A review on genetic alterations in CNS metastases related to breast cancer treatment. Is there a role for liquid biopsies in CSF?

Acquired mutations or altered gene expression patterns in brain metastases (BM) and/or leptomeningeal metastases (LM) of breast cancer may play a role in therapy-resistance and offer new molecular targets and treatment options. Despite expanding knowledge of genetic alterations in breast cancer and their metastases, clinical applications for patients with central nervous system (CNS) metastases are currently limited. An emerging tool are DNA-techniques that may detect genetic alterations of the CNS metastases in the cerebrospinal fluid (CSF). In this review we discuss genetic studies in breast cancer and CNS metastases and the role of liquid biopsies in CSF.

VOILA on the LUVMI-X Rover: Laser-Induced Breakdown Spectroscopy for the Detection of Volatiles at the Lunar South Pole.

The project Lunar Volatiles Mobile Instrumentation-Extended (LUVMI-X) developed an initial system design as well as payload and mobility breadboards for a small, lightweight rover dedicated for in situ exploration of the lunar south pole. One of the proposed payloads is the Volatiles Identification by Laser Analysis instrument (VOILA), which uses laser-induced breakdown spectroscopy (LIBS) to analyze the elemental composition of the lunar surface with an emphasis on sampling regolith and the detection of hydrogen for the inference of the presence of water. It is designed to analyze targets in front of the rover at variable focus between 300 mm and 500 mm. The spectrometer covers the wavelength range from 350 nm to 790 nm, which includes the hydrogen line at 656.3 nm as well as spectral lines of most major rock-forming elements. We report here the scientific input that fed into the concept and design of the VOILA instrument configuration for the LUVMI-X rover. Moreover, we present the measurements performed with the breadboard laboratory setup for VOILA at DLR Berlin that focused on verifying the performance of the designed LIBS instrument in particular for the detection and quantification of hydrogen and other major rock forming elements in the context of in situ lunar surface analysis.

Local and systemic therapy in breast cancer patients with central nervous system metastases.

PURPOSE: As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases. METHODS: Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes. RESULTS: We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P < 0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P < 0.001). No significant difference in OS was observed between different systemic treatment regimens. CONCLUSION: Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

Central Nervous System Progression in Primary Vitreoretinal Lymphoma with Bilateral and Unilateral Involvement: A Systematic Review and Meta-Analysis.

BACKGROUND: Primary vitreoretinal lymphoma (PVRL) is either unilateral or bilateral at initial presentation. Progression to a central nervous system (CNS) lymphoma is regularly observed and these patients seem to have an inferior survival. Knowledge of the predictive value of laterality for CNS progression may facilitate risk stratification and the development of more effective treatment strategies, and eventually, improve outcomes. The objective of this analysis is to estimate the risk of CNS progression for patients with bilateral versus unilateral involvement of PVRL. METHODS: Systematic literature search for studies on CNS progression in PVRL with bilateral and unilateral involvement according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We assessed the risk of bias and the methodological quality of studies using the Quality in Prognosis Studies (QUIPS) tool. Risk ratios of CNS progression in PVRL with bilateral and unilateral involvement were calculated and combined via a meta-analysis. RESULTS: Twenty-five small-sized (total n = 371 cases) studies were included. The majority of the studies were at medium to high risk of bias. Results suggest no significant difference in CNS progression between bilateral and unilateral PVRL, with a pooled relative risk ratio of 1.12 (95% confidence interval 0.89-1.41). CONCLUSIONS: CNS progression is common in PVRL. From the limited available evidence, there is no significant difference in CNS progression between bilateral and unilateral PVRL.

Passively Q-switched microchip laser based picosecond light source in the visible-red to near-infrared band for semiconductor excitation.

We developed a visible-red to near-infrared wavelength tunable all-solid-state laser system utilizing an optical parametric generation process in a MgO doped PPLN crystal pumped at 532 nm by an amplified and frequency doubled picosecond passively Q-switched Nd:YVO4 microchip laser. A broad bandwidth, tuneable over 300 nm between 710 nm to 1015 nm, is accessible. Depending on the green pump light pulse energy, pulses with durations down to 69 ps as well as pulses with energies above 2 µJ were achieved with kHz repetition rates.

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C.

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.

Two-Dimensional Laser Melting of Lunar Regolith Simulant Using the MOONRISE Payload on a Mobile Manipulator.

Laser melting experiments were carried out with the MOONRISE payload, installed on the mobile manipulator, MIRA3D. The MOONRISE payload was developed to demonstrate the feasibility of additive processing of lunar regolith with the help of lasers on the Moon within a lunar surface mission in the next years. The development of hardware for the flight to the moon is well advanced and, if successful, would pave the way for the use of laser melting for production of components from regolith. The aim of the experiments described in this article was to test the planned scenario on the Moon, especially the interaction between laser payload, manipulator, and soil surface, and to identify suitable process parameters for production of two-dimensional (2D) objects. The ability to produce 2D objects is an important intermediate step on the way to produce large three-dimensional structures such as habitats, walls, or foundations. During the experiments, specimens with a size of ∼20 × 20 × 4 mm were repeatedly produced. As analog material, two synthetic lunar soils produced with the modular regolith simulant systems from Technische Universität Braunschweig (TUBS) were used. The experiments were conducted under Earth gravity and atmospheric conditions. This article describes the hardware used, procedure for carrying out the experiments, and properties of the produced samples.

Wedged Nd:YVO4 crystal for wavelength tuning of monolithic passively Q-switched picosecond microchip lasers.

We present a monolithic integrated passively Q-switched sub-150 ps microchip laser at 1064 nm with a wedged Nd:YVO4 crystal operating up to a repetition rate of 1 MHz. The wedge enables to change the cavity length by a small amount to fine tune the spectral cavity mode position over the full gain bandwidth of Nd:YVO4 and hence to optimize the output power. This additional degree of freedom may be a suitable approach to increase the wafer scale mass production yield or also to simplify frequency tuning of CW single-frequency microchip lasers.

Low noise 400 W coherently combined single frequency laser beam for next generation gravitational wave detectors.

Design studies for the next generation of interferometric gravitational wave detectors propose the use of low-noise single-frequency high power laser sources at 1064 nm. Fiber amplifiers are a promising design option because of their high output power and excellent optical beam properties. We performed filled-aperture coherent beam combining with independently amplified beams from two low-noise high-power single-frequency fiber amplifiers to further scale the available optical power. An optical power of approximately 400 W with a combining efficiency of more than 93% was achieved. The combined beam contained 370 W of linearly polarized TEM00-mode and was characterized with respect to the application requirements of low relative power noise, relative beam pointing noise, and frequency noise. The noise performance of the combined beam is comparable to the single amplifier noise. This represents, to our knowledge, the highest measured power in the TEM00-mode of single frequency signals that fulfills the low noise requirements of gravitational wave detectors.

Performance study of a high-power single-frequency fiber amplifier architecture for gravitational wave detectors.

The next generation of interferometric gravitational wave detectors will use low-noise single-frequency laser sources at 1064 nm. Fiber amplifiers are a promising design option because of high efficiency, compact design, and superior optical beam properties compared to the current generation of laser sources for gravitational wave detectors. We developed a reliable 200 W single-frequency fiber amplifier architecture to meet the application requirements regarding relative power noise, relative pointing noise, frequency noise, linear polarization, and beam quality. We characterized several of these amplifiers and discuss performance variations resulting from manufacturing tolerances and variations in amplifier architecture. This study serves as a baseline for further power scaling via e.g., coherent beam combining experiments.

Multi-parametric assessment of biological stability of drinking water produced from groundwater: Reverse osmosis vs. conventional treatment.

Although water produced by reverse osmosis (RO) filtration has low bacterial growth potential (BGP), post-treatment of RO permeate, which is necessary prior to distribution and human consumption, needs to be examined because of the potential re-introduction of nutrients/contaminants. In this study, drinking water produced from anaerobic groundwater by RO and post-treatment (ion exchange, calcite contactors, and aeration) was compared with that produced by conventional treatment comprising (dry) sand filtration, pellet softening, rapid sand filtration, activated carbon filtration, and UV disinfection. The multi-parametric assessment of biological stability included bacterial quantification, nutrient concentration and composition as well as bacterial community composition and diversity. Results showed that RO permeate remineralised in the laboratory has an extremely low BGP (50 ± 12 × 103 ICC/mL), which increased to 130 ± 10 × 103 ICC/mL after site post-treatment. Despite the negative impact of post-treatment, the BGP of the finished RO-treated water was >75% lower than that of conventionally treated water. Organic carbon limited bacterial growth in both RO-treated and conventionally treated waters. The increased BGP in RO-treated water was caused by the re-introduction of nutrients during post-treatment. Similarly, OTUs introduced during post-treatment, assigned to the phyla of Proteobacteria and Bacteroidetes (75-85%), were not present in the source groundwater. Conversely, conventionally treated water shared some OTUs with the source groundwater. It is clear that RO-based treatment achieved an extremely low BGP, which can be further improved by optimising post-treatment, such as using high purity calcite. The multi-parametric approach adopted in this study can offer insights into growth characteristics including limiting nutrients (why) and dominating genera growing (who), which is essential to manage microbiological water quality in water treatment and distribution systems.

360-Degree Distribution of Biofilm Quantity and Community in an Operational Unchlorinated Drinking Water Distribution Pipe.

In the present study, triplicate rings of 360° pipe surfaces of an operational drinking water distribution pipe were swabbed. Each ring was equally divided into 16 parts for swabbing. The collected swabs were grouped into 3 sections and compared with the biofilm samples sampled by sonication of specimens from the same pipe. The results showed that the biofilm is unevenly distributed over the 16 parts and the 3 sections of the pipe surface. Both the active biomass and the number of observed OTUs increased as the measurements proceeded from the top to the bottom of the pipe. The bacterial community was dominated in all sections by Proteobacteria. At the genus level, Nitrospira spp., Terrimonas spp., and Hyphomicrobium spp. were dominant in all sections. Gaiella spp. and Vicinamibacter spp. dominated in S-I, Blastopirellula spp. and Pirellula spp. dominated in S-II, while Holophaga spp. and Phaeodactylibacter spp. dominated in S-III. When swabbing and pipe specimen sonication were compared, the results showed that the sampling strategy significantly influences the obtained biofilm bacterial community. A consistent multisectional swabbing strategy is proposed for future biofilm sampling; it involves collecting swabs from all sections and comparing the swabs from the same position/section across locations.

Single-frequency chirally coupled-core all-fiber amplifier with 100 W in a linearly polarized TEM00 mode.

Large mode area fibers have become indispensable in addressing the power requirements of laser sources in gravitational wave detectors. Besides high power capabilities, the system must provide an excellent beam quality and polarization. In this Letter, we present the characterization of a monolithic high-power fiber amplifier at 1064 nm, built using an ytterbium-doped chirally coupled-core fiber, which achieves an output power of 100 W in a linearly polarized $ {{\rm TEM}_{00}} $TEM00 mode in an all-fiber setup.

[Post-traumatic benign paroxysmal positional vertigo; an underdiagnosed cause of dizziness following trauma]. / Posttraumatische benigne paroxymale positieduizeligheid.

Dizziness is a frequently reported symptom following head trauma. Although often ascribed to concussion, post-traumatic benign paroxysmal positional vertigo (BPPV) must be included in the differential diagnosis. In this article, three patients who attended a neurology outpatient clinic with persistent dizziness following head trauma were ultimately diagnosed with post-traumatic BPPV. Dizziness lessened substantially once a canalith repositional manoeuvre was performed. Patients with post-traumatic BPPV are generally younger, report more severe symptoms and have a higher rate of relapse. Diagnosing post-traumatic BPPV can be challenging due to the presence of more urgent injuries in the initial phase and the habitual attribution of symptoms to concussion. A timely diagnosis is crucial, however, since treatment is easy to perform, non-invasive and effective.

Single-frequency fiber amplifier at 1.5 µm with 100 W in the linearly-polarized TEM00 mode for next-generation gravitational wave detectors.

Next-generation gravitational wave detectors require single-frequency and high power lasers at a wavelength of 1.5 µm addressing a set of demanding requirements such as linearly-polarized TEM00 radiation with low noise to run for long periods. In this context, fiber amplifiers in MOPA configuration are promising candidates to fulfill these requirements. We present a single-frequency monolithic Er:Yb co-doped fiber amplifier (EYDFA) at 1.5 µm with a linearly-polarized TEM00 output power of 100 W. The EYDFA is pumped off-resonant at 940 nm to enhance the Yb-to-Er energy transfer efficiency and enable higher ASE threshold. We also performed numerical simulations to investigate the off-resonant pumping scheme and confirm the corresponding experimental results.

Influence of the third energy level on the gain dynamics of EDFAs: analytical model and experimental validation.

We report an analytical model and experimental validation of the temporal dynamics of 3-level system fiber amplifiers. The model predictions show a good agreement with the measured pump power to output power and the pump power to output phase transfer functions in an EDFA pumped at 976 nm, as well as with the typical literature values for the spontaneous lifetime of the involved energy levels. The measurements show a linear relation between the effective lifetime of the meta-stable level and the output power, and a filtering of the temperature-induced phase-shift due to the quantum defect at a sufficiently high frequency modulation.

1 kHz 3.3 µm Nd:YAG KTiOAsO4 optical parametric oscillator system for laser ultrasound excitation of carbon-fiber-reinforced plastics.

We present a new laser prototype for laser ultrasonics excitation. The fundamental wavelength of a Q-switched Nd:YAG laser with a repetition rate of 1 kHz is converted to 3.3 µm with a KTiOAsO4 optical parametric oscillator. The achieved pulse energy at 3.3 µm is 1.7 mJ, and the pulse duration at the fundamental wavelength of 1.06 µm has been measured to be 21 ns. The ultrasonic excitation efficiency is about 3.5 times better compared to the application of state-of-the-art CO2 lasers.

Effect of Pile-Driving Sounds on the Survival of Larval Fish.

Concern exists about the potential effects of pile-driving sounds on fish, but evidence is limited, especially for fish larvae. A device was developed to expose larvae to accurately reproduced pile-driving sounds. Controlled exposure experiments were carried out to examine the lethal effects in common sole larvae. No significant effects were observed at zero-to-peak pressure levels up to 210 dB re 1 µPa(2) and cumulative sound exposure levels up to 206 dB re 1 µPa(2)·s, which is well above the US interim criteria for nonauditory tissue damage in fish. Experiments are presently being carried out for European sea bass and herring larvae.

TEM00 mode content measurements on a passive leakage channel fiber.

Mode content measurements with a scanning ring cavity were performed in order to determine the TEM00 mode content of the output beam profile of a resonantly enhanced leakage channel fiber. The measurements were performed at 1.0 and 1.5 µm. In addition, the influence of different bending diameters as well as launching conditions has been investigated. Furthermore, a numerical simulation was used to determine the maximum theoretical TEM00 overlap, if only the fundamental fiber mode is guided. The simulation was also used to analyze how the TEM00 overlap for the case of any additional higher order fiber mode can be determined consistently.

[A score for rating instability in spinal metastases and the usefulness of conservative measures for instability]. / Instabiliteit bij spinale metastasen: objectieve score en nut van conservatieve maatregelen.

Spinal instability in patients with spinal metastatic disease plays a role in the selection of surgical intervention. The classic 'three-column model' used in traumatology to assess the stability of the spinal column is not always applicable to spinal metastatic disease. The recently introduced Spinal Instability Neoplastic Score (SINS) is the first instrument that can be used to classify instability in spinal metastatic disease. Utilisation of the SINS by the medical community could lead to more uniformity, which could prevent a delay in the treatment of patients with spinal instability. Only a select group of patients with spinal instability due to metastatic disease is eligible for spinal surgery. Other patients are often prescribed bed rest or other conservative treatment. The usefulness of such treatments, however, has not been adequately substantiated.