Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.

Relation of sputum neutrophilia to the development of chronic lung allograft dysfunction after lung transplantation.

Chronic lung allograft dysfunction (CLAD) is a serious complication after lung transplantation (LuTx) and is associated with elevated proportions of neutrophils in bronchoalveolar lavage (BAL). Induced sputum is a less-invasive sampling method than BAL and assesses markers of inflammation on the surfaces of large central airways. We wanted to examine whether % neutrophil levels in induced sputum were elevated prior to CLAD diagnosis among LuTx recipients, and whether sputum markers of inflammation can be used as a tool for predicting the development of CLAD. Induced sputum samples were collected at 1, 3, 6, 12, and 24 months post-LuTx in 36 patients with a history of COPD or pulmonary fibrosis, and of these, 16 developed CLAD either during or after the sputum surveillance period. At 2 years, median (IQR) % neutrophils in induced sputum were significantly higher among patients with CLAD compared with those without CLAD [73 (52-80) % vs 59 (41-76) %, p = .01]. Interestingly, we found a significant increase in the rate of change in % neutrophils beginning at 90 days preceding the diagnosis of CLAD. This suggests using sputum neutrophil percentage as a surveillance modality for monitoring lung allograft function after LuTx.

Sputum neutrophils are elevated in smelter workers, and systemic neutrophils are associated with rapid decline in FEV1.

OBJECTIVES: In a previous study on smelter workers we, found significant relationship between exposure to dust and accelerated annual decline in forced expiratory volume in 1 s (FEV1). In this cross-sectional study at the end of a follow-up, we aimed to investigate the possible association between annual decline in FEV1 and markers of airways, and systemic inflammation in smelter workers. METHODS: Employees (n=76 (27 current smokers)) who had been part of a longitudinal study (9-13 years) that included spirometry (>6 measurements) and respiratory questionnaires, performed induced sputum, exhaled NO and had blood drawn. Participants with annual decline in FEV1≥45 mL were compared with participants with annual decline <45 mL; also 26 non-exposed controls were included. RESULTS: Compared with non-exposed controls, smelter workers demonstrated a significantly increased percentage of neutrophils (mean (SD)) (57% (17) vs 31% (15)) and matrix metalloproteinases 8 (MMP-8) levels in sputum, and MMP-9, surfactant protein D (SpD) and transforming growth factor ß (TGFb) levels in blood. A significant association in FEV1≥45 mL was found for blood neutrophils when controlling for smoking habits (OR=1.7 (95% CI 1.0 to 2.8), p=0.045). Airway and blood protein markers were not associated with annual decline in FEV1. CONCLUSIONS: All workers displayed airway and systemic inflammation characterised by increased levels of neutrophils and MMP-8 in sputum, and MMP-9, SpD and TGFß in blood compared with non-exposed controls. Blood neutrophils in particular were significantly elevated in those workers with the most rapid decline in lung function. A similar observation was not seen with airway neutrophils. In the present study, we were able to identify systemic but not airway inflammatory markers that can predict increased decline in FEV1 in smelter workers.