Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

[Heparin-induced thrombocytopenia type II (HIT II) : A medical-economic view]. / Die heparininduzierte Thrombozytopenie (HIT II) : Eine medizinökonomische Betrachtung.

BACKGROUND: In the context of inpatient and increasingly ambulatory thrombosis prophylaxis, heparins have been recognised as standard therapy for decades. In addition to the therapeutic benefit, therapy with heparins also entails the risk of undesirable side effects, such as bleeding and thrombocytopenia. Heparin-induced thrombocytopenia (HIT II) is deemed a serious side effect. AIM: In the following work, HIT II is subjected to a medico-economic consideration (treatment, pharmaceuticals, subsequent costs due to possible complications) and, with regard to a possible HIT II prophylaxis, aspects of increasingly respected patient safety are also considered. METHODS: In the context of a literature search the active ingredients argatroban and danaparoid, which are approved for HIT II treatment, were evaluated. RESULTS: HIT II - especially in combination with thromboembolic complications - represents a medical-economic burden for the hospital. Although this is only an orientation guide, it shows that HIT II syndrome is not adequately cost-covered by the G­DRG system. An early thrombosis prophylaxis with argatroban/danaparoid for HIT II risk patients should therefore be taken into account for medical-related as well as patient safety-relevant aspects. According to experience, the pharmaceutical supply for these medically needed products (anticoagulants) should be ensured for reasons of patient safety. CONCLUSION: The risk of an immunological response to heparin therapy is known. Within the context of increased patient safety, thrombosis prophylaxis should be issued with a risk-adjusted prophylaxis.

Improved neutron-gamma discrimination for a (6)Li-glass neutron detector using digital signal analysis methods.

A (6)Li-glass scintillator (GS20) based neutron Anger camera was developed for time-of-flight single-crystal diffraction instruments at Spallation Neutron Source. Traditional Pulse-Height Analysis (PHA) for Neutron-Gamma Discrimination (NGD) resulted in the neutron-gamma efficiency ratio (defined as NGD ratio) on the order of 10(4). The NGD ratios of Anger cameras need to be improved for broader applications including neutron reflectometers. For this purpose, six digital signal analysis methods of individual waveforms acquired from photomultiplier tubes were proposed using (i) charge integration, (ii) pulse-amplitude histograms, (iii) power spectrum analysis combined with the maximum pulse-amplitude, (iv) two event parameters (a1, b0) obtained from a Wiener filter, (v) an effective amplitude (m) obtained from an adaptive least-mean-square filter, and (vi) a cross-correlation coefficient between individual and reference waveforms. The NGD ratios are about 70 times those from the traditional PHA method. Our results indicate the NGD capabilities of neutron Anger cameras based on GS20 scintillators can be significantly improved with digital signal analysis methods.

T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis.

The transcription factor T-bet is highly expressed by Th cells isolated from the inflamed intestine of Crohn's disease patients, and has been regarded a critical driver of murine T cell-induced colitis. However, we show here that T-bet expression by Th cells is not required for the manifestation of T-cell-induced colitis in the presence of segmented filamentous bacteria and Helicobacter hepaticus. T-bet expression by Th cells controls their survival and localization, their repertoire of chemokine and chemokine receptor expression, the accumulation of monocytes and macrophages in the inflamed colon, and their differentiation to the M1 type, i.e., type 1 inflammation. Nevertheless, T-bet-deficient Th cells efficiently induce colitis, as reflected by weight loss, diarrhea, and colon histopathology. T-bet-deficient Th cells differentiate into Th1/17 cells, able to express IFN-γ and IL-17A upon restimulation. While neutralization of IL-17A exacerbated colitis induced by wild-type or T-bet-deficient Th cells, neutralization of IFN-γ completely abolished colitis.

Smallest molecular chalcogenidometalate anions of the heaviest metals: syntheses, structures, and their interconversion.

The syntheses of the first molecular meta-selenidomercurate(ii), ortho-telluridothallate(iii) and a hydrate of an ortho-selenidoplubate(iv) are presented alongside an improved and facile synthesis of the selenidobismuthate(iii) with almost quantitative yields. By means of quantum chemical calculations, the energetics of the interconversions of small metalate anions is discussed and the existence of the heaviest homologues of [NO2](-), [NO3](-), [PO4](2-) and [CO3](2-) are predicted.

Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice.

During systemic immune responses, plasma blasts are generated in secondary lymphoid organs and migrate to the bone marrow, where they can become long-lived, being responsible for the maintenance of long-term antibody titers. Plasma blasts generated in mucosal immune responses of the small intestine home to the lamina propria (LP), producing mainly immunoglobulin A. The migration of these antibody-secreting cells is well characterized during acute immune responses. Less is known about their lifetime and contribution to the long-lived bone marrow compartment. Here we investigate the lifetime of plasma cells (PCs) and the relationship between the PC compartments of the gut and bone marrow after oral immunization. Our findings indicate that PCs in the LP can survive for extended time periods. PCs specific for orally administered antigens can be detected in the bone marrow for at least 9 months after immunization, indicating that the mucosal PC compartment can contribute to the long-lived PC pool in this organ, independent of the participation of splenic B cells. Our findings suggest that the compartmentalization between mucosal and systemic PC pools is less strict than previously thought. This may have implications for the development of vaccines as well as for autoantibody-mediated diseases.

Anti-inflammatory and antinociceptive activity of Urera aurantiaca.

Urera aurantiaca Wedd. (Urticaceae) is a medicinal plant commonly used in traditional medicine to relieve pain in inflammatory processes. In the present study, the in vivo anti-inflammatory and antinociceptive effects of U. aurantiaca methanolic extract and its possible mechanisms of action were investigated. The extract showed anti-inflammatory activity in the ear edema in mice test (34.3% inhibition), myeloperoxidase (MPO) activity was markedly reduced in animals administered with the extract: within 49.6% and 68.5%. In the histological analysis, intense dermal edema and intense cellular infiltration of inflammatory cells were markedly reduced in the ear tissue of the animals treated with the extract. In the carrageenan-induced hind paw edema in rats assay the extract provoked a significant inhibition of the inflammation (45.5%, 5 h after the treatment) and the MPO activity was markedly reduced (maximum inhibition 71.7%), The extract also exhibited significant and dose-dependent inhibitory effect on the increased vascular permeability induced by acetic acid. The extract presented antioxidant activity in both 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis 3-ethylbenzothiazoline 6-sulfonic acid tests and its total phenol content was 35.4 ± 0.06 mg GAE/g of extract. Also, the extract produced significant inhibition on nociception induced by acetic acid (ED50 : 8.7 mg/kg, i.p.) administered intraperitoneally and orally. Naloxone significantly prevented this activity.

New design of a multi-jet target for quasi phase matching.

An improved dual-gas quasi-phase matching (QPM) foil target for high harmonic generation (HHG) is presented. The target can be setup with 12 individual gas inlets each feeding multiple nozzles separated by a minimum distance of 10 µm. Three-dimensional gas density profiles of these jets were measured using a Mach-Zehnder Interferometer. These measurements reveal how the jets influence the density of gas in adjacent jets and how this leads to increased local gas densities. The analysis shows that the gas profiles of the jets are well defined up to a distance of about 300 µm from the orifice. This target design offers experimental flexibility, not only for HHG/QPM investigations, but also for a wide range of experiments due to the large number of possible jet configurations. We demonstrate the application to controlled phase tuning in the extreme ultraviolet using a 1 kHz-10 mJ-30 fs-laser system where interference between two jets in the spectral range from 17 to 30 nm was observed.

Thermal properties of borate crystals for high power optical parametric chirped-pulse amplification.

The potential of borate crystals, BBO, LBO and BiBO, for high average power scaling of optical parametric chirped-pulse amplifiers is investigated. Up-to-date measurements of the absorption coefficients at 515 nm and the thermal conductivities are presented. The measured absorption coefficients are a factor of 10-100 lower than reported by the literature for BBO and LBO. For BBO, a large variation of the absorption coefficients was found between crystals from different manufacturers. The linear and nonlinear absorption coefficients at 515 nm as well as thermal conductivities were determined for the first time for BiBO. Further, different crystal cooling methods are presented. In addition, the limits to power scaling of OPCPAs are discussed.

Power scaling of supercontinuum seeded megahertz-repetition rate optical parametric chirped pulse amplifiers.

Optical parametric chirped-pulse amplifiers with high average power are possible with novel high-power Yb:YAG amplifiers with kW-level output powers. We demonstrate a compact wavelength-tunable sub-30-fs amplifier with 11.4 W average power with 20.7% pump-to-signal conversion efficiency. For parametric amplification, a beta-barium borate crystal is pumped by a 140 W, 1 ps Yb:YAG InnoSlab amplifier at 3.25 MHz repetition rate. The broadband seed is generated via supercontinuum generation in a YAG crystal.

Design considerations for a high power, ultrabroadband optical parametric chirped-pulse amplifier.

A conceptual design of a high power, ultrabroadband optical parametric chirped-pulse amplifier (OPCPA) was carried out comparing nonlinear crystals (LBO and BBO) for 810 nm centered, sub-7.0 fs pulses with energies above 1 mJ. These amplifiers are only possible with a parallel development of kilowatt-level OPCPA-pump amplifiers. It is therefore important to know good strategies to use the available OPCPA-pump energy efficiently. Numerical simulations, including self- and cross-phase modulation, were used to investigate the critical parameters to achieve sufficient spectral and spatial quality. At high output powers, thermal absorption in the nonlinear crystals starts to degrade the output beam quality. Strategies to minimize thermal effects and limits to the maximum average power are discussed.

Demographic change and its impact on the health-care budget for heart failure inpatients in Germany during 1995-2025.

AIMS: Demographic change affects the health system in many countries. Heart failure is used as an example in demonstrating the effects of these changing demographics. METHODS: We analyzed trends for demographic change and their effects on heart failure and its costs over the period 1995-2025. RESULTS: Changing demographics are associated with higher treatment costs. The number of patients with heart failure is expected to increase by 61.8 % overall and as much as 74.6 % among the population aged over 65 years. The number of hospital admissions due to heart failure is forecast to increase to 448,752 in 2025. The cost of inpatient treatment will also rise by almost 50 % to around  1.80 billion in 2025. CONCLUSION: It is important to reduce the number of inpatient cases; this can be achieved, for example, by the implementation of adequate guideline-oriented patient-care programs, as well as patient education for the improvement of therapy adherence.

International standards for health economic evaluation with a focus on the German approach.

WHAT IS KNOWN AND OBJECTIVE: Health economic evaluation (HEE) is increasingly used in healthcare decision-making on the allocation of limited resources in national healthcare systems. Although the methods used for HEE vary in different countries, all economic evaluations address two questions: Are limited resources used optimally? Is value for money achieved in their use? Our objective is to explain some fundamental concepts in HEE and how these concepts are adapted in different countries, notably in Germany. METHODS: We performed a bibliographic search to identify existing methods of health economic evaluation of new drugs used by the official agencies of 11 countries (Austria, Australia, Canada, Finland, France, the Netherlands, Norway, New Zealand, Sweden, the United States and England and Wales) and compared them with that used by the German national agency IQWiG. RESULTS AND DISCUSSION: All countries considered follow internationally established standards of HEE. The majority of countries, including Germany, utilize primary outcome parameters such as disease-related morbidity and mortality for assessing relative efficacy and effectiveness. The most frequently recommended form of health economic evaluation is the cost-utility analysis (CUA). The German IQWIG is the only HTA body to use the cost-benefit concept of 'efficiency frontier' in its assessment. WHAT IS NEW AND CONCLUSION: While the core principles of HEE are the same worldwide, there is a lack of harmonization in the details. This requires resource-consuming adaptations in the analyses to meet different national requirements. We describe the core principles of HEE as a common basis for further discussions by all stakeholders.

Single-shot pulse duration monitor for extreme ultraviolet and X-ray free-electron lasers.

The resolution of ultrafast studies performed at extreme ultraviolet and X-ray free-electron lasers is still limited by shot-to-shot variations of the temporal pulse characteristics. Here we show a versatile single-shot temporal diagnostic tool that allows the determination of the extreme ultraviolet pulse duration and the relative arrival time with respect to an external pump-probe laser pulse. This method is based on time-resolved optical probing of the transient reflectivity change due to linear absorption of the extreme ultraviolet pulse within a solid material. In this work, we present measurements performed at the FLASH free-electron laser. We determine the pulse duration at two distinct wavelengths, yielding (184±14) fs at 41.5 nm and (21±19) fs at 5.5 nm. Furthermore, we demonstrate the feasibility to operate the tool as an online diagnostic by using a 20-nm-thin Si3N4 membrane as target. Our results are supported by detailed numerical and analytical investigations.

Long-term stabilization of high power optical parametric chirped-pulse amplifiers.

The long-term stability of optical parametric chirped-pulse amplifiers is hindered by thermal path length drifts affecting the temporal pump-to-signal overlap. A kilowatt-pumped burst amplifier is presented delivering broadband 1.4 mJ pulses with a spectral bandwidth supporting sub-7 fs pulse duration. Active temporal overlap control can be achieved by feedback of optical timing signals from cross-correlation or spectral measurements. Using a balanced optical cross-correlator, we achieve a pump-to-signal synchronization with a residual jitter of only (46 ± 2) fs rms. Additionally, we propose passive pump-to-signal stabilization with an intrinsic jitter of (7.0 ± 0.5) fs rms using white-light continuum generation.

Coherent spectral enhancement of carrier-envelope-phase stable continua with dual-gas high harmonic generation.

Attosecond science is enabled by the ability to convert femtosecond near-infrared laser light into coherent harmonics in the extreme ultraviolet spectral range. While attosecond sources have been utilized in experiments that have not demanded high intensities, substantially higher photon flux would provide a natural link to the next significant experimental breakthrough. Numerical simulations of dual-gas high harmonic generation indicate that the output in the cutoff spectral region can be selectively enhanced without disturbing the single-atom gating mechanism. Here, we summarize the results of these simulations and present first experimental findings to support these predictions.

Pulsed operation of a high average power Yb:YAG thin-disk multipass amplifier.

An Yb:YAG thin-disk multipass laser amplifier system was developed operating in a 10 Hz burst operation mode with 800 µs burst duration and 100 kHz intra-burst repetition rate. Methods for the suppression of parasitic amplified spontaneous emission are presented. The average output pulse energy is up to 44.5 mJ and 820 fs compressed pulse duration. The average power of 4.45 kW during the burst is the highest reported for this type of amplifier.

[CorBene: a new model for collaborative care of patients with congestive heart failure]. / CorBene: Ein neues, kooperatives Versorgungsmodell für Patienten mit Herzinsuffizienz.

Congestive heart failure (CHF) is one of the most common medical disorders. The prognosis tends to be unfavorable and the quality of care needs further improvement. The aim of the CorBene project is to improve the health-related quality of life and the prognosis in patients in all stages of CHF and to reduce the hospitalization rate. For this purpose a modern collaborative treatment program involving all relevant health care professionals was developed. The key feature is the close collaboration between family physicians, practicing cardiologists, hospitals and rehabilitation facilities. The CorBene model was launched in Cologne and then spread to North-Rhine/Westphalia and to Saarland. Currently, there is the possibility to offer it in all German states. Preliminary analyses confirm an optimal, guideline-based therapy of CHF.