Rare case of a synchronous pleural solitary fibrous tumour and a thymic cyst.

We present a unique case of a 41-year-old man with an anterior mediastinal mass and a pulmonary nodule, found incidentally on a thoracic CT. Further evaluation with an MRI revealed a thymic cyst which was multiloculated with several septations. Biopsy of the pulmonary nodule was performed and histology was consistent with a solitary fibrous tumour (SFT), on the benign spectrum. Both lesions were successfully resected simultaneously via a median sternotomy approach. Final full histological diagnoses confirmed a multiloculated thymic cyst and a completely excised SFT.

Mutation and drug-specific intracellular accumulation of EGFR predict clinical responses to tyrosine kinase inhibitors.

BACKGROUND: Clinical responses to EGFR tyrosine kinase inhibitors (TKIs) are restricted to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. All TKIs however, effectively inhibit EGFR phosphorylation regardless of the mutation present. METHODS: High-throughput, high-content imaging analysis, western blot, Reversed phase protein arrays, mass spectrometry and RT-qPCR. FINDINGS: We show that the addition of TKIs results in a strong and rapid intracellular accumulation of EGFR. This accumulation mimicked clinical efficacy as it was observed only in the context of the combination of a TKI-sensitive mutation with a clinically effective (type I) TKI. Intracellular accumulation of EGFR was able to predict response to gefitinib in a panel of cell-lines with different EGFR mutations. Our assay also predicted clinical benefit to EGFR TKIs on a cohort of pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004 [Cox proportional hazard model]) and could predict the clinical response in patients harboring rare mutations with unknown TKI-sensitivity. All investigated TKIs, regardless of clinical efficacy, inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present. Intracellular accumulation of EGFR depended on a continued presence of TKI indicating (type I) TKIs remain associated with the protein even after its dephosphorylation. Accumulation therefore is likely caused by two consecutive conformational changes, induced by both activating mutation and TKI, that combined block EGFR-membrane recycling. INTERPRETATION: We report on an assay that mimics the discrepancy between molecular and clinical activity of EGFR-TKIs, which may allow response prediction in vitro and helps understand the mechanism of effective inhibitors.

A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients.

BACKGROUND: Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC). METHODS: In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type. RESULTS: Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m2 and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma. CONCLUSIONS: Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.