Three-photon and four-photon absorption in lithium niobate measured by the Z-scan technique.

Open-aperture Z-scan measurements have been carried out to investigate the three-photon (3 PA) and four-photon absorption (4 PA) coefficients at 800 nm and 1030 nm wavelengths, respectively in congruent and stoichiometric lithium niobate (cLN, sLN) with different concentrations of Mg doping. The laser pulse duration at the two wavelengths were 40 and 190 fs. The peak intensity inside the crystals varied between approximately 110 and 550 GW/cm2. The 3 PA and 4 PA coefficients were evaluated using a theoretical model and the results suggest that their minima are at or around the Mg doping level corresponding to the threshold for suppressing photo-refraction for both cLN and sLN. This result can be attributed to the contribution of crystal defects to the 3 PA and 4 PA processes. Furthermore, the 4 PA at 1030 nm exhibited greater nonlinear absorption than the 3 PA at 800 nm under the same intensity level. Possible reasons for this unexpected behavior are discussed. Overall, comparing the 3 PA and 4 PA values of these crystals will enable for selection of the optimum composition of LN crystal for efficient THz generation and for other nonlinear optical processes requiring high pump intensities.

Few-Cycle Surface Plasmon Polaritons.

Surface plasmon polaritons (SPPs) can confine and guide light in nanometer volumes and are ideal tools for achieving electric field enhancement and the construction of nanophotonic circuitry. The realization of the highest field strengths and fastest switching requires confinement also in the temporal domain. Here, we demonstrate a tapered plasmonic waveguide with an optimized grating structure that supports few-cycle surface plasmon polaritons with >70 THz bandwidth while achieving >50% light-field-to-plasmon coupling efficiency. This enables us to observe the─to our knowledge─shortest reported SPP wavepackets. Using time-resolved photoelectron microscopy with suboptical-wavelength spatial and sub-10 fs temporal resolution, we provide full spatiotemporal imaging of co- and counter-propagating few-cycle SPP wavepackets along tapered plasmonic waveguides. By comparing their propagation, we track the evolution of the laser-plasmon phase, which can be controlled via the coupling conditions.

Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Subcycle surface electron emission driven by strong-field terahertz waveforms.

The advent of intense terahertz (THz) sources opened a new era when the demonstration of the acceleration and manipulation of free electrons by THz pulses became within reach. THz-field-driven electron emission was predicted to be confined to a single burst due to the single-cycle waveform. Here we demonstrate the confinement of single-cycle THz-waveform-driven electron emission to one of the two half cycles from a solid surface emitter. Either the leading or the trailing half cycle was active, controlled by reversing the field polarity. THz-driven single-burst surface electron emission sources, which do not rely on field-enhancement structures, will impact the development of THz-powered electron acceleration and manipulation devices, all-THz compact electron sources, THz waveguides and telecommunication, THz-field-based measurement techniques and solid-state devices.

Carrier-envelope phase on-chip scanner and control of laser beams.

The carrier-envelope phase (CEP) is an important property of few-cycle laser pulses, allowing for light field control of electronic processes during laser-matter interactions. Thus, the measurement and control of CEP is essential for applications of few-cycle lasers. Currently, there is no robust method for measuring the non-trivial spatial CEP distribution of few-cycle laser pulses. Here, we demonstrate a compact on-chip, ambient-air, CEP scanning probe with 0.1 µm3 resolution based on optical driving of CEP-sensitive ultrafast currents in a metal-dielectric heterostructure. We successfully apply the probe to obtain a 3D map of spatial changes of CEP in the vicinity of an oscillator beam focus with pulses as weak as 1 nJ. We also demonstrate CEP control in the focal volume with a spatial light modulator so that arbitrary spatial CEP sculpting could be realized.

A potentially new thromboembolic event scoring system in polycythaemia vera patients: An audit of the Hungarian Philadelphia negative chronic myeloproliferative neoplasia register.

OBJECTIVE: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms was used to analyse the thromboembolic events (TE) of Hungarian patients with polycythemia vera (PV). METHODS: Data from 351 JAK2 V617F-positive patients diagnosed with PV were collected online from 15 haematology centres reporting clinical characteristics, therapeutic interventions and thromboembolic events. TE events were evaluated before and after diagnosis based upon the Landolfi and Tefferi risk assessment scales. RESULTS: TE were reported on 102 patients before diagnosis and 100 during the follow-up period. Comparing to the frequency of major arterial events before PV diagnosis, we can notice a decreasing tendency after diagnosis: from 12.3% to 2.6% (p < .00003). There was no significant change in the rate of major venous events (from 5.1% to 8.5%; p = .1134) or minor arterial events (from 11.7% to 17.4%; p = .073). Bleeding events were recorded in 5.7% of patients. Despite treatment with HU + ASA, 44 patients (43.1%) with prior TE had recurrent thromboembolic complications. The particular analysis of our data revealed a new TE scoring system based on: age, gender, previous TE and iron deficiency at the time of diagnosis. CONCLUSIONS: Our registry enables characterisation of patients with PV. The high level of recurrent TE events highlights the need for more effective and risk-adapted therapy.

Ultrasensitive probing of plasmonic hot electron occupancies.

Non-thermal and thermal carrier populations in plasmonic systems raised significant interest in contemporary fundamental and applied physics. Although the theoretical description predicts not only the energies but also the location of the generated carriers, the experimental justification of these theories is still lacking. Here, we demonstrate experimentally that upon the optical excitation of surface plasmon polaritons, a non-thermal electron population appears in the topmost domain of the plasmonic film directly coupled to the local fields. The applied all-optical method is based on spectroscopic ellipsometric determination of the dielectric function, allowing us to obtain in-depth information on surface plasmon induced changes of the directly related electron occupancies. The ultrahigh sensitivity of our method allows us to capture the signatures of changes induced by electron-electron scattering processes with ultrafast decay times. These experiments shed light on the build-up of plasmonic hot electron population in nanoscale media.

Nonadiabatic Nano-optical Tunneling of Photoelectrons in Plasmonic Near-Fields.

Nonadiabatic nano-optical electron tunneling in the transition region between multiphoton-induced emission and adiabatic tunnel emission is explored in the near-field of plasmonic nanostructures. For Keldysh γ values between ∼1.3 and ∼2.2, measured photoemission spectra show strong-field recollision driven by the nanoscale near-field. At the same time, the photoemission yield shows an intensity scaling with a constant nonlinearity, which is characteristic for multiphoton-induced emission. Our observations in this transition region were well reproduced with the numerical solution of Schrödinger's equation, mimicking the nanoscale geometry of the field. This way, we determined the boundaries and nature of nonadiabatic tunneling photoemission, building on a key advantage of a nanoplasmonic system, namely, that high-field-driven recollision events and their signature in the photoemission spectrum can be observed more efficiently due to significant nanoplasmonic field enhancement factors.

Femtosecond LIPSS on indium-tin-oxide thin films at IR wavelengths.

We investigated laser-induced periodic surface structures (LIPSS) generated on indium-tin-oxide thin films with femtosecond laser pulses in the infrared region. Using pulses between 1.6 and 2.4 µm central wavelengths, we observed robust LIPSS morphologies with a periodicity close to λ/10. Supporting finite-difference time-domain calculations suggests that the surface forms are rooted in the field localization in the surface pits leading to a periodically increased absorption of the laser pulse energy that creates the observed periodic structures.

Few-cycle localized plasmon oscillations.

The generation of few-cycle laser pulses proved to be a key enabling technology in strong-field physics and ultrafast science. The question naturally arises whether one can induce few-cycle localized plasmon oscillations in optical near-fields. Here, we perform a comparative study of different plasmonic nanoresonators illuminated by few-cycle pulses. We analyze the number of cycles (NOC) of the plasmonic field, the near-field enhancement (NFE) as well as the figure of merit NFE/NOC. The pulse length dependence of these quantities is also investigated. Throughout the inspected pulse-length interval silica-gold and silica-silver core-shell monomers have the potential to preserve the NOC of the incoming pulse, silver bow-ties result in the highest NFE, whereas gold core-shell dimers have the highest NFE/NOC. Based on the analysis, silver bow-ties, gold core-shell and silver nanorod dimers proved to be the most suitable for few-cycle near-field amplification.

Anagrelide influences thrombotic risk, and prolongs progression-free and overall survival in essential thrombocythaemia vs hydroxyurea plus aspirin.

OBJECTIVE: We report an extension study of patients with essential thrombocythaemia (ET) in the Hungarian Myeloproliferative Neoplasm (HUMYPRON) Registry, which demonstrated that over 6 years anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous thrombotic events (TEs) vs hydroxyurea+aspirin. METHODS: Data on patients with ET were collected through completion of a questionnaire developed according to 2008 WHO diagnostic criteria and with regard to Landolfi, Tefferi and IPSET criteria for thrombotic risk. Data were entered into the registry from 14 haematological centres. TEs, secondary malignancies, disease progression and survival were compared between patients with ET treated with anagrelide (n = 116) and with hydroxyurea+aspirin (n = 121). RESULTS: Patients were followed for (median) 10 years. A between-group difference in the number of patients with TEs was observed (25.9% anagrelide vs 38.0% hydroxyurea+aspirin; P = .052). Minor arterial events were more frequently reported in the hydroxyurea+aspirin group (P < .001); there were marginally more reports of major arterial events in the anagrelide group (P = .049). TE prior to diagnosis was found to significantly influence TE incidence (P > .001). Progression-free survival (P = .004) and survival (P = .001) were significantly increased for the anagrelide group vs hydroxyurea+aspirin. CONCLUSIONS: Anagrelide reduced TEs, and increased progression-free and overall survival vs hydroxyurea+aspirin over (median) 10 years.

High harmonic generation on noble gas clusters.

High order harmonics (HHG) were generated on noble gas cluster targets with different cluster sizes. The independently characterized cluster sources enabled experimental investigation of the recombination mechanism. HHG spectra were recorded for different backing pressures and gases (Ar, Xe) as a function of driver pulse ellipticity. Since the ellipticity-dependent HHG decay is essentially the same for the different gas-pressure pairs, we can conclude that the recombination process is dominated by atom-to-itself recollisions irrespective of cluster size and material.

The efficacy and safety of bevacizumab in addition to platinum-based chemotherapy for the first-line treatment of patients with advanced nonsquamous non-small-cell lung cancer: Final results of AVALANCHE, an observational cohort study.

The previous results of former clinical studies confirmed that first-line bevacizumab (BEV) in combination with chemotherapy improves clinical outcomes in patients with advanced non-squamous non-small cell lung cancer. The AVALANCHE study (ClinicalTrials.gov Identifier NCT03170284) was undertaken to assess the clinical outcomes of first-line BEV combined with standard platinum-based regimens in the Hungarian clinical practice. This observational study was conducted in 28 Hungarian sites, with patients enrolled between July 2008 and April 2011. Patients with untreated locally advanced, metastatic or recurrent lung adenocarcinoma received BEV (7.5 mg/kg, q3w) with any platinum-doublet for up to 6 cycles, and then non-progressors proceeded to receive BEV until disease progression or unacceptable toxicity. The primary endpoint was time-to-progression, and secondary endpoints included overall survival (OS), tumour control rate and safety. Patients were also analysed as two cohorts (non-progressors vs. progressors) based on whether or not they received BEV maintenance therapy following completion of first-line chemotherapy plus BEV. The study enrolled 283 patients (median age: 58.2 (18-78) years; males: 50.5%; stage: III/B: 18.4%, IV: 79.9%; adenocarcinoma/other: 95.8/4.2%; ECOG PS 0/1/2/≥3: 30.8/59.7/2.6/1.4%). Centrally located tumours were reported in 21.6%. Cisplatin/carboplatin-based regimens: 53.8/46.2%. A total of 43% of patients received BEV maintenance therapy. The median number of BEV cycles was 6. Median progression-free survival (PFS) was 7.2 months and OS was 15.2 months for the entire cohort. Longer PFS and OS were observed in patients who received BEV maintenance therapy [median OS, 26.2 vs. 10.2 months (P<0.001); median PFS, 9.2 vs. 5.8 months (P<0.001)]. Contrary to the results of previous OCS no significant difference was recorded in the different age groups or gender. Best tumour response: Complete remission/partial remission/stable disease/progressive disease/not reported were: 1.5/29.9/26.9/9.1/32.6% of all patients. In conclusion, clinical outcomes obtained in this real-life population were consistent with pivotal studies. BEV maintenance treatment was associated with a significantly longer PFS and OS.

Effectiveness of the Combination of Rituximab and Standard Chemotherapeutic Regimens in Previously Untreated Patients with Chronic Lymphocytic Leukaemia in Real-Life: Results from a Noninterventional Study (CILI Study).

Chronic lymphocytic leukemia (CLL) is one of the most common haematological malignancies exhibiting remarkable heterogeneity in clinical course. Rituximab added to standard chemotherapy has been proven to increase response rate and eventually survival among previously untreated CLL patients. CILI was an open-label, non-randomized, single arm, multicentric, observational study aimed to collect real-life effectiveness data for rituximab used according to the current label in combination with standard chemotherapy in previously untreated CLL patients. Overall response rates (ORR) in the entire study population as well as in various subgroups were estimated. Adverse events were recorded during the entire course of the study. A total number of 150 patients were enrolled by 15 Hungarian study sites. Out of these, 82 patients received 6 cycles of rituximab containing treatment. Overall response rates of 88.24% (CI95%: 81.6-93.12%) and 94.59% (CI95%: 86.73-98.51%) were recorded in the intent-to-treat (ITT) and per-protocol (PP) populations, respectively. In both study populations, somewhat higher ORR was observed in patients aged ≥65 years. Subgroups defined according to either chromosomal aberrations (presence of 11q and 17p deletions) showed apparently high ORRs, though these rates were most probably biased by low patient numbers. 144 adverse events were reported during the study, of which 15 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those previously reported by controlled clinical trials.

Plasmon-plasmon coupling probed by ultrafast, strong-field photoemission with <7 Å sensitivity.

The coupling of propagating surface plasmon waves and localized plasmon oscillations in nanostructures is an essential phenomenon determining electromagnetic field enhancement on the nanoscale. Here, we use our recently developed ultrafast photoemission near-field probing technique to investigate the fundamental question of plasmon-plasmon coupling and its effect on large field enhancement factors. By measuring and analyzing plasmon field enhancement values at different nanostructured surfaces, we can separate the contributions from propagating and localized plasmons. When resonance conditions are met, a significant field enhancement factor can be attributed to the generation of localized plasmons on surface nanostructures, acting as dipole sources resonantly driven by the propagating plasmon field. Our plasmon-plasmon coupling results can contribute directly to applications in surface-enhanced Raman scattering (SERS) and the development of plasmonic sensors and nanostructured photocathodes.

Ultrafast multipulse damage threshold of femtosecond high reflectors.

Laser-induced damage threshold is a fundamental figure of merit of femtosecond optical components used in large-scale laser systems. We tested a series of ultrafast mirrors featuring high band-gap dielectric materials as well as improved design and coating techniques. In a broad range of the damage test pulse train involving between 10 and 100,000 pulses (40 fs, 800 nm), pure dielectric high reflectors exhibit around 1.5 J/cm2 and hybrid Ag-multilayer mirrors can exhibit well above 1.2 J/cm2 damage threshold. In addition, a reference antireflection coating exceeded 2 J/cm2. Damage threshold dependence on the number of pulses was similar for all optics involved.

Efficacy and Tolerability of a 2-Year Rituximab Maintenance Therapy in Patients with Advanced Follicular Lymphoma after Induction of Response with Rituximab-Containing First Line-Regimens (HUSOM Study).

Follicular lymphoma is a lymphoid malignancy commonly showing slow progression which makes the treatment of the disease challenging. Rituximab monotherapy and rituximab added to standard chemotherapy has been proven to increase survival among patients with advanced stage of the disease. However, the benefit of a rituximab maintenance therapy after induction was still unclear at the time of the initiation of this study. HUSOM was a phase III open-label, single-arm, multi-centre study aimed to assess the efficacy and the safety of the 12 cycles of rituximab (375 mg/m2 every 8 weeks) maintenance therapy in patients had already presented partial or complete response to R-CVP or R-CHOP. Efficacy endpoints such as event-free survival and overall survival were estimated. Adverse events were recorded during the entire course of the study. A total number of 124 patients were enrolled by 15 Hungarian study sites. Out of these, 86 patients received 12 cycles of rituximab and 69 patients completed the 3-year follow-up phase as well. The probabilities of the event free survival and progression at 4.3 years were estimated to be 70.3% and 74.4%, respectively. The overall and the disease free survival at 4 years were estimated to be 90.7% and 87.9%, respectively. A total number of 85 adverse events were reported during the study out of which 5 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those reported by controlled clinical trials (EORTC 20981, PRIMA) conducted in parallel with the HUSOM study.

[Hungarian Philadelphia negative chronic myeloproliferative neoplasia registry. Evaluation of the Polycythemia vera patients]. / Philadelphia-negatív krónikus Myeloproliferativ Neoplasia Magyarországi Regiszter. Polycythaemia verás betegeink adatainak elemzése.

Intruduction and aim: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms has been developed. The aim of the recent study is to assess the clinical characteristics of Hungarian patients with polycythemia vera. METHOD: Data of 351 JAK2V617F and exon 12 mutation positive polycythemia vera patients were collected online from 15 haematology centres reporting epidemiologic, clinical characteristics, diagnostic tools, therapeutic interventions, thromboembolic complications, disease transformations. Vascular events prior to and after diagnosis were evaluated upon the Landolfi risk assessment scale. RESULTS: 116 thromboembolic events were reported in 106 PV patients prior to diagnosis and 152 occasions in 102 patients during follow-up. The frequency of major arterial events were significantly reduced (p<0.0001) and the minor venous events were significantly elevated (p<0.0001) after the diagnosis. Major hemorrhagic complications were found in 25 and transformation in 26 cases. CONCLUSIONS: Our registry allows to collect and evaluate the features of patients with polycythemia vera. The Landolfi risk stratification was proven to be useful. Based on evaluated data, accuracy of diagnostic criteria and compliance to risk-adapted therapeutic guidelines are needed. Orv Hetil. 2017; 158(23): 901-909.

Measurement of Nanoplasmonic Field Enhancement with Ultrafast Photoemission.

Probing nanooptical near-fields is a major challenge in plasmonics. Here, we demonstrate an experimental method utilizing ultrafast photoemission from plasmonic nanostructures that is capable of probing the maximum nanoplasmonic field enhancement in any metallic surface environment. Directly measured field enhancement values for various samples are in good agreement with detailed finite-difference time-domain simulations. These results establish ultrafast plasmonic photoelectrons as versatile probes for nanoplasmonic near-fields.

[An audit of the Hungarian Philadelphia negative chronic myeloproliferative neoplasia registry. Evaluation of the essential thrombocythaemic patients]. / Philadelphia-negatív krónikus Myeloproliferativ Neoplasia Magyarországi Regiszter. Essentialis thrombocythaemiás betegeink adatainak elemzése.

INTRODUCTION: In order to establish and use a national registry, several Hungarian hematology centers collected data of myeloproliferative neoplasia patients. AIM: The recent publication is an analysis of the data of registered essential thrombocythaemic patients. METHOD: an online electronic registry has been established, using 2008 World Health Organization's diagnostic criteria and thrombotic risk was evaluated according to Landolfi stratification. RESULTS: Data of 350 essential thrombocythaemic patients from 15 Hungarian hematology centers entered up to the date of June 30, 2015 were used for analysis. Patients were followed up to (median) 6 years. The epidemiologic data (age, gender) and thrombotic events prior and after the diagnosis, were similar to the literature. The thrombotic events of anagrelide treated patient (n = 139) and the hydroxyurea + aspirin treated patients (n = 141) have been compared. The major arterial and venous events were similar between the groups, but there were fivefold less minor arterial and venous events in the anagrelide group (p<0.001). Thrombotic incidence after diagnosis were influenced only by medication and thrombotic events before the diagnosis. CONCLUSIONS: Anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous thrombosis, vs hydroxyurea + aspirin. Despite of the treatment the risk of thrombotic events after diagnosis remained high, and was significantly increased in patients with thrombosis before diagnosis. Orv. Hetil., 2017, 158(3), 111-116.