Optimising primary molecular profiling in non-small cell lung cancer.

INTRODUCTION: Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. METHODS: This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. RESULTS: Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. CONCLUSION: This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1ß in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1ß plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1ß and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1ß levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1ß ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1ß ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1ß might contribute to a proinflammatory and pro-fibrotic environment in their lungs.

Predicting prognosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. In 2002, the ATS/ERS published new criteria that significantly changed the definition of IPF, resulting in a more homogeneous group of patients. IPF has a poor prognosis with a median of 2.5-3.5 years, but varying from a few months to a decade. In order to predict survival at diagnosis or during follow-up, a considerable number of studies were conducted identifying promising prognostic biomarkers. However, many had been performed before the new ATS/ERS consensus and included patients who would not meet current IPF criteria. This review provides an overview of prognostic markers of survival in IPF after the ATS/ERS consensus statement in 2002. Molecular biomarkers in serum, especially so-called pneumoproteins are relatively easy to obtain and have been independently replicated as predictors of prognosis. Cellular constituents of bronchoalveolar lavage (BAL) have been investigated as predictors of survival, but results remain contradictory. Further, a robust marker of prognosis is the change in lung function over time. However, calculating change in lung function is usually only possible over a 6-12 months period, and is therefore not useful at first presentation. The extent of fibrosis on HRCT scan and the number of fibroblast foci on lung biopsy can be measured at presentation and correlate with prognosis, but the applicability of these markers is being hampered by the lack of user- and patient friendliness. In conclusion, a number of biomarkers are potential candidates for an individualised prognosis of IPF, of which so-called pneumoproteins appear most promising and should be a major focus of fu-

Surfactant protein-D predicts survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease with a high mortality rate. As lung transplantation is the only therapeutic option, it is important to predict survival. OBJECTIVE: This study evaluates the clinical value of surfactant protein-D as a marker of prognosis in patients with idiopathic pulmonary fibrosis. DESIGN: Surfactant protein-D was measured in serum of 72 patients and 305 healthy controls. The optimal cut-off level to define unfavourable prognosis was determined using a ROC analysis. A Cox's proportional Hazards model was used to evaluate variables that were significant predictors of survival. RESULTS: Serum levels of surfactant protein-D were significantly higher in patients than in controls. ROC analysis showed 460 ng/ml to be the optimal cut-off level to discriminate survivor from non-survivors after 1 year. Patients with high levels (> 460 ng/ml) had a median survival time of 13 months, compared to 67 months in the group with low levels (< 460 ng/ml). Surfactant protein-D showed to be a significant predictor of prognosis, even when corrected for age, sex, smoking, and lung function. CONCLUSION: The measurement of surfactant protein-D in serum of patients with idiopathic pulmonary fibrosis might be a clinically relevant tool to predict survival.

Therapeutic strategies for epidemic Kaposi's sarcoma.

Kaposi's sarcoma (KS) remains the most commonly diagnosed malignancy in HIV-infected patients, and is one of the AIDS-defining diagnoses. Several different therapeutic options are available, but the optimal therapy is still unclear. The incidence of KS has sharply declined since highly active antiretroviral therapy (HAART) became widely available, making HAART indispensable in the treatment of epidemic KS. HAART can be given alone or in combination with systemic and local therapy. Systemic therapy can be given in disseminated, progressive or symptomatic disease. Treatment options are interferon-alpha and chemotherapy including pegylated-liposomal anthracyclines and paclitaxel. For local disease, radiotherapy, intralesional chemotherapy or cryotherapy may be used. In resource-limited settings, intravenous vincristine, oral etoposide or intramuscular bleomycin may be feasible options. Other therapies, such as angiogenesis inhibitors, are under investigation in clinical trials.