Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The... Show morePleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naive and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies. Show less
Dammeijer, F.; Gulijk, M. van; Mulder, E.E.; Lukkes, M.; Klaase, L.; Bosch, T. van den; ... ; Aerts, J.G. 2020
PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and... Show morePD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1(+) T cells which closely associate with PD-L1(+) cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy. Show less
Dumoulin, D.W.; Visser, S.; Cornelissen, R.; Gelder, T. van; Vansteenkiste, J.; Thusen, J. von der; Aerts, J.G.J.V. 2020
The combination of chemotherapy and immune check-point inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this... Show moreThe combination of chemotherapy and immune check-point inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this combination, renal toxicity was slightly higher than with chemotherapy alone in initial clinical trials. However, in recent real-world data, loss of kidney function is reported to be more frequent. Both chemotherapy and ICI therapy can induce renal impairment, although the mechanism of renal damage is different. Renal injury from chemo-therapy is often ascribed to acute tubular injury and necrosis, whereas the main mechanism of injury caused by ICI therapy is acute tubulointerstitial nephritis. In cases of concomitant use of chemotherapy and ICI therapy, distinguishing the cause of renal failure is a challenge. Discriminating between these two causes is of utmost importance, as it would help assess which drug can be safely continued and which drug must be halted. This review aims to describe the underlying mecha-nisms of the renal adverse effects caused by chemo-therapy and ICI therapy, leading to a suggested diagnostic and treatment algorithm on the basis of clinical, laboratory, radiographic, and pathologic param-eters. This algorithm could serve as a supportive tool for clinicians to diagnose the underlying cause of acute kidney injury in patients treated with the combination of chemotherapy and immunotherapy. Show less
Grewal, N.; Gittenberger-de Groot, A.C.; Thusen, J. von der; Wisse, L.J.; Bartelings, M.M.; DeRuiter, M.C.; ... ; Poelmann, R.E. 2020
Background: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in... Show moreBackground: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in the tricuspid aortic valve (TAV) and the BAV populations as a reference for future studies on aortopathy and related syndromes. Methods: Non-dilated TAV and BAV ascending aortic wall samples were collected, including 60 TAV (embryonic-70 years) and 32 BAV specimens (fetal-72 years, categorized in eight age groups. Results: In TAV, intimal development starts in the neonatal phase. After birth, the thickness of the medial layer increases significantly by increase of elastic lamellae up to and including the "young child" phase stabilizing afterwards. The BAV shows already prenatal intimal thickening becoming significantly thinner after birth subsequently stabilizing. In BAV, increase in elastic lamellae is seen between the young child and the adolescent phases, stabilizing afterwards. Conclusions: Vascular development in TAV is described in three phases: maturation, stabilization, and degeneration. For BAV, the development can be described in two phases: maturation (already prenatally) and degeneration. After birth, the development of the aorta is characterized by degeneration, leading to weakening of the ascending aortic wall and increasing the risk of aortopathy. Show less
Grewal, N.; Gittenberger-de Groot, A.C.; Thusen, J. von der; Wisse, L.J.; Bartelings, M.M.; DeRuiter, M.C.; ... ; Poelmann, R.E. 2020
