Immuno-chemotherapy reduces recurrence of malignant pleural mesothelioma: an experimental setting

Objective: To assess the effect of immuno-chemotherapy on the extent of local tumour recurrence in an established rat model of malignant pleural mesothelioma (MPM). Methods: Six days after subpleural inoculation of a syngeneic MPM cell line Interleukin-45 (IL-45), left-sided pneumonectomy and resection of the tumour nodule was performed. Animals were randomised into four treatment groups for intrapleural therapy: control (n=6), 500μg cytosine phosphate guanosine oligodeoxynucleotide (CpG-ODN) (n=6), cisplatin-fibrin (n=6), cisplatin-fibrin+500μg CpG (n=6). Six days later the volume of tumour recurrence was assessed, which was the primary endpoint. Secondary endpoints were quantification of the ratio host/tumour cells in the local recurrence and cytokine expression profile in the tumour tissue by real time quantitative PCR (qPCR). T lymphocyte subpopulations in the tumour recurrence tissue were evaluated by immunohistochemistry. Treatment-related toxicity was monitored by measuring blood chemistry and complete blood count. Results: The volume of tumour recurrence was significantly reduced from 610mm3 in the control group to 11.7mm3 in the cisplatin-fibrin group (p=0.004) and to 21.8mm3 in the cisplatin-fibrin+CpG group (p=0.004). Pro-inflammatory cytokines (Interferon-γ (IFN-γ), Interleukin-6 (IL-6), Interleukin-12 (IL-12)) were increased after treatment with cisplatin-fibrin+CpG in comparison to cisplatin-fibrin alone but differences were not statistically significant. We found a higher ratio of host/tumour cells in the cisplatin-fibrin+CpG group (45/55%) compared to the cisplatin-fibrin group (27/73%). In comparison to the control group, animals treated with cisplatin-fibrin+CpG showed a higher number of CD8+ T-cells in the tumour tissue. No significant treatment-related toxicity was observed. Conclusions: Adjuvant treatment with chemotherapy or immuno-chemotherapy leads to significant reduction of mesothelioma recurrence after surgery in this rat MPM model. Immuno-chemotherapy resulted in an increased recruitment of inflammatory cells to the site of tumourigenesis and elicited higher level of tumour growth inhibiting cytokine

Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC

n/

Disciplinary problems among high achiever students: the types and the causes

This qualitative study has been done to 24 teachers and 72 students from various secondary schools in Penang, Malaysia, in order to investigate the effect of between class ability grouping (BCAG) on high achiever secondary school students. Studies reported that BCAG triggered correspondence bias among teachers, which eventually affect them to show different perception and expectations towards high achiever classes (HAC) and low achiever classes (LAC) students. Symbolic interaction theories explained that individuals tend to be affected by others’ expectation, and therefore behave in a way they were expected to. Therefore, according to the previous studies on BCAG, it was assumed that HAC students would achieve better and would not be significantly involved in disciplinary problems. After semi-structured interview had been conducted in order to collect the data, and two-cycled analyses method, namely In-Vivo and Thematic Analyses had been operated in order to analyze the massive amount of qualitative data, the it was discovered that HAC students were involved with disciplinary problems, such as being disrespectful to teachers, paying less attention in the classroom, neglecting assignments and doing external work during classes. Other findings of this study showed that the disciplinary problems among HAC are related to their self-esteem types due to locus of control difference, as well as bigger issues apart from the competition among themselves. School management system, BCAG itself, reciprocal envy between HAC and LAC students, as well as their inclination towards tuition centers contributed to disciplinary problems among HAC students

Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells.

Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM

Pathological and clinical features of multiple cancers and lung adenocarcinoma: a multicentre study

OBJECTIVES: Lung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes.METHODS: We retrospectively reviewed data of patients radically operated on for stage I-II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups.RESULTS: We included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008).CONCLUSIONS: In patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

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 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-naïve 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

Retrospective immunophenotypical evaluation of MET, PD-1/PD-L1, and mTOR pathways in primary tumors and pulmonary metastases of renal cell carcinoma: the RIVELATOR study addresses the issue of biomarkers heterogeneity

Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations