Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma

Aims: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches

Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics—Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer

Companion diagnostics (CDx) have become a major tool in molecular pathology and assist in therapy decisions in an increasing number of various cancers. Particularly, the developments in lung cancer have been most impressing in the last decade and consequently lung cancer mutation testing and molecular profiling has become a major business of diagnostic laboratories. However, it has become difficult to decide which biomarkers are currently relevant for therapy decisions, as many of the new biomarkers are not yet approved as therapy targets, remain in the status of clinical studies, or still have not left the experimental phase. The current review is focussed on those markers that do have current therapy implications, practical implications arising from the respective companion diagnostics, and thus is focused on daily practice

Atypical bilateral ventilation/perfusion mismatches in an asymptomatic patient suffering from metastatic thyroid cancer

Background!#!Pulmonary embolism is indicated by ventilation/perfusion (V/P) mismatches in ventilation/perfusion scintigraphy. However, other pathologies may also evoke segmental or lobar mismatches. Thus, diagnosis can be difficult in asymptomatic patients with equivocal clinical presentation.!##!Case presentation!#!We present a case of multiple bilateral pulmonary ventilation/perfusion mismatches in a poorly differentiated thyroid cancer patient. Exact diagnosis was difficult, as the patient was asymptomatic and pulmonary embolism is commonly unilateral in tumour patients and not typical for thyroid cancer. External pulmonary artery compression by aortic aneurysm, multiple metastases or additional bronchopulmonary malignancies were considered as differential diagnosis. After unilateral pulmonary and hilar metastasectomy, perfusion normalised on the operated side. Pulmonary perfusion defects due to pulmonary artery compression by hilar metastases were finally diagnosed. Pulmonary embolism was deemed unlikely due to the left-sided post-operative normalisation, persistence of right-sided V/P mismatches, and the lack of clinical symptoms.!##!Conclusion!#!Pulmonary artery compression may mimic pulmonary artery embolism in lung perfusion scintigraphy and should be considered in bronchopulmonary tumour patients with hilar metastases and unilateral ventilation/perfusion mismatches affecting a complete lobe or even lung. Following the presented case, also bilateral segmental and subsegmental mismatches in patients with hilar metastases from non-bronchopulmonary cancer entities should be carefully evaluated

Lung Cancer Surgery after Neoadjuvant Immunotherapy

In early-stage lung cancer, recurrences are observed even after curative resection. Neoadjuvant immunotherapy might be a promising approach to eliminate micrometastasis and to potentially reduce recurrence rates and improve survival. Early trials have shown encouraging rates of pathologic response to neoadjuvant therapy and have demonstrated that surgery can be safely performed after neoadjuvant immunotherapy with various agents and in combination with chemo-(radio)therapy. However, whether these response rates translate into improved disease-free survival rates and overall survival rates remains to be determined by ongoing phase III studies

CCL18 serum level and survival of patients with NSCLC in days from time point of diagnosis.

<p>Survival time varies significantly with different serum CCL18 levels (p<0.004).</p

Mean CCL18 levels of all T stages was significantly increased compared with controls (p<0.0002).

<p>In addition, there was a significant difference between patient groups with lowest versus the two highest T-stages.</p

Roflumilast-N-oxide Induces Surfactant Protein Expression in Human Alveolar Epithelial Cells Type II

<div><p>Surfactant proteins (SPs) are important lipoprotein complex components, expressed in alveolar epithelial cells type II (AEC-II), and playing an essential role in maintenance of alveolar integrity and host defence. Because expressions of SPs are regulated by cyclic adenosine monophosphate (cAMP), we hypothesized that phosphodiesterase (PDE) inhibitors, influence SP expression and release. Analysis of PDE activity of our AEC-II preparations revealed that PDE4 is the major cAMP hydrolysing PDE in human adult AEC-II. Thus, freshly isolated human AEC-II were stimulated with two different concentrations of the PDE4 inhibitor roflumilast-N-oxide (3 nM and 1 µM) to investigate the effect on SP expression. SP mRNA levels disclosed a large inter-individual variation. Therefore, the experiments were grouped by the basal SP expression in low and high expressing donors. AEC-II stimulated with Roflumilast-N-oxide showed a minor increase in SP-A1, SP-C and SP-D mRNA mainly in low expressing preparations. To overcome the effects of different basal levels of intracellular cAMP, cyclooxygenase was blocked by indomethacin and cAMP production was reconstituted by prostaglandin E2 (PGE2). Under these conditions SP-A1, SP-A2, SP-B and SP-D are increased by roflumilast-N-oxide in low expressing preparations. Roflumilast-N-oxide fosters the expression of SPs in human AEC-II via increase of intracellular cAMP levels potentially contributing to improved alveolar host defence and enhanced resolution of inflammation.</p> </div

mRNA levels of surfactant proteins in human AEC-II.

<p>SP-A1, SP-A2, SP-B, SP-C and SP-D mRNA expression level of human AEC-II (freshly isolated or cultured for 24 h) were measured by real-time PCR. Bar charts show mean ± SD (n = 5, native = freshly isolated non-cultured cells; 24 h culture  =  isolated cells cultured as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038369#s2" target="_blank">Material and Methods</a>).</p

SP-B, C, and D mRNA level in presence of indomethacin and PGE2.

<p>Freshly isolated AEC-II were cultured for 24 h with indomethacin/PGE2 and the indicated substances. After the culture period SP-B (A), SP-C (B) and SP-D (C) mRNA expression was measured by real-time PCR. Due to the large variation in surfactant protein mRNA expression cultures were separated according their basal median expression of the respective surfactant protein (low level SP-B<1088, SP-C<970059, SP-D<11515 black bars; high level SP-B>1088, SP-C>970059, SP-D>11515 hatched bars; A, B, C). Bar charts show means ± SD (n_low = 6, n_high = 5, A, B,; n_low = 6, n_high =6, C; c = non-stimulated control; dbcAMP = dibutyryl-cAMP; RNO = roflumilast-N-oxide; PGE2 = prostaglandin E2).</p