Immunotherapy based on immune checkpoint inhibitors (ICIs) represents a novel anticancer treatment strategy. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA4), programmed cell death-1 receptor (PD1) and programmed cell death-1 ligand (PD-L1) have shown efficacy and safety in the treatment of various malignancies. Some of them have recently found their place in a routine clinical practice, while others are at different phases of clinical trials. Treatment with ICIs may be accompanied by undesirable impairment of immunotolerance to non-tumoural tissues, leading to a specific side-effect also called immune-related adverse events (irAE). There is an increasing body of evidence that the development of irAEs is associated with a beneficial effect of immunotherapy, thus it has become a hot topic in the field of clinical oncology. This review is focused on data from recently published studies evaluating the association between irAEs and outcome of patients with cancer treated with ICIs.
The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents.The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab.We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011).PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.
This paper presents a way how a simulation model of an industrial Ethernet network is designed and how it is parametrised according to a real network. The parameter set up is done by capturing the Ethernet frames in the network and by performing their detailed analysis. The device types in the simulation have been designed as generic that can be parametrised externally and automatically based on the identification of a real network. Thus the parameters of the real devices such as switch delay are used to adapt the simulation and the simulation results are compared to the real traffic in a series of long-term observations. Such a setting can be used to perform diagnostics of industrial Ethernet networks to identify e.g. bursts of messages and thus discovering potential bottlenecks and problems aiming at interrupting or disturbing the connected application process, eventually.
INTRODUCTION: Patients in advanced stages of non-small cell lung carcinomas (NSCLC), who and unsuited for targeted biological therapy because of lack of actionable molecular predictors are frequently treated by anti-angiogenic therapy. The effectiveness of such therapy is primarily relying on imaging techniques including CT or hybrid PET/CT evaluating a combination of morphological factors (dimensions and volume) and, more recently, also functional parameters including the metabolic activity, tumor vascularization etc. The ability to track the course of the disease at the same time all of these parameters is prerequisite to enable timely monitoring and therapy change in case of an early detection of resistance. This study was aimed at utility of circulating-tumor DNA (ctDNA) as an tool for monitoring of therapy response. and assessment of phenotypic parameters of the tumor.PATIENTS AND METHODS: A total of 50 patients with confirmed Stage IV lung adenocarcinomas showing negativity on ALK, BRAF, EGFR, RET, ROS1 and MET predictors were prospectively enrolled into the study. Patients were treated under a standard protocol by a combination of paclitaxes/carboplatin/bevacizumab and followed by dual PET/CT. For each patient cytology tissue sample was subjected to test for a panel of somatic mutations. The found mutations were subsequently detected in ctDNA in plasma extracted from peripheral blood collected prior to therapy start and then in 1-month intervals during the therapy. The occurrence and quantity of ctDNA were correlated with the objective therapy response (RECIST) and to the functional imaging parameters of metabolic activity and vascularization.RESULTS: ctDNA was initially positive in 29 patients. ctDNA levels closely reflected the response to the therapy with complete or partial remission expressed as reduction or absence of ctDNA, while disease stabilization or progression signaled by persisting or increasing ctDNA levels. There was a borderline correlation between ctDNA and vascularization evaluated by dual PET/CT (p=0.055).CONCLUSION: In a subset of patients ctDNA can readily serve as a surrogate marker for semi-continuous monitoring of the effect of anti-angiogenic therapy. Work supported by Czech Ministry of Health project AZV 17-30748A.Citation Format: Marek Minarik, Martin Svaton, Barbora Belsanova, Anastasiya Semyakina, Jan Baxa, Ondrej Fiala, Milos Pesek, Lucie Benesova. Application of a serial liquid biopsy ctDNA assay for monitoring efficacy of anti-angiogenic lung cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 412.
Background
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent novel effective agents approved for the treatment of patients with advanced-stage non-small cell lung cancer (NSCLC). KRAS mutations have been reported as a negative prognostic and predictive factor in patients with NSCLC treated with EGFR-TKIs. Several studies have recently shown that statins can block tumor cell growth, invasion and metastatic potential.
Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC.Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes.Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib.Rash is associated with a good therapeutic response.We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed.Comparison of ORR, PFS and OS according to the occurrence of rash was performed.In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124).Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis.The comparison of ORR was performed using Fisher's exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test.Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001),median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001).ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001).Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027).Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082).Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes.Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment.Patients who were not observed with rash during the first month of treatment are in high risk of progression.Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.
