Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer - the MetAction study.

Background: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014-2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016-2019).Material and methods: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints.Results: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2-3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment.Conclusions: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity versus resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies. ClinicalTrials.gov, identifier: NCT02142036.

Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate.

OBJECTIVE: Through the conduct of an individual-based intervention study, the main purpose of this project was to build and evaluate the required infrastructure that may enable routine practice of precision cancer medicine in the public health services of Norway, including modelling of costs. METHODS: An eligible patient had end-stage metastatic disease from a solid tumour. Metastatic tissue was analysed by DNA sequencing, using a 50-gene panel and a study-generated pipeline for analysis of sequence data, supplemented with fluorescence in situ hybridisation to cover relevant biomarkers. Cost estimations compared best supportive care, biomarker-agnostic treatment with a molecularly targeted agent and biomarker-based treatment with such a drug. These included costs for medication, outpatient clinic visits, admission from adverse events and the biomarker-based procedures. RESULTS: The diagnostic procedures, which comprised sampling of metastatic tissue, mutation analysis and data interpretation at the Molecular Tumor Board before integration with clinical data at the Clinical Tumor Board, were completed in median 18 (8-39) days for the 22 study patients. The 23 invasive procedures (12 from liver, 6 from lung, 5 from other sites) caused a single adverse event (pneumothorax). Per patient, 0-5 mutations were detected in metastatic tumours; however, no actionable target case was identified for the current single-agent therapy approach. Based on the cost modelling, the biomarker-based approach was 2.5-fold more costly than best supportive care and 2.5-fold less costly than the biomarker-agnostic option. CONCLUSIONS: The first project phase established a comprehensive diagnostic infrastructure for precision cancer medicine, which enabled expedite and safe mutation profiling of metastatic tumours and data interpretation at multidisciplinary tumour boards for patients with end-stage cancer. Furthermore, it prepared for protocol amendments, recently approved by the designated authorities for the second study phase, allowing more comprehensive mutation analysis and opportunities to define therapy targets.

Reliability and validity of a Norwegian version of the Epworth sleepiness scale.

OBJECTIVE: The objective of this study was to assess the reliability and validity of a Norwegian version of the self-administered Epworth sleepiness scale (ESS). MATERIALS AND METHODS: Two samples responded to the ESS: (1) 226 patients previously evaluated for obstructive sleep apnea, of whom 51 also responded to a retest 2 weeks later, and (2) 37 ambulant patients complaining of excessive daytime sleepiness, who were referred to multiple sleep latency testing (MSLT). We assessed internal consistency reliability with Cronbach's alpha and test-retest reliability with weighted kappa (Kw) or an intraclass correlation coefficient (ICC). The validity of the Norwegian ESS was assessed by correlating ESS item and total scores with the number of times a patient fell asleep and the mean latency found on the MSLT. RESULTS: Internal consistency reliability, as assessed with Cronbach's alpha, was 0.84 (n = 154). Test-retest reliability for the eight ESS items ranged from Kw of 0.61 to 0.80 (n = 50) and for the total score. ICC was 0.81.There was only fair to moderate correlation of ESS item and total scores with MSLT variables, mainly in a subset of patients with total ESS score >10. CONCLUSIONS: The Norwegian version of the ESS had acceptable internal consistency and test-retest reliability. The association of the ESS items and total score with the MSLT was only fair to moderate, in line with previous studies.

Predictors of symptoms of anxiety and depression in obstructive sleep apnea.

BACKGROUND AND PURPOSE: To assess factors associated with anxiety and depression in patients with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: The study was comprised of a postal survey with a hospital chart review. Questionnaires were mailed to 242 previously hospitalised patients with OSAS. We assessed anxiety and depression with the Hospital Anxiety and Depression scale (HAD). Scores on the two HAD scales (0-21 scale, higher scores represent poor health) were categorized as normal/borderline (< or =10), and corresponding to a clinical diagnosis of anxiety or depression (> or =11). In logistic regression analysis, we assessed the association with HAD scores > or =11, using variables from the chart review and self-reported data on demographics, disease history, smoking status, CPAP/BiPAP use, and daytime sleepiness as assessed with the Epworth Sleepiness Scale (ESS), as potential predictors. RESULTS: One hundred and seventy-eight patients (74%) with mean (SD) age 55 (11) years and body mass index (BMI) of 31 (5) kgm(-2) responded to the questionnaire. In multivariate logistic regression analysis, only low compliance with CPAP therapy (odds ratio (OR) 5.60, P=0.005) predicted high level of anxiety, and low compliance with CPAP therapy (OR 3.59, P=0.03) and daytime sleepiness (OR 1.14 per unit increase in ESS score, P=0.02) were the only predictors of high level of depression. CONCLUSIONS: High anxiety score was associated with non-compliance with CPAP therapy. High depression score was associated with daytime sleepiness and non-compliance with CPAP therapy.

Reliability and validity of the Norwegian version of the Functional Outcomes of Sleep Questionnaire.

The aim of this study was to validate the Norwegian version of a self-administered 30-item quality of life questionnaire designed to assess disorders of excessive sleepiness, the Functional Outcomes of Sleep Questionnaire (FOSQ). In total 226 patients previously evaluated for obstructive sleep apnea were included in the study. The patients received a postal questionnaire with the FOSQ, the Short Form 36 (SF-36) questionnaire, and a scale for assessment of excessive daytime sleepiness, the Epworth sleepiness scale (ESS). Among the 178 respondents, all five subscales of the FOSQ showed good internal consistency reliability (Cronbach's alpha = 0.84-0.93). Test-retest on average 18 days apart was satisfactory with intraclass correlation coefficients ranging from 0.61 to 0.86. The pattern of Spearman's rank correlation coefficients between FOSQ scales and related and unrelated scales SF-36 scales gave support to the construct validity of the FOSQ. In conclusion, the Norwegian translation of the FOSQ showed satisfactory internal consistency reliability, test-retest reliability and construct validity, in line with the original version.

[Coding of diagnoses in chronic obstructive pulmonary disease--economic consequences]. / Diagnosekoding ved kronisk obstruktiv lungesykdom--økonomiske konsekvenser.

BACKGROUND: We wanted to assess the quality of coding of diagnoses and procedures, the resulting DRG classification and the financial consequences of coding errors for the hospital owner in patients with chronic obstructive pulmonary disease. MATERIAL AND METHODS: We identified 330 hospitalizations in the Central Hospital of Akershus 1 January to 30 November 1999 in DRG 088 (chronic obstructive pulmonary diseases) after an initial DRG classification. The patients' discharge summaries were reviewed for errors in coding of diagnoses and procedures and, where applicable, recoded. DRG classification was then redone and the changes analysed. RESULTS: After review of 302 available discharge summaries (92%) and recoding, the most common primary diagnoses were chronic obstructive pulmonary disease (68%), respiratory failure (17%), and pneumonia (8%). The recoding led to change of the primary diagnosis in 16% of the patient stays, additional secondary diagnosis (18%) or both (18%). The coding was changed for 175 (58%) patients, of which 94 recodings (31%) led to changes in the resulting DRG. On average, the recoding led to an increase per hospitalization of 0.30 DRG points. Two of five coders frequently used respiratory failure as the primary diagnosis (37-43% for hospitalization). INTERPRETATION: The initial routine coding was incomplete. There was large variation in recoding between medically qualified coders; this may have considerable financial consequences for a hospital. There were several problems related to the interpretation of ICD-10 coding, creating opportunities for "upcoding".