Electrospun Produced 3D Matrices for Covering of Vascular Stents:Paclitaxel Release Depending on Fiber Structure and Composition of the External Environment

Paclitaxel is a natural, highly lipophilic anti proliferative drug widely used in medicine. We have studied the release of tritium-labeled paclitaxel (3H-PTX) from matrices destined for the coating of vascular stents and produced by the electrospinning method from the solutions of polycaprolactone (PCL) with paclitaxel (PTX) in hexafluoisopropanol (HFIP) and/or solutions of PCL with PTX and human serum albumin (HSA) in HFIP or HIFP-dimethyl sulphoxide (DMSO) blend. The release of PTX has been shown to depend on the composition of electrospinning solution, as well as the surrounding medium, particularly the concentration of free PTX and PTX-binding biomolecules present in human serum. It was shown that 3D matrices can completely release PTX without weight loss. Two-phase PTX release from optimized 3D matrices was obtained: ~27% of PTX was released in the first day, another 8% were released over the next 26 days. Wherein ~2.8%, ~2.3%, and ~0.25% of PTX was released on day 3, 9, and 27, respectively. Considering PTX toxicity, the rate of its diffusion through the arterial wall, and the data obtained the minimum cytostatic dose of the drug in the arterial wall will be maintained for at least three months. © 2018 by the authors

Utility of cfDNA Fragmentation Patterns in Designing the Liquid Biopsy Profiling Panels to Improve Their Sensitivity

Genotyping of cell-free DNA (cfDNA) in plasma samples has the potential to allow for a noninvasive assessment of tumor biology, avoiding the inherent shortcomings of tissue biopsy. Next generation sequencing (NGS), a leading technology for liquid biopsy analysis, continues to be hurdled with several major issues with cfDNA samples, including low cfDNA concentration and high fragmentation. In this study, by employing Ion Torrent PGM semiconductor technology, we performed a comparison between two multi-biomarker amplicon-based NGS panels characterized by a substantial difference in average amplicon length. In course of the analysis of the peripheral blood from 13 diagnostic non-small cell lung cancer patients, equivalence of two panels, in terms of overall diagnostic sensitivity and specificity was shown. A pairwise comparison of the allele frequencies for the same somatic variants obtained from the pairs of panel-specific amplicons, demonstrated an identical analytical sensitivity in range of 140 to 170 bp amplicons in size. Further regression analysis between amplicon length and its coverage, illustrated that NGS sequencing of plasma cfDNA equally tolerates amplicons with lengths in the range of 120 to 170 bp. To increase the sensitivity of mutation detection in cfDNA, we performed a computational analysis of the features associated with genome-wide nucleosome maps, evident from the data on the prevalence of cfDNA fragments of certain sizes and their fragmentation patterns. By leveraging the support vector machine-based machine learning approach, we showed that a combination of nucleosome map associated features with GC content, results in the increased accuracy of prediction of high inter-sample sequencing coverage variation (areas under the receiver operating curve: 0.75, 95% CI: 0.750–0.752 vs. 0.65, 95% CI: 0.63–0.67). Thus, nucleosome-guided fragmentation should be utilized as a guide to design amplicon-based NGS panels for the genotyping of cfDNA samples

Afatinib in EGFR TKI-naïve patients (pts) with locally advanced/metastatic NSCLC harbouring EGFR mutations: An interim analysis of a phase IIIB trial

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Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer

In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non-small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407. Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided. A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125). Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC

Сравнительный анализ современных систем стадирования гепатоцеллюлярного рака – TNM/AJCC, CUPI, CLIP И BCLC в российской онкологической практике. Опыт Российского онкологического научного центра им. Н. Н. Блохина

Aims: to explore the prognostic and practical utilit y of several internationally validated hepatocellular cancer (HCC) staging systems for Russian patient’s cohor t. Methods: retrospective trial of 380 HCC cases referred to Russian Cancer Research center n. a.N.N.Blokhin from Jan 2006 till Dec 2015. Results: median follow-up duration was 16,5 months. All HCC staging systems showed statistical significance for prognosis by univariate analysis: TNM/AJCC (p<0,0001; HR1,294; 95% CI 1,207–1,398); BCLC (p<0,0001; HR1,782; 95% CI 1,518–2,093); CLIP (p<0,0001; HR1,777; 95% CI 1,565–2,017); CUPI (p<0,0001; HR2,537; 95% CI 1,985–3,234). Significant sur vival difference was found across groups of early and late TNM/AJCC stages only. At multivariate analysis, prognosis was independently predicted by CUPI (HR1,512, р=0,004), CLIP (HR1,392, р<0,0001) and BCLC (HR1,337, р=0,001) for Russian patient’s cohort.Conclusions: the Barcelona Clinic Liver Cancer (BCLC) system was shown to have excellent discrimination of survival in patients with HCC and had a practically meaningful for Russian HCC patient’s cohort staging. BCLC staging and Child-Pugh-driven liver function assessment have to be obligatory supplement to TNM/AJCC in HCC diagnosis.Цель исследования: сравнить прогностическую и практическую ценность современных международных систем стадирования гепатоцеллюлярного рака (ГЦР) в российской популяции. Материалы и методы: ретроспективно проведено стадирование 380 случаев ГЦР, наблюдавшихся в ФГБУ «РОНЦ им. Н. Н. Блохина» МЗ РФ с 2006 по 2015 гг. Результаты: медиана наблюдения составила 16,5 мес. При однофакторном анализе все системы стадирования ГЦР обладают достоверной прогностической значимостью: TNM/AJCC (p<0,0001; OP 1,294 95% ДИ 1,207–1,398); BCLC (p<0,0001; OP 1,782 95% ДИ 1,518–2,093); CLIP (p<0,0001; OP 1,777 95% ДИ 1,565–2,017); CUPI (p<0,0001; OP 2,537 95% ДИ 1,985–3,234). TNM/AJCC обладает прогностической значимостью только при ранних стадиях ГЦР, различие кривых ОВ между другими стадиями недостоверно. Многофакторный анализ подтвердил независимую прогностическую значимость индекса CUPI (ОР 1,512, р=0,004), CLIP (ОР 1,392, р<0,0001) и стадии BCLC (ОР 1,337, р=0,001) в российской когорте больных ГЦР. Заключение: стадирование ГЦР по классификации BCLC обладает очевидной прогностической и практической ценностью в российской популяции больных ГЦР. Учитывая технические сложности стадирования по CUPI и CLIP, классификация BCLC и определение функционального статуса печени (Child-Pugh) должны быть обязательным дополнением при стадировании печеночно-клеточного рака по TNM/AJCC

Professional Communication Strategies in the Design Process of an Open Education Tutor

The article describes the professional communication strategies in the design activities of an open education tutor and the process of mastering these strategies. This process is based on the close relationship between the tutor's professional-oriented goals and his/her design levels in open education. Communication strategies allow the tutor to implement successfully professional activities in open education. Nowadays the problem of tutors’ mastering the professional communication strategies is very relevant due to the increasing opportunities of open education. The article presents the progress and results of the experimental work on the testing of the effectiveness of the proposed model of mastering the professional communication strategies by open education tutors. This model is aimed at developing communication skills in the process of their professional activity. In particular, the model is thought to achieve the necessary level of motivation for mastering the professional communication strategies in open education. The article presents the results of experimental work processed by methods of mathematical statistics. The results presented in the paper confirm the proposed provisions

Pseudochaotic behavior of deterministic automatic control systems of technical devices

А method for generating a pseudo-random response in a linear dynamic system is considered. An example of the system transition to pseudochaotic behavior is given. The calculation of fatigue loads in the toggle plate by the given method is presented. The advantage of this method in calculating fatigue loads is shown

Professional communication strategies in the design process of an open education tutor

The article describes the professional communication strategies in the design activities of an open education tutor and the process of mastering these strategies. This process is based on the close relationship between the tutor's professional-oriented goals and his/her design levels in open education. Communication strategies allow the tutor to implement successfully professional activities in open education. Nowadays the problem of tutors’ mastering the professional communication strategies is very relevant due to the increasing opportunities of open education. The article presents the progress and results of the experimental work on the testing of the effectiveness of the proposed model of mastering the professional communication strategies by open education tutors. This model is aimed at developing communication skills in the process of their professional activity. In particular, the model is thought to achieve the necessary level of motivation for mastering the professional communication strategies in open education. The article presents the results of experimental work processed by methods of mathematical statistics. The results presented in the paper confirm the proposed provisions

CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations

Gent gran; Nivolumab; Càncer de pulmó de cèl·lules no petitesAnciano; Nivolumab; Cáncer de pulmón de células no pequeñasElderly; Nivolumab; Non-small cell lung cancerBackground CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial. Methods Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3–4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety. Results Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3–4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. Conclusion These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population.Funded by Bristol-Myers Squibb