SAF and other assessment change scores reflect evidence of score sensitivity. Clinically important difference and response estimates were 7-10 and 19, respectively. DISCUSSION: ISM-SAF produced reliable, construct-valid, sensitive scores when administered in PIONEER to patients in the target population. Results of this study support the use of the ISM-SAF as a reliable and valid measure to evaluate disease symptomology in ISM patients. Trial registration ClinicalTrials.gov, NCT03731260. Registered 10 October 2018, https://clinicaltrials.gov/ct2/show/study/NCT03731260 .

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF).

BACKGROUND: The Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines. METHODS: The 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM. Score distribution, reliability, construct-related validity, sensitivity to change, and interpretation guidelines were evaluated for AdvSM-SAF items, gastrointestinal symptom score (GSS), skin symptom score (SSS), and total symptom score (TSS). RESULTS: Thirty-one patients contributed to the analyses. At Baseline, the GSS, SSS, and TSS had adequate internal consistency (α > 0.7) and test-retest reliability (intraclass correlation coefficients >0.7). AdvSM-SAF scores were moderately to strongly correlated with variables as expected, and distinguished among clinically distinct groups. Observed relationships between change scores in the AdvSM-SAF and other assessments reflect evidence that AdvSM-SAF scores change in concert with other assessments designed to measure similar constructs. The magnitude of AdvSM-SAF weekly TSS mean change scores based on different anchor groupings was as expected (improvement > stable > worsening). Candidate clinically meaningful between-group difference estimates (GSS = 2-4, SSS = 2-3, and TSS = 4-7 points) and within-person change estimates (GSS = 6-9, SSS = 1-4, TSS = 9-14) for AdvSM-SAF weekly scores were generated. CONCLUSION: The AdvSM-SAF produced reliable, construct-valid, and sensitive scores when administered in the target patient population. These results, along with its strong development history and evidence of content validity, indicate that the AdvSM-SAF is fit for the purpose of measuring treatment benefit in individuals with AdvSM.

FABry Disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI): A new Fabry disease-specific gastrointestinal outcomes instrument.

PURPOSE: Fabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The FABry disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI). METHODS: Findings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI. RESULTS: Literature review (n = 17 articles), expert advisory meetings (n = 5), and patient CEIs (n = 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs (n = 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI. CONCLUSION: With evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.

First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1.

INTRODUCTION: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). METHODS: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. RESULTS: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.

Revisional ileoanal pouch surgery: a systematic literature review assessing outcomes over the last 40 years.

AIM: Failure of primary ileal pouch-anal anastomosis (IPAA) occurs in up to 15% of patients. Revision surgery may be offered to patients wishing to maintain gastrointestinal continuity. This paper explores the literature relating to IPAA revision surgery, focusing on pouch function after revision and factors associated with pouch failure. METHODS: Search of PubMed database was carried out for 'ileal pouch anal anastomoses', 'ileoanal pouch', 'restorative proctocolectomy', 'revision surgery', 'redo surgery', 'failure', 'refashion surgery', 'reconstruction surgery' and 'salvage surgery'. Papers were screened using the PRISMA literature review strategy. Studies of adults published after 1980 in English with an available abstract were included. Case reports and studies that were superseded using the same data were excluded. RESULTS: Nineteen papers (1424 patients) were identified. Bowel motion frequency doubled following revision surgery compared to primary IPAA although the increase was not always statistically significant. In patients failing primary IPAA, frequency of daytime bowel motions improved following revision in three studies but only reached significance in one (12.1 vs. 6.9, P = 0.021). Risk of pouch failure is increased in patients who develop pelvic sepsis after the primary procedure with the largest study demonstrating a four-fold increased risk (hazard ratio 3.691, P < 0.0001). A final diagnosis of Crohn's causes a four-fold increased risk of pouch failure (n = 81; OR 3.92, 95% CI 1.1-15.9, P = 0.04). CONCLUSIONS: In patients undergoing revisional surgery, improved outcomes are observed but are inferior compared to primary IPAA patients. Pelvic sepsis after primary IPAA and a final diagnosis of Crohn's are associated with increased risk of pouch failure.

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716.

OBJECTIVES: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. MATERIALS AND METHODS: Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. RESULTS: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. CONCLUSIONS: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

Effect of carboplatin when administered after dacarbazine failure: Clinical benefit of sequential therapy.

Dacarbazine chemotherapy has been the mainstay of melanoma treatment for >30 years. In the early 2000s, carboplatin (with or without other agents, such as paclitaxel) was the most commonly used second-line therapy in the UK. The aim of the present study was to report a significant response rate to second-line carboplatin in patients from three UK institutions who had been previously treated and failed to respond to dacarbazine, and investigate whether sequential therapy may be more effective compared with combination therapy. A total of 104 patients were identified, the majority of whom were treated with carboplatin (area under the curve 5-6) every 3 weeks for a maximum of 6 cycles. A total of 102 patients were evaluable for response, among whom 11 patients had an objective response (1 complete response and 10 partial responses) and 15 had stable disease, giving an overall response rate of 11% and disease control rate of 26%. The median progression-free survival was 1.8 months (range, 0.2-36+ months) and the median overall survival was 4.6 months (range, 0.2-36+ months). Surprisingly, the majority of the patients who benefited from second-line carboplatin therapy were those with visceral metastases, the survival of whom would not be expected to exceed 6 months after first-line treatment.