First-Line Therapy for Patients with Advanced Hodgkin’s Lymphoma: Efficacy and Toxicity of Intensive ЕАСОРР-14 Program (NN Blokhin National Medical Cancer Research Center Data)

Aim. To assess the efficacy and toxicity of intensive 6 courses EACOPP-14 treatment with or without radiotherapy (RT) for advanced stages of Hodgkin’s lymphoma (HL). Materials & Methods. From November 2009 to February 2015, 95 patients with advanced stages of HL (IIX–IIE, III–IV) aged between 17 and 50 years (median 29 years) were selected for the participation in the protocol ЛХМосква1-3. The study population consisted of 46.3 % men and 53.7 % women. The results of the treatment were assessed in 91 patients who have received more than 2 courses of EACOPP-14. The follow up period was at least 3 months after the receiving the therapy. Consolidation RT with a total dose of 30 Gy for residual tumor lesions and/or initially large tumors was performed after the chemotherapy. Results. Complete remission was achieved in 82 (90.1 %) patients, partial remission in 2 (2.2 %), and the progression was observed in 7 (7.7 %) patients. The overall 4-year survival rate was 90.8 %, the progression-free survival was 88.2 %. The toxicity of the ЕАСОРР-14 program was slightly lower than that of 8 courses of ВЕАСОРРesc, and was comparable to the toxicity of other modifications of intensified ВЕАСОРР scheme. Hematological toxicity grade 3 and 4 was most commonly observed: leukopenia was observed after 64.9 % of courses, anemia — after 24 % of courses, thrombocytopenia — after 3.8 % of courses. The rate of infections did not singificantly differ and accounted for 24 %. The most frequent non-infectious complications were mucositis (21.1 %) and polyneuropathy (11.7 %). Complications resulted in the change of treatment in only 3 (3.01 %) of patients. The exclusion of bleomycine from the ЕАСОРР-14 program reduced the frequency of RT complications. Grade 3 pulmonitis developed in 4.5 % of cases, while radiation-induce pulmonary fibrosis verified by CT developed in 15.2 % of cases. The ЕАСОРР-14 6 courses program showed its high efficacy both with and without RT, high tolerance and the possibility of full administration for the majority of patients with the various stages of HL. Conclusion. Current research showed the efficacy of treatment without RT for patients with advanced stages of HL with negative PET results and small (< 2.5 cm) residual tumors after intensive ЕАСОРР-14 program. This approach allowed to avoid a number of late treatment complications

A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279

It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10^5 gravitational radii.Comment: Published in Nature issued on 18 February 2010. Corresponding authors: Masaaki Hayashida and Greg Madejsk

Relevance of Positron-Emission Therapy for Optimization of Treatment of Advanced Hodgkin’s Lymphoma Using Intensive ЕАСОРР-14 Program

Aim. To evaluate the relevance of the positron-emission therapy (PET) for optimization of the therapy of advanced Hodgkin’s lymphoma (HL) using the intensive EACOPP-14 program. Materials & Methods. 91 patients with advanced HL (IIX–IIE, III–IV) received the treatment according to the “ЛХМосква1-3” protocol over the period from November 2009 to February 2015, and then the treatment was analyzed. The median age was 29 years (range: 17–50); there were 42 men (46.3 %) and 49 (53.7 %) women. The treatment included 6 cycles of polychemotherapy according to the regimen ЕА(50)СОРР-14 ± radiation therapy. The radiation therapy was performed in 66 patients (72.5 %) after the completion of the chemotherapy. The cumulative focal dose was 30 Gy onto the areas of residual lesions and/or initially large tumor masses. Results. PET performed during the initial HL diagnosing permited to identify new areas of neoplastic lesions without changes in staging and treatment scheme, as well as specify areas and field size of planned radiation consolidation. The paper confirms the prognostic value of the intermediate PET in patients with advanced HL during the intensive first-line chemotherapy. The intensive therapy at the beginning of the treatment program is associated with higher chances for survival for patients with extremely unfavorable prognosis. After completion of the drug therapy, negative PET findings had a higher prognostic value, than the positive ones. The analysis of the relevance of residual tumor dimensions in the PET negative group demonstrated that the relapses were more common, if the residual tumor was more than 4.5 cm (according to CT findings). Conclusion. This study confirmed that it reasonable to discuss the discontinuation of the radiation therapy in patients with advanced HL, negative PET findings and small (< 2.5 cm) residual tumor after the intensive ЕАСОРР-14 program. This tactics permits avoiding a number of delayed complications

Blazar spectral variability as explained by a twisted inhomogeneous jet

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming1. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles2, with possible intervention of shock waves3,4 or turbulence5. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events6,7,8,9,10 and can also explain specific properties of blazar emission, such as intra-day variability11, quasi-periodicity12,13 and the delay of radio flux variations relative to optical changes14. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions—such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution—can explain snapshots of the spectral behaviour of blazars in many cases15,16. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities17 or rotation of the twisted jet6 cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016–2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory

The complex variability of blazars: time-scales and periodicity analysis in S4 0954+65

Among active galactic nuclei, blazars show extreme variability properties. We here investigate the case of the BL Lac object S4 0954+65 with data acquired in 2019-2020 by the Transiting Exoplanet Survey Satellite (TESS) and by the Whole Earth Blazar Telescope (WEBT) Collaboration. The 2-min cadence optical light curves provided by TESS during three observing sectors of nearly 1 month each allow us to study the fast variability in great detail. We identify several characteristic short-term time-scales, ranging from a few hours to a few days. However, these are not persistent, as they differ in the various TESS sectors. The long-term photometric and polarimetric optical and radio monitoring undertaken by the WEBT brings significant additional information, revealing that (i) in the optical, long-term flux changes are almost achromatic, while the short-term ones are strongly chromatic; (ii) the radio flux variations at 37 GHz follow those in the optical with a delay of about 3 weeks; (iii) the range of variation of the polarization degree and angle is much larger in the optical than in the radio band, but the mean polarization angles are similar; (iv) the optical long-term variability is characterized by a quasi-periodicity of about 1 month. We explain the source behaviour in terms of a rotating inhomogeneous helical jet, whose pitch angle can change in time

Dissecting the long-term emission behaviour of the BL Lac object Mrk 421

We report on long-term multiwavelength monitoring of blazar Mrk 421 by the GLAST-AGILE Support Program of the Whole Earth Blazar Telescope (GASP-WEBT) collaboration and Steward Observatory, and by the Swift and Fermi satellites. We study the source behaviour in the period 2007-2015, characterized by several extreme flares. The ratio between the optical, X-ray and gamma-ray fluxes is very variable. The gamma-ray flux variations show a fair correlation with the optical ones starting from 2012. We analyse spectropolarimetric data and find wavelength-dependence of the polarization degree (P), which is compatible with the presence of the host galaxy, and no wavelength dependence of the electric vector polarization angle (EVPA). Optical polarimetry shows a lack of simple correlation between P and flux and wide rotations of the EVPA. We build broad-band spectral energy distributions with simultaneous near-infrared and optical data from the GASP-WEBT and ultraviolet and X-ray data from the Swift satellite. They show strong variability in both flux and X-ray spectral shape and suggest a shift of the synchrotron peak up to a factor of similar to 50 in frequency. The interpretation of the flux and spectral variability is compatible with jet models including at least two emitting regions that can change their orientation with respect to the line of sight

Investigation of the correlation patterns and the Compton dominance variability of Mrk 421 in 2017

Aims. We present a detailed characterisation and theoretical interpretation of the broadband emission of the paradigmatic TeV blazar Mrk 421, with a special focus on the multi-band flux correlations.Methods. The dataset has been collected through an extensive multi-wavelength campaign organised between 2016 December and 2017 June. The instruments involved are MAGIC, FACT, Fermi-LAT, Swift, GASP-WEBT, OVRO, Medicina, and Metsahovi. Additionally, four deep exposures (several hours long) with simultaneous MAGIC and NuSTAR observations allowed a precise measurement of the falling segments of the two spectral components.Results. The very-high-energy (VHE; E > 100 GeV) gamma rays and X-rays are positively correlated at zero time lag, but the strength and characteristics of the correlation change substantially across the various energy bands probed. The VHE versus X-ray fluxes follow different patterns, partly due to substantial changes in the Compton dominance for a few days without a simultaneous increase in the X-ray flux (i.e., orphan gamma-ray activity). Studying the broadband spectral energy distribution (SED) during the days including NuSTAR observations, we show that these changes can be explained within a one-zone leptonic model with a blob that increases its size over time. The peak frequency of the synchrotron bump varies by two orders of magnitude throughout the campaign. Our multi-band correlation study also hints at an anti-correlation between UV-optical and X-ray at a significance higher than 3 sigma. A VHE flare observed on MJD 57788 (2017 February 4) shows gamma-ray variability on multi-hour timescales, with a factor ten increase in the TeV flux but only a moderate increase in the keV flux. The related broadband SED is better described by a two-zone leptonic scenario rather than by a one-zone scenario. We find that the flare can be produced by the appearance of a compact second blob populated by high energetic electrons spanning a narrow range of Lorentz factors, from gamma(min)' = 2 x 10(4) to gamma(max)' = 6 x 10(5).</p

Unraveling the Complex Behavior of Mrk 421 with Simultaneous X-Ray and VHE Observations during an Extreme Flaring Activity in 2013 April*

We report on a multiband variability and correlation study of the TeV blazar Mrk 421 during an exceptional flaring activity observed from 2013 April 11 to 19. The study uses, among others, data from GLAST-AGILE Support Program (GASP) of the Whole Earth Blazar Telescope (WEBT), Swift, Nuclear Spectroscopic Telescope Array (NuSTAR), Fermi Large Area Telescope, Very Energetic Radiation Imaging Telescope Array System (VERITAS), and Major Atmospheric Gamma Imaging Cherenkov (MAGIC). The large blazar activity and the 43 hr of simultaneous NuSTAR and MAGIC/VERITAS observations permitted variability studies on 15 minute time bins over three X-ray bands (3-7 keV, 7-30 keV, and 30-80 keV) and three very-high-energy (VHE; >0.1 TeV) gamma-ray bands (0.2-0.4 TeV, 0.4-0.8 TeV, and >0.8 TeV). We detected substantial flux variations on multi-hour and sub-hour timescales in all of the X-ray and VHE gamma-ray bands. The characteristics of the sub-hour flux variations are essentially energy independent, while the multi-hour flux variations can have a strong dependence on the energy of the X-rays and the VHE gamma-rays. The three VHE bands and the three X-ray bands are positively correlated with no time lag, but the strength and characteristics of the correlation change substantially over time and across energy bands. Our findings favor multi-zone scenarios for explaining the achromatic/chromatic variability of the fast/slow components of the light curves, as well as the changes in the flux-flux correlation on day-long timescales. We interpret these results within a magnetic reconnection scenario, where the multi-hour flux variations are dominated by the combined emission from various plasmoids of different sizes and velocities, while the sub-hour flux variations are dominated by the emission from a single small plasmoid moving across the magnetic reconnection layer

Multiband variability studies and novel broadband SED modeling of Mrk 501 in 2009

Aims. We present an extensive study of the BL Lac object Mrk 501 based on a data set collected during the multi-instrument campaign spanning from 2009 March 15 to 2009 August 1, which includes, among other instruments, MAGIC, VERITAS, Whipple 10 m, and Fermi-LAT to cover the gamma-ray range from 0.1 GeV to 20 TeV; RXTE and Swift to cover wavelengths from UV to hard X-rays; and GASP-WEBT, which provides coverage of radio and optical wavelengths. Optical polarization measurements were provided for a fraction of the campaign by the Steward and St. Petersburg observatories. We evaluate the variability of the source and interband correlations, the gamma-ray flaring activity occurring in May 2009, and interpret the results within two synchrotron self-Compton (SSC) scenarios.Methods. The multiband variability observed during the full campaign is addressed in terms of the fractional variability, and the possible correlations are studied by calculating the discrete correlation function for each pair of energy bands where the significance was evaluated with dedicated Monte Carlo simulations. The space of SSC model parameters is probed following a dedicated grid-scan strategy, allowing for a wide range of models to be tested and offering a study of the degeneracy of model-to-data agreement in the individual model parameters, hence providing a less biased interpretation than the "single-curve SSC model adjustment" typically reported in the literature.Results. We find an increase in the fractional variability with energy, while no significant interband correlations of flux changes are found on the basis of the acquired data set. The SSC model grid-scan shows that the flaring activity around May 22 cannot be modeled adequately with a one-zone SSC scenario (using an electron energy distribution with two breaks), while it can be suitably described within a two (independent) zone SSC scenario. Here, one zone is responsible for the quiescent emission from the averaged 4.5-month observing period, while the other one, which is spatially separated from the first, dominates the flaring emission occurring at X-rays and very-high-energy (> 100 GeV, VHE) gamma-rays. The flaring activity from May 1, which coincides with a rotation of the electric vector polarization angle (EVPA), cannot be satisfactorily reproduced by either a one-zone or a two-independent-zone SSC model, yet this is partially affected by the lack of strictly simultaneous observations and the presence of large flux changes on sub-hour timescales (detected at VHE gamma rays).Conclusions. The higher variability in the VHE emission and lack of correlation with the X-ray emission indicate that, at least during the 4.5-month observing campaign in 2009, the highest energy (and most variable) electrons that are responsible for the VHE gamma rays do not make a dominant contribution to the similar to 1 keV emission. Alternatively, there could be a very variable component contributing to the VHE gamma-ray emission in addition to that coming from the SSC scenario. The studies with our dedicated SSC grid-scan show that there is some degeneracy in both the one-zone and the two-zone SSC scenarios probed, with several combinations of model parameters yielding a similar model-to-data agreement, and some parameters better constrained than others. The observed gamma-ray flaring activity, with the EVPA rotation coincident with the first gamma-ray flare, resembles those reported previously for low frequency peaked blazars, hence suggesting that there are many similarities in the flaring mechanisms of blazars with different jet properties