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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Impact of amplified spontaneous emission on Brillouin scattering of a single-frequency signal.

We experimentally investigated the influence of amplified spontaneous emission within the Brillouin gain bandwidth on the Brillouin scattering of a single-frequency signal. The experiments were performed for the case of artificial ASE injected in backward direction into a passive fiber, as well as in forward direction of a low-power fiber amplifier. A significant influence could be observed, when the ASE was counter-propagating to the signal. Injecting 160.6 nW of ASE within the Brillouin gain bandwidth led to a decrease of about 3 dB of the SBS-threshold of an approximately 335 m long passive fiber from about 80 mW to less than 40 mW. At a fixed signal power of 81 mW the backscattered power and the power in the Brillouin scattered Stokes maximum increased by a factor of 19.

Gain dynamics and refractive index changes in fiber amplifiers: a frequency domain approach.

Gain dynamics and refractive index changes in fiber amplifiers are important in many areas. For example, the knowledge of the frequency responses for seed and pump power modulation are required to actively stabilize low noise fiber amplifiers. Slow and fast light via coherent population oscillations rely on the change of group index to delay or advance pulses, and refractive index changes in fiber amplifiers are a possible explanation for mode fluctuations in high power fiber amplifiers. Here, we analyze the frequency dependent influence of seed and pump power modulation on the fiber amplifier output power and the refractive index. We explain the observed power and refractive index modulation with an analytic model originally developed for telecom amplifiers and discuss a further simplification of the model.

TEM 00 mode content of a two stage single-frequency Yb-doped PCF MOPA with 246 W of output power.

Gravitational wave detectors require linearly polarized single-frequency laser sources with a high fractional TEM 00 mode content. We investigated the modal decomposition of a polarization maintaining photonic crystal fiber with a mode field diameter of 29 µm, operating in a single-frequency master-oscillator power-amplifier scheme, with respect to the TEM nm modes. Low degradation of the beam quality with increasing pump power could be observed, while a maximum power in the TEM 00 mode of 203 W was achieved.

High power single frequency solid state master oscillator power amplifier for gravitational wave detection.

High power single frequency, single mode, linearly polarized laser output at the 1 µm regime is in demand for the interferometric gravitational wave detectors (GWDs). A robust single frequency solid state master oscillator power amplifier (MOPA) is a promising candidate for such applications. We present a single frequency solid state multistage MOPA system delivering 177 W of linearly polarized output power at 1 µm with 83.5% TEM(00) mode content.

Frequency resolved analysis of thermally induced refractive index changes in fiber amplifiers.

Temperature induced refractive index changes are an important aspect in today's fiber amplifiers with high average power. For many processes, their time dependence is critical. Here, we analyze the impact of radial heat diffusion on the optical phase. We modulated the pump power in a 10 W amplifier and measured the frequency response of the optical phase. We compared the result with the calculated frequency response of the temperature in the fiber core, which shows the same characteristics. Additionally, we analyzed the influence of fiber parameters on the temperature dynamics.

Beam quality degradation of a single-frequency Yb-doped photonic crystal fiber amplifier with low mode instability threshold power.

A current limit in power scaling of Yb-doped fiber amplifiers is the sudden onset of mode instabilities. We investigated this effect on a single-frequency Yb-doped photonic crystal fiber amplifier with a low mode instability threshold power. By measuring the overlap of the fiber output beam with the fundamental mode of an external cavity to be about 95%, we could exclude significant modal power transfer below a sharp power threshold. Furthermore, we directly measured the frequency resolved intensity noise spectra. No fluctuations in the overall output power were observed, but for the modal content different oscillation regimes were identified.