Disclosing large-scale directed functional connections in MEG with the multivariate phase slope index.

Abstract The phase slope index (PSI) is a method to disclose the direction of frequency-specific neural interactions from magnetoencephalographic (MEG) time series. A fundamental property of PSI is that of vanishing for linear mixing of independent neural sources. This property allows PSI to cope with the artificial instantaneous connectivity among MEG sensors or brain sources induced by the field spread. Nevertheless, PSI is limited by being a bivariate estimator of directionality as opposite to the multidimensional nature of brain activity as revealed by MEG. The purpose of this work is to provide a multivariate generalization of PSI. We termed this measure as the multivariate phase slope index (MPSI). In order to test the ability of MPSI in estimating the directionality, and to compare the MPSI results to those obtained by bivariate PSI approaches based on maximizing imaginary part of coherency and on canonical correlation analysis, we used extensive simulations. We proved that MPSI achieves the highest performance and that in a large number of simulated cases, the bivariate methods, as opposed to MPSI, do not detect a statistically significant directionality. Finally, we applied MPSI to assess seed-based directed functional connectivity in the alpha band from resting state MEG data of 61 subjects from the Human Connectome Project. The obtained results highlight a directed functional coupling in the alpha band between the primary visual cortex and several key regions of well-known resting state networks, e.g. dorsal attention network and fronto-parietal network

ALK rearrangement in a large series of consecutive non-small cell lung cancers: Comparison between a new immunohistochemical approach and fluorescence in situ hybridization for the screening of patients eligible for crizotinib treatment

Context. - Echinoderm microtubule associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase (EML4-ALK) translocation has been described in a subset of patients with non-small cell lung cancer (NSCLC) and has been shown to have oncogenic activity. Fluorescence in situ hybridization (FISH) is used to detect ALK-positive NSCLC, but it is expensive, time-consuming, and difficult for routine application. Objective. - To evaluate the potential role of immunohistochemistry (IHC) as a screening tool to identify candidate cases for FISH analysis and for ALK inhibitor therapy in NSCLC. Design. - We performed FISH and IHC for ALK and mutational analysis for epidermal growth factor receptor (EGFR) and KRAS in 523 NSCLC specimens. We conducted IHC analysis with the monoclonal antibody D5F3 (Ventana Medical Systems, Tucson, Arizona) and a highly sensitive detection system. We also performed a MassARRAY-based analysis (Sequenom, San Diego, California) in a small subset of 11 samples to detect EML4-ALK rearrangement. Results. - Of the 523 NSCLC specimens, 20 (3.8%) were positive for ALK rearrangement by FISH analysis. EGFR and KRAS mutations were identified in 70 (13.4%) and 124 (23.7%) of the 523 tumor samples, respectively. ALK rearrangement and EGFR and KRAS mutations were mutually exclusive. Of 523 tumor samples analyzed, 18 (3.4%) were ALK+ by IHC, 18 samples (3.4%) had concordant IHC and FISH results, and 2 ALK+ cases (0.3%) by FISH failed to show ALK protein expression. In the 2 discrepant cases, we did not detect any mass peaks for the EML4-ALK variants by MassARRAY. Conclusions. - Our results show that IHC may be a useful technique for selecting NSCLC cases to undergo ALK FISH analysis

Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA

INTRODUCTION: KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR). AIM: The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance. METHODS: This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI. RESULTS: p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively. CONCLUSIONS: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance

Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.

PURPOSE: MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. PATIENTS AND METHODS: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts. RESULTS: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. CONCLUSIONS: Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Non-linear Analysis of Scalp EEG by Using Bispectra: The Effect of the Reference Choice

Bispectral analysis is a signal processing technique that makes it possible to capture the non-linear and non-Gaussian properties of the EEG signals. It has found various applications in EEG research and clinical practice, including the assessment of anesthetic depth, the identification of epileptic seizures, and more recently, the evaluation of non-linear cross-frequency brain functional connectivity. However, the validity and reliability of the indices drawn from bispectral analysis of EEG signals are potentially biased by the use of a non-neutral EEG reference. The present study aims at investigating the effects of the reference choice on the analysis of the non-linear features of EEG signals through bicoherence, as well as on the estimation of cross-frequency EEG connectivity through two different non-linear measures, i.e., the cross-bicoherence and the antisymmetric cross-bicoherence. To this end, four commonly used reference schemes were considered: the vertex electrode (Cz), the digitally linked mastoids, the average reference, and the Reference Electrode Standardization Technique (REST). The reference effects were assessed both in simulations and in a real EEG experiment. The simulations allowed to investigated: (i) the effects of the electrode density on the performance of the above references in the estimation of bispectral measures; and (ii) the effects of the head model accuracy in the performance of the REST. For real data, the EEG signals recorded from 10 subjects during eyes open resting state were examined, and the distortions induced by the reference choice in the patterns of alpha-beta bicoherence, cross-bicoherence, and antisymmetric cross-bicoherence were assessed. The results showed significant differences in the findings depending on the chosen reference, with the REST providing superior performance than all the other references in approximating the ideal neutral reference. In conclusion, this study highlights the importance of considering the effects of the reference choice in the interpretation and comparison of the results of bispectral analysis of scalp EEG