Эффективность и пути оптимизации эндоваскулярной лазерной коагуляции при варикозном расширении вен нижних конечностей

The purpose of the work is to assess the efficiency of endovascular laser coagulation (EVLC) of varicose vein disease of lower limb and to define the ways of optimization of such treatment. Material and methods. Out of 263 patients isolated EVLC was performed in 33.8% of the cases, with crossectomy and chemical sclerotherapy by sclerovein or fibro-vein – in 8.0%, with sclerotherapy without crossectomy – in 58.2%. EVLC was carried out by means of the device “Fotonika-Lika-Surgeon” (Ukraine). Results. In a month, a considerable improvement was noted in 39.9% of patients after EVLC, and later in a half a year – at 93.9%, at the same time the risk factors of the lower efficiency of the operation were the male and advanced age of the patients, high arterial blood pressure, the narrowing of the femoral arteries and the presence of comorbide gonarthrosis, within the first 4 weeks from the time of the operation the results of the treatment were closely connected with the changes of initial superficial adsorptive and rheological viscose properties of venous blood, whereas later on they depend on the condition of endothelial function of the vessels (the indicators of superficial viscosity, thromboxane-A2 and prostacyclin can have the predictive value), and the best effect is reached after holding of sclerotherapy conjoint with EVLC and the prescription of rivaroxaban within the first two weeks, besides, low-molecular heparins and cyclo-3-fort.Цель работы – оценить эффективность эндоваскулярной лазерной коагуляции (ЭВЛК) при варикозном расширении вен нижних конечностей и определить пути оптимизации такого лечения. Материал и методы. Среди 263 больных изолированная ЭВЛК выполнена в 33,8% случаев, с кроссэктомией и химической склеротерапией склеровейном или фибровейном – в 8,0%, со склеротерапией без кроссэктомии – в 58,2%. ЭВЛК осуществляли с помощью аппарата ≪Фотоніка-Ліка-Хірург≫ (Украина). Результаты. Значительное улучшение через месяц после ЭВЛК отмечено в 39,9% случаев, а спустя полгода – в 93,9%, при этом факторами риска более низкой эффективности операции являлись мужской пол и пожилой возраст больных, высокое артериальное давление, сужение бедренных артерий и наличие коморбидного гонартроза, причем в течение первых 4 недель от времени оперативного вмешательства результаты лечения были тесно связаны с изменени- ями исходных поверхностных адсорбционно-реологических вязких свойств венозной крови, тогда как в последующем зависели от состояния эндотелиальной функции сосудов (показате- ли поверхностной вязкости, тромбоксана-А2 и простациклина могут обладать прогностичес- кой значимостью), а наилучший эффект достигался после проведения совместной с ЭВЛК склеротерапии и применения ривароксабана, в течение первых двух недель – низкомолекулярных гепаринов и цикло-3-форта

Шляхи оптимізації лазерної та хімічної абляції вен при варикозній хворобі з коморбідним цукровим діабетом

The aim of the work: to assess the effectiveness of endovascular laser and chemical ablation in varicose vein disease (VVD) with type 2 comorbid diabetes mellitus (DM), develop the most optimal technology of therapeutic measures in this category of patients. Materials and Methods. Under the survey there were 162 patients with VVD (19 % of men and 81 % of women with the average age of 50 years) among whom the ratio of classes II, III, IV, V and VI of venous insufficiency was 1:1:3:1:2. DM occurred in 14 % of the cases while the distribution of mild, moderate and severe forms of the disease was 1:2:4 and the distribution of the phases of compensation, subcompensation and decompensation was 1:4:6. The content of glucose, glycosylated hemoglobin, insulin, C-peptide, fructosamine and microelements associated with carbohydrate metabolism (chromium, manganese, selenium, zinc) was studied in the blood from the cubital vein and the affected vein of the lower extremities. Laser vein ablation was performed using the device “Photonika-Lika-Surgeon” (Ukraine) and performing the paravasal “pillow” with Klein's solution using a pump for tuminascent anesthesia under ultrasound guidance and chemical (sclerotherapy) with a scleraine or fibrovascular solution. The first method was performed in 63 (39 %) patients, the second – in 99 (61 %). Results and Discussion. The effectiveness of laser ablation depends on the class of venous insufficiency, previous phlebothrombosis, additional use of rivaroxaban and low-molecular-weight heparins in the complex of therapeutic measures, laser coagulation techniques, the presence and the severity of comorbid DM, the parameters of carbohydrate metabolism in the target vein besides the parameters of selenium and zincemia increase after the surgery, and the number of complications arising depends on the phase of DM and the level of chromium in the blood from a varicose vein. The results of sclerotherapy in women were better, the number of complications was less which depended on the level of venous insufficiency, previous phlebothrombosis and the lumen of the target vein of the leg, the parameters insulin, C-peptide and fructosamine in the blood from it. In a comparative assessment of various methods of surgical treatment of VVD laser ablation (coagulation) was characterized by a greater severity of comorbid DM, more frequent additional use of rivaroxaban and cyclo-3-fort, with the exception of patients with diabetic encephalopathy from the development, and sclerotherapy was not used in patients with nephropathy while the effectiveness of the activities carried out in both groups was about the same. In patients with VVD a therapeutic algorithm has been developed for applying the most optimal medical technology for laser and chemical ablation taking into account the nature of the flow of venous pathology and comorbid DM, systemic and local changes in carbohydrate metabolism, and background drug therapy.Цель работы: оценить эффективность эндоваскулярной лазерной и химической абляции вен при варикозной болезни (ВБ) с коморбидным сахарным диабетом (СД) типа 2, разработать наиболее оптимальную технологию лечебных мероприятий у такой категории больных. Материалы и методы. Под наблюдением находились 162 больных ВБ (19 % мужчин и 81 % женщин со средним возрастом 50 лет), среди которых соотношение II, III, IV, V и VI классов венозной недостаточности составило 1:1:3:1:2. СД имел место в 14 % случаев, при этом распределение легкой, средней тяжести и тяжелой формы болезни составило 1:2:4, а фаз компенсации, субкомпенсации и декомпенсации – 1:4:6. В крови из локтевой вены и пораженной вены нижних конечностей изучено содержание показателей глюкозы, гликозилированного гемоглобина, инсулина, С-пептида, фруктозамина и ассоциированных с углеводным метаболизмом микроэлементов (хрома, марганца, селена, цинка). Лазерную абляцию вен осуществляли с помощью аппарата “Фотоніка-Ліка-Хірург” (Украина) и выполнения паравазальной “подушки” раствором Кляйна при помощи помпы для туминесцентной анестезии под ультразвуковым контролем, а химическую (склеротерапию) – раствором склеровейна или фибровейна. Первый метод выполнен 63 (39 %) больным, второй – 99 (61 %). Результаты исследований и их обсуждение. Эффективность лазерной аблации зависит от класса венозной недосточности, перенесенного в прошлом флеботромбоза, дополнительного использования в комплексе лечебных мероприятий ривароксабана и низкомолекулярных гепаринов, методики проводимой лазерной коагуляции, наличия и тяжести течения коморбидного СД, показателей углеводного обмена в целевой вене, причем после хирургического вмешательства возрастают параметры селен- и цинкемии, а число возникших осложнений зависит от фазы СД и уровня хрома в крови из варикозно расширенной вены. Результаты склеротерапии у женщин были лучше, число осложнений меньше, которые зависели от уровня венозной недостаточности, перенесенного в прошлом флеботромбоза и просвета целевой вены голени, параметров в крови из нее инсулина, С-пептида и фруктозамина. При сравнительной оценке разных методов хирургического лечения ВБ, лазерная абляция (коагуляция) отличалась большей тяжестью течения коморбидного СД, более частым дополнительным использованием ривароксабана и цикло-3-форта, исключением из разработки больных с диабетической энцефалопатией, а склеротерапия не была использована у пациентов с нефропатией, при этом эффективность выполненных мероприятий в обеих группах оказалась примерно одинаковой. У больных ВБ разработан лечебный алгоритм применения наиболее оптимальной медицинской технологии лазерной и химической абляции с учетом характера течения венозной патологии и коморбидного СД, системных и локальных изменений углеводного метаболизма, фоновой медикаментозной терапии.Мета роботи: оцінити ефективність ендоваскулярної лазерної та хімічної абляції вен при варикозній хворобі (ВХ) із коморбідним цукровим діабетом (ЦД) типу 2, розробити найбільш оптимальну технологію лікувальних заходів у такої категорії хворих. Матеріали і методи. Під наглядом перебували 162 хворих на ВХ (19 % чоловіків і 81 % жінок із середнім віком 50 років), серед яких співвідношення II, III, IV, V і VI класів венозної недостатності склало 1:1:3:1:2. ЦД мав місце в 14 % випадків, при цьому розподіл легкої, середньої тяжкості та тяжкої форми хвороби склав 1:2:4, а фаз компенсації, субкомпенсації й декомпенсації – 1:4:6. У крові з ліктьової вени і ураженої вени нижніх кінцівок вивчено вміст показників глюкози, глікованого гемоглобіну, інсуліну, С-пептиду, фруктозаміну та асоційованих із вуглеводним метаболізмом мікроелементів (хрому, марганцю, селену, цинку). Лазерну абляцію вен здійснювали за допомогою апарата “Фотоніка-Ліка-Хірург” (Україна) і виконання паравазальної “подушки” розчином Кляйна за допомогою помпи для тумесцентної анестезії під ультразвуковим контролем, а хімічну (склеротерапію) – розчином склеровейну або фібровейну. Перший метод виконаний 63 (39%) хворим, другий – 99 (61 %). Результати досліджень та їх обговорення. Ефективність лазерної абляції залежить від класу венозної недостатності, перенесеного у минулому флеботромбозу, додаткового використання в комплексі лікувальних заходів ривароксабану та низькомолекулярних гепаринів, методики лазерної коагуляції, що проводиться, наявності й тяжкості перебігу коморбідного ЦД, показників вуглеводного обміну в цільовій вені, причому після хірургічного втручання зростають параметри селен- і цинкемії, а число виниклих ускладнень залежить від фази ЦД та рівня хрому в крові з варикозно розширеної вени. Результати склеротерапії у жінок були кращі, а число ускладнень менше, які залежали від рівня венозної недостатності, перенесеного у минулому флеботромбозу і просвіту цільової вени гомілки, параметрів у крові з неї інсуліну, С-пептиду й фруктозаміну. При порівняльній оцінці різних методів хірургічного лікування ВХ, лазерна аблація (коагуляція) відрізнялася більшою тяжкістю перебігу коморбідного ЦД, частішим додатковим використанням ривароксабану і цикло-3-форту, виключенням із розробки хворих із діабетичною енцефалопатією, а склеротерапія не була використана у пацієнтів з нефропатією, при цьому ефективність виконаних заходів в обох групах виявилася приблизно однаковою. У хворих на ВХ розроблено лікувальний алгоритм застосування найбільш оптимальної медичної технології лазерної і хімічної аблації з урахуванням характеру перебігу венозної патології та коморбідного ЦД, системних й локальних змін вуглеводного метаболізму, фонової медикаментозної терапії

Superconducting Submm Integrated Receiver for TELIS

In this report we present design and first experimental results for development of the submm superconducting integrated receiver spectrometer for Terahertz Limb Sounder (TELIS). TELIS is a collaborative European project to build up a three-channel heterodyne balloon-based spectrometer for measuring a variety of atmospheric constituents of the stratosphere. The 550 - 650 GHz channel of TELIS is based on a phase-locked Superconducting Integrated Receiver (SIR). SIR is an on-chip combination of a low-noise Superconductor-Insulator-Superconductor (SIS) mixer with quasioptical antenna, a superconducting Flux Flow Oscillator (FFO) acting as Local Oscillator (LO), and SIS harmonic mixer (HM) for FFO phase locking. A number of new solutions were implemented in the new generation of SIR chips. To achieve the wide-band performance of the spectrometer, a side-feed twin-SIS mixer and balanced SIS mixer with 0.8 µm2 junctions integrated with a double-dipole (or double-slot) antenna is used. An improved design of the FFO for TELIS has been developed and optimized providing a free-running linewidth between 10 and 2 MHz in the frequency range 500 - 700 GHz. It is important to ensure that tuning of a phase-locked (PL) SIR can be performed remotely by telecommand. For this purpose a number of approaches for the PL SIR automatic computer control have been developed. All receiver components (including input optical elements and Martin-Puplett polarization rotating interferometer for single side band operation) will be mounted on a single 4.2 K plate inside a 40 × 180 × 80 mm3 box. First measurements give an uncorrected double side band (DSB) noise temperature below 250 K measured with the phase-locked FFO; more detailed results are presented at the conference

Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT. Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562

Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM. Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21·0% vs 34·3%; OR 0·50, [95% CI 0·32-0·79]; P=0.0013) were lower with SVd. There were 47 (24%) deaths on SVd and 62 (30%) on Vd. Interpretation Once-weekly SVd is a novel, effective, and convenient treatment option for patients with MM who have received 1-3 prior therapies. Funding Karyopharm Therapeutics In

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): And randomised, phase 3, open-label, multicentre study

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary

Active-site structure, binding and redox activity of the heme–thiolate enzyme CYP2D6 immobilized on coated Ag electrodes: a surface-enhanced resonance Raman scattering study

Surface-enhance resonance Raman scattering spectra of the heme–thiolate enzyme cytochrome P450 2D6 (CYP2D6) adsorbed on Ag electrodes coated with 11-mercaptoundecanoic acid (MUA) were obtained in various experimental conditions. An analysis of these spectra, and a comparison between them and the RR spectra of CYP2D6 in solution, indicated that the enzyme’s active site retained its nature of six-coordinated low-spin heme upon immobilization. Moreover, the spectral changes detected in the presence of dextromethorphan (a CYP2D6 substrate) and imidazole (an exogenous heme axial ligand) indicated that the immobilized enzyme also preserved its ability to reversibly bind a substrate and form a heme–imidazole complex. The reversibility of these processes could be easily verified by flowing alternately solutions of the various compounds and the buffer through a home-built spectroelectrochemical flow cell which contained a sample of immobilized protein, without the need to disassemble the cell between consecutive spectral data acquisitions. Despite immobilized CYP2D6 being effectively reduced by a sodium dithionite solution, electrochemical reduction via the Ag electrode was not able to completely reduce the enzyme, and led to its extensive inactivation. This behavior indicated that although the enzyme’s ability to exchange electrons is not altered by immobilization per se, MUA-coated electrodes are not suited to perform direct electrochemistry of CYP2D6