Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

YB-1 regulates mesothelioma cell migration via snail but not EGFR, MMP1, EPHA5 or PARK2.

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y-box-binding protein-1 (YB-1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB-1 on target gene regulation and PM cell behavior. Whereas siRNA-mediated YB-1 knockdown reduced cell motility, YB-1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB-1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB-1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB-1. Finally, we identified snail as a critical regulator of YB-1-mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB-1 in this cancer. In this context, we found that YB-1 closely regulates EGFR and snail, and, moreover, that YB-1-induced cell migration depends on snail.

Gender differences in molecular-guided therapy recommendations for metastatic malignant mesothelioma.

BACKGROUND: Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile. METHODS: In this single-center, real-world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next-generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off-label therapy custom-tailored to the individual patient. RESULTS: In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD-L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender-specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease. CONCLUSIONS: Our observations suggest that a molecular-guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.

Infraglottic versus supraglottic jet-ventilation for endobronchial ultrasound-guided transbronchial needle aspiration: A randomised controlled trial.

BACKGROUND: For endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under general anaesthesia, both rigid bronchoscopy and laryngeal masks (LMAs) with superimposed high-frequency jet ventilation can be used. Despite the fact that in Europe rigid bronchoscopy for EBUS-TBNA is still widely used, an increasing number of centres use jet ventilation via the LMA for this procedure. To our knowledge no clinical trials have ever been made to compare these two methods. This trial aimed to evaluate whether patients recover from the procedure more quickly when a LMA is used for ventilation compared with rigid bronchoscopy where muscle relaxants and deep anaesthesia are required. OBJECTIVES: We wanted to test the hypothesis that there is no difference in the postoperative recovery of patients in the postanaesthesia care unit (PACU) after EBUS-TBNA with jet ventilation via a rigid bronchoscope and a LMA. Secondary outcomes were the difference of duration of anaesthesia, the diagnostic outcome of the procedure and drug quantities for both groups. DESIGN: Prospective randomised single blinded two centre controlled trial. SETTING: Two centres in Austria participated. Patients were enrolled from December 2016 until January 2018. PATIENTS: Ninety patients for elective EBUS-TBNA were enrolled and assigned to one of two intervention groups. Two patients were excluded before and eleven patients were excluded after EBUS-TBNA. Seventy-seven were analysed. INTERVENTIONS: Patients assigned to group 1 were ventilated with a LMA; those assigned to group 2 were ventilated via a rigid bronchoscope. Vital signs, drug dosage, duration of anaesthesia, recovery, PACU stay and Aldrete score at the PACU were recorded. MAIN OUTCOME MEASURES: The primary endpoint was an integral over time of a modified Aldrete score. Secondary endpoints were the durations of the interventions, the recovery from anaesthesia and PACU stay, initial and mean Aldrete values at PACU, the effect site concentration of Propofol according to the Schnider pharmacokinetic model, the peak ultiva rates and the diagnostic outcome. RESULTS: We were not able to show any significant difference regarding the postoperative recovery criteria based on the Aldrete score, the durations measured and the diagnostic outcomes. Vital signs remained stable and in an equal range in both groups. There were no differences in the mean effect site propofol concentration and the peak ultiva rates. CONCLUSION: EBUS-TBNA under general anaesthesia using a LMA with SHJV is equal to rigid bronchoscopy with superimposed high-frequency jet ventilation for the variables analysed. TRIAL REGISTRATION: ISRCTN (ISRCTN58911367).

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.

Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity.

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.

Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro.

Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50 values ≤ 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xL as a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro Thus, it represents a promising new therapeutic option for MPM. Mol Cancer Ther; 15(10); 2357-69. ©2016 AACR.

Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.

RATIONALE: Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined. OBJECTIVES: To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition. METHODS: Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation. MEASUREMENTS AND MAIN RESULTS: FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin. CONCLUSIONS: Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.

Lobar lung transplantation--is it comparable with standard lung transplantation?

Lobar lung transplantation is used mainly for urgent small recipients who are less likely to obtain size matched lungs in due time. Only limited numbers have been published, and we herewith report the largest series of lobar-LuTX. We analyzed our LuTX database from 1/2001 to 12/2012 and compared the outcome of lobar-LuTX recipients with those receiving standard LuTX. Seven hundred and seventy-eighty LuTX (group 1) were performed either in standard technique by implanting the whole lungs (n = 539) or with downsizing by wedge resection of the right middle lobe and/or the left lingula (n = 239). One hundred and thirty-eight LuTX were performed in lobar technique (group 2) to overcome more pronounced size discrepancies. Patients in group 1 had a different spectrum of diagnoses and were less frequently bridged to LuTX (P < 0.001). Intubation time, ICU stay, and hospital stay were shorter in group 1 (P < 0.001). One-year survival was 84.8% vs. 65.1%, and 5-years survival 69.9% vs. 54.9% (P < 0.001). In multivariate analyzes, procedure, diagnosis, and pre-operative bridging were shown to be significant prognostic factors in survival. Early postoperative outcome in Lobar LuTX was significantly inferior to standard LuTX recipients. However, survival rates of successfully dismissed patients were comparable with standard LuTX (P = 0.168); thereby, Lobar-LuTX remains an important option in the management of urgent small recipients.

The role of microRNAs in the diagnosis and treatment of malignant pleural mesothelioma--a short review.

MicroRNAs are a class of small, non-coding RNAs that can function as tumor suppressors or oncogenes by regulating gene expression. This link was first reported in 2004, and has since been tied to a variety of malignancies, including malignant pleural mesothelioma (MPM). MPM is a malignancy arising in the mesothelial cells lining the lung pleura and is associated with chronic asbestos exposure. Despite the possibility for observing declining localized occurrence, global MPM is predicted to remain constant or increase slightly over the next decade. Global occurrence in combination with poor overall survival, difficulty in diagnosis, and limited effective treatment options signal the need for further exploration of miRNA involvement in MPM. Accordingly, this review highlights miRNA profiles associated with the diagnosis, prognosis, and therapeutic approaches in MPM.

The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease that comprises sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells, and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding array of novel therapies; however, IPAH remains a progressive disease with poor outcome in most instances. To identify new regulatory pathways of vascular remodeling in IPAH, we performed transcriptome-wide expression profiling of laser-microdissected pulmonary arterial resistance vessels derived from explanted IPAH and nontransplanted donor lung tissues. Statistical analysis of the data derived from six individuals in each group showed significant regulation of several mediators of the canonical and noncanonical WNT pathway. As to the noncanonical WNT pathway, the planar cell polarity (PCP) pathway, the ras homolog gene family member A (RHOA), and ras-related C3 botulinum toxin substrate-1 (RAC1) were strongly up-regulated. Real-time PCR of laser-microdissected pulmonary arteries confirmed these array results and showed in addition significant up-regulation of further PCP mediators wingless member 11 (WNT11), disheveled associated activator of morphogenesis-1 (DAAM1), disheveled (DSV), and RHO-kinase (ROCK). Immunohistochemical staining and semiquantitative expression analysis confirmed the markedly enhanced expression of the PCP mediators in the pulmonary resistance vessels, in particular in the endothelial layer in IPAH. Therefore we propose the PCP pathway to be critically involved in the regulation of vascular remodeling in IPAH.

Does gastric dilatation limit the success of sleeve gastrectomy as a sole operation for morbid obesity?

BACKGROUND: Sleeve gastrectomy as the sole bariatric operation has been reported for high-risk super-obese patients or as first-step followed by Roux-en-Y gastric bypass (RYGBP) or duodenal switch (DS) in super-super obese patients. The efficacy of laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients with a BMI of <50 kg/m2 and the incidence of gastric dilatation following LSG have not yet been investigated. METHODS: 23 patients (15 morbidly obese, 8 super-obese) were studied prospectively for weight loss following LSG. The incidence of sleeve dilatation was assessed by upper GI contrast studies in patients with a follow-up of >12 months. RESULTS: Patients who underwent LSG achieved a mean excess weight loss (EWL) at 6 and 12 months postoperatively of 46% and 56%, respectively. No significant differences were observed in %EWL comparing obese and super-obese patients. At a mean follow-up of 20 months, dilatation of the gastric sleeve was found in 1 patient and weight regain after initial successful weight loss in 3 of the 23 patients. CONCLUSION: LSG has been highly effective for weight reduction for morbid obesity even as the sole bariatric operation. Gastric dilatation was found in only 1 patient in this short-term follow-up. Weight regain following LSG may require conversion to RYGBP or DS. Follow-up will be necessary to evaluate long-term results.