Fluorescence-guided laser lithotripsy: Estimation of the potential effectiveness and safety increase based on first clinical data.

In clinically approved laser lithotripsy systems, there is no automatic monitoring of fiber position to date. We investigated whether detecting stone autofluorescence, excited by a green aiming beam, is possible via the fiber during fragmentation by continuously recording the fluorescence signal in 12 ureterosopic lithotripsy procedures. We estimated which threshold the fluorescence signal's amplitude exceeds before laser pulses with visible stone removal by retrospective inspection of the endoscope's video data. For all procedures, blocking the laser when the fluorescence amplitude is below a threshold corresponding to the signal's baseline plus its range (maximum-minimum value) would have been appropriate to suppress ineffective pulses-the energy input could have been reduced by a mean of 14% (1%-29%) without changing the operation time. Ablation of the PTFE coating of the guidewire could have been prevented three times and cutting of a wire of the retrieval basket two times.

Energy Compression and Stabilization of Laser-Plasma Accelerators.

Laser-plasma accelerators outperform current radio frequency technology in acceleration strength by orders of magnitude. Yet, enabling them to deliver competitive beam quality for demanding applications, particularly in terms of energy spread and stability, remains a major challenge. In this Letter, we propose to combine bunch decompression and active plasma dechirping for drastically improving the energy profile and stability of beams from laser-plasma accelerators. Realistic start-to-end simulations demonstrate the potential of these postacceleration phase-space manipulations for simultaneously reducing an initial energy spread and energy jitter of ∼1-2% to ≲0.1%, closing the beam-quality gap to conventional acceleration schemes.

Compact Multistage Plasma-Based Accelerator Design for Correlated Energy Spread Compensation.

The extreme electromagnetic fields sustained by plasma-based accelerators could drastically reduce the size and cost of future accelerator facilities. However, they are also an inherent source of correlated energy spread in the produced beams, which severely limits the usability of these devices. We propose here to split the acceleration process into two plasma stages joined by a magnetic chicane in which the energy correlation induced in the first stage is inverted such that it can be naturally compensated in the second. Simulations of a particular 1.5-m-long setup show that 5.5 GeV beams with relative energy spreads of 1.2×10^{-3} (total) and 2.8×10^{-4} (slice) could be achieved while preserving a submicron emittance. This is at least one order of magnitude below the current state of the art and would enable applications such as compact free-electron lasers.

Observation of the Self-Modulation Instability via Time-Resolved Measurements.

Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton-driven plasma accelerator schemes aiming to utilize the same physical effect.

Chirp Mitigation of Plasma-Accelerated Beams by a Modulated Plasma Density.

Plasma-based accelerators offer the possibility to drive future compact light sources and high-energy physics applications. Achieving good beam quality, especially a small beam energy spread, is still one of the major challenges. Here, we propose to use a periodically modulated plasma density to shape the longitudinal fields acting on an electron bunch in the linear wakefield regime. With simulations, we demonstrate an on-average flat accelerating field that maintains a small beam energy spread.

Resection of calcified aortic heart leaflets in vitro by Q-switched 2 µm microsecond laser radiation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) can result in paravalvular leakage and stent deformation in the presence of severe calcification. This study was undertaken to determine the efficacy of laser-assisted resection of calcific aortic valve leaflets as a method to minimize the effects of calcium on perivalvular leakage during TAVI. METHODS: A Q-switched Tm:YAG laser emitting at a wavelength of 2.01 µm was used to evaluate the cutting efficiency on highly calcified human aortic leaflets in vitro (N = 10). A pulse energy of 4.3 mJ, a pulse duration of 0.8-1 µs, and a repetition rate of 1 kHz were used. The radiation was transmitted via a 200 µm core diameter quartz fiber. Resection was performed in a fiber-tissue contact mode on water-covered samples in a dish. The remnant particles were analyzed with respect to quantity and size by light microscopy. RESULTS: A resection rate of 40.4 ± 22.2 mg/min on highly calcified aortic leaflets was achieved. This corresponds to a cutting speed of approximately 1 cm/min; a laser dissection time of 3 min per leaflet is expected. The majority of the remnant particles (85.4%) were <6 µm in diameter, with only 0.1% exceeding 300 µm. CONCLUSIONS: The Q-switched Tm:YAG laser system showed promising results in cutting calcified aortic valves, by transmitting sufficient energy through a small flexible fiber. Catheter-based removal of aortic valve calcification may help to improve TAVI technology.

Vectorial release of matrix metalloproteinases (MMPs) from porcine RPE-choroid explants following selective retina therapy (SRT): towards slowing the macular ageing process.

The purpose of this study was to investigate release of matrix metalloproteinases (MMP) 2 and 9 during retinal pigment epithelium (RPE) wound healing after Selective Retina Therapy (SRT) with laser energy levels below and above the threshold of RPE cell death. Following exposure to SRT using a prototype pulsed Nd:YLF laser with energies of 80-180 mJ/cm(2) fresh porcine RPE-monolayers with Bruch's membrane and choroid were cultured in modified Ussing chambers which separate the apical (RPE-facing) and basal (choroid facing) sides of the RPE monolayer. Threshold energy for RPE cell death and wound healing were determined with calcein-AM viability test. Inactive and active forms of MMP 2 and 9 were quantified within tissue samples and in the culture medium of the apical and basal compartments of the Ussing chamber using gelatine zymography. Laser energies of 160-180 mJ/cm(2) resulted in cell death within 1 h while 120-140 mJ/cm(2) resulted in delayed death of exposed RPE cells. All cells survived 80 and 100 mJ/cm(2). Laser spots healed within 6 days after SRT accompanied by a transient vectorial increase of MMPs. SRT with 180 mJ/cm(2) increased active MMP 2 by 1.9 (p < 0.05) and 1.6 (p < 0.05) fold in tissue and basal compartments, respectively, without alterations in the apical compartment. Pro-MMP 2 levels were also significantly increased in all compartments (p < 0.05). Release of MMP 9 was not altered. Laser energy below the threshold of RPE cell death did not alter the release of MMP 2 or 9. The findings suggest that the release of active MMP 2 on the basal side of the RPE during wound healing following SRT may address age-related pathological changes of Bruch's membrane with a potential to slow degenerative macular ageing processes before irreversible functional loss has occurred.

Selective retina therapy for acute central serous chorioretinopathy.

AIMS: To evaluate selective retina therapy (SRT) as a treatment of acute central serous chorioretinopathy. METHODS: 30 eyes of 30 patients with central serous chorioretinopathy of at least a 3 months' duration were recruited. 14 eyes were randomised to an SRT group (Q-switched neodymium-doped yttrium lithium fluoride (Nd:YLF) laser, wavelength 527 nm, t=1.7 µs, energy 100-370 µJ, spot diameter 200 µm, pulse repetition rate 100 Hz,) and 16 eyes to a control group. After 3 months of follow-up, patients in the control group with persistence of subretinal fluid (SRF) were allocated to a cross-over group, treated with SRT and followed up for further 3 months. The main outcome measures were change of best-corrected Early Treatment Diabetic Retinopathy Study visual acuity (BCVA) and SRF. RESULTS: At 3 months of follow-up, the mean (SD) improvement of BCVA was significantly greater after SRT than in the control group: 12.7 (7.2) versus 6.3 (8.9) letters (p=0.04). SRF had decreased significantly more after SRT as compared with that the control group: 203 (136) µm versus 41 (150) µm (p=0.005). In eight eyes allocated to the cross-over group, the mean BCVA had increased during 3 months of follow up before SRT by 1.4 (5.2) letters and continued to increase during 3 months following SRT by 7.4 (6.3) letters, while SRF increased by 39.5 (160.2) µm before SRT and decreased by 151.5 (204.9) µm after SRT. In six of the eight eyes, SRF had completely resolved 3 months after SRT. CONCLUSIONS: SRT appears to expedite functional recovery and the re-absorption of SRF as compared with that in untreated controls. A larger prospective, randomised phase 3 confirmative patient study is warranted. TRIAL REGISTRATION NUMBER: NCT00987077.

Enhancement of ohmic and stochastic heating by resonance effects in capacitive radio frequency discharges: a theoretical approach.

In low-pressure capacitive radio frequency discharges, two mechanisms of electron heating are dominant: (i) Ohmic heating due to collisions of electrons with neutrals of the background gas and (ii) stochastic heating due to momentum transfer from the oscillating boundary sheath. In this work we show by means of a nonlinear global model that the self-excitation of the plasma series resonance which arises in asymmetric capacitive discharges due to nonlinear interaction of plasma bulk and sheath significantly affects both Ohmic heating and stochastic heating. We observe that the series resonance effect increases the dissipation by factors of 2-5. We conclude that the nonlinear plasma dynamics should be taken into account in order to describe quantitatively correct electron heating in asymmetric capacitive radio frequency discharges.

[Basic principles and clinical application of retinal laser therapy]. / Grundlagen und klinische Anwendung der Lasertherapie an der Netzhaut.

The scientific background of laser photocoagulation of the ocular fundus was studied extensively by several investigators in the 1970 s and 1980 s. The basic principles were successfully resolved during that time and clinical consequences for proper application of the laser photocoagulation for various diseases were deduced. The present paper gives an overview about the physical basics of laser-tissue interactions during and after retinal laser treatment and the particular laser strategies in the treatment of different retinal diseases. Thus, it addresses the issue of the impact on tissue of laser parameters as wavelength, spot size, pulse duration and laser power. Additionally, the different biological tissue reactions after laser treatment are presented, such as, e. g., for retinopexia or macular treatments as well as for diabetic retinopathies. Specific laser strategies such as the selective laser treatment of the RPE (SRT) or the transpupillary thermotherapy (TTT) are presented and discussed.

Numerical modelling of conductive and convective heat transfers in retinal laser applications.

The control of the temperature increase is an important issue in retinal laser treatments. Within the fundus of the eye heat, generated by absorption of light, is transmitted by diffusion in the retinal pigment epithelium and in the choroid and lost by convection due to the choroidal blood flow. The temperature can be spatially and temporally determined by solving the heat equation. In a former analytical model this was achieved by assuming uniform convection for the whole fundus of the eye. A numerical method avoiding this unrealistic assumption by considering convective heat transfer only in the choroid is used here to solve the heat equation. Numerical results are compared with experimental results obtained by using a novel method of noninvasive optoacoustic retinal temperature measurements in rabbits. Assuming global convection the perfusion coefficient was evaluated to 0.07 s(-1), whereas a value of 0.32 s(-1)--much closer to values found in the literature (between 0.28 and 0.30 s(-1))--was obtained when choroidal convection was assumed, showing the advantage of the numerical method. The modelling of retinal laser treatment is thus improved and could be considered in the future to optimize treatments by calculating retinal temperature increases under various tissues and laser properties.

[Selective retina therapy: methods, technique, and online dosimetry]. / Selektive Retinatherapie: Methodik, Technik und Online-Dosimetrie.

Selective retina therapy (SRT) is currently under evaluation, as a new and very subtle laser method, for the treatment of retinal disorders associated with a degradation of the retinal pigmentary epithelium (RPE). SRT makes it possible to selectively effect the RPE, sparing the adjacent neural retina with the photoreceptors and also the choroid below the RPE. In the best case, the therapy leads to regeneration of the RPE and a long-term metabolic increase at the chorio-retinal junction. In contrast to conventional laser photocoagulation, which is associated with complete thermal necrosis of and around the treated site, absolutely no scotoma occurs in SRT. This paper reviews the methods and mechanisms behind the selective effects of the RPE. In vitro and preclinical results are used to describe the bandwidth of selective effects with respect to different irradiation settings. An optoacoustic technique is introduced to visualize effects that cannot be seen by ophthalmoscopy and to facilitate dosimetry control without recourse to angiography completes the report.

[Selective retina therapy in central serous chorioretinopathy with detachment of the pigmentary epithelium]. / Selektive Retina-Therapie bei Retinopathia centralis serosa mit Pigmentepithelabhebung.

BACKGROUND: Selective Retina Therapy (SRT) is a new and innovative laser treatment modality that selectively treats the retinal pigmentary epithelium while sparing the photoreceptors. This therapeutic concept appears to be particularly suitable for treating patients with acute or chronic central serous chorioretinopathy (CSC). We present preliminary results obtained in five patients who had CSC associated with pigmentary epithelium detachment (PED) and serous subretinal fluid (SRF) and who were treated with SRT. METHODS: This case series was made up of five male patients (mean age 47 years) with chronic CSC and SRF resulting from PED. Examinations performed before and at 1 month and 3 months after the treatment were: BCVA, FLA, OCT (Zeiss OCT III). For SRT, confluent treatment of the PED (area of leakage) was carried out using a pulsed frequency-doubled, Q-switched Nd-YLF prototype laser (lambda=527 nm, t= 1.7 s, 100 Hz, energy = 150-250 J). RESULTS: Best corrected visual acuity at baseline was 0.53, while after 4 weeks it was 0.56 and after 12 weeks, 0.5. At baseline leakage was seen at the PED on fluorescein angiography in all patients. After 4 weeks leakage activity was no longer noted on angiography in 4 of 5 patients. OCT at baseline showed SRF at the edge of the PED in all patients, but in 4 of the 5 patients this was no longer detectable after 4 weeks. CONCLUSION: SRT is a safe and effective treatment for patients with CSC in which PED has caused SRF. Not a single case of rip syndrome was observed in this study, even though the PED was treated confluently. Since SRT spares the photoreceptors it is particularly suitable for the treatment of CSC, especially when the origin of leakage is located close to the fovea. The results indicate that SRT leads to reconstruction of the outer blood-retina barrier.

[Selective retina therapy in patients with diabetic maculopathy]. / Selektive Retina-Therapie bei Patienten mit diabetischer Makulopathie.

Selective Retina Therapy (SRT) is a new laser treatment that selectively targets the retinal pigmen epithelium (RPE). In this study, we treated 39 patients presenting with nonischemic, focal and focal-diffuse diabetic maculopathy with SRT. In the main. the results indicate that SRT had stabilizing effects on visual acuity, angiographic leakage, lipid exudation, and foveal retinal thickness. SRT is safe and is especially useful for treating pathologies that are located close to the fovea, which cannot be treated with conventional argon laser photocoagulation.

Selective retina therapy in patients with central serous chorioretinopathy.

BACKGROUND: Central serous chorioretinopathy (CSC) is a disease with a localized breakdown of the outer blood-retinal barrier located within the retinal pigment epithelium (RPE) causing subretinal fluid accumulation. Selective retina therapy (SRT) is a new, minimally invasive laser technology that has been designed to selectively target the RPE. SRT spares retinal tissue. METHODS: Twenty-seven eyes of 27 patients with active CSC were treated with SRT using a pulsed double-Q-switched Nd-YLF prototype laser (lambda=527 nm, t=1.7 micros). At baseline, best-corrected visual acuity was determined and fluorescein angiography and optical coherence tomography were performed. The patients were followed for up to 3 months. RESULTS: After 4 weeks 85.2% of patients showed complete resolution of subretinal fluid and in 96.3% there was no leakage visible on fluorescein angiography. After 3 months 100% of patients demonstrated no subretinal fluid and 100% of patients had no leakage activity on fluorescein angiography. Visual acuity, 20/40 at baseline, improved to 20/28 after 4 weeks and to 20/20 after 3 months. CONCLUSION: SRT is a safe and effective treatment for active CSC. Especially if the RPE leak is located close to the fovea, SRT is the favoured therapeutic option. We recommend earlier treatment of patients with acute CSC in order to prevent development of chronic changes due to CSC with irreversible anatomical and functional damage. SRT might be considered as a first-line treatment for active CSC.

Selective retina therapy (SRT): a review on methods, techniques, preclinical and first clinical results.

Selective retina therapy (SRT) is a new laser procedure for retinal diseases that are thought to be associated with a degradation of the retinal pigment epithelium (RPE). The aim of the irradiation is to selectively damage the RPE without affecting the neural retina, the photoreceptors and the choroid. Goal of the treatment is to stimulate RPE cell migration and proliferation into the irradiated areas in order to improve the metabolism at the diseased retinal sites. In a pilot study more than 150 patients with soft drusen, retinopathia centralis serosa (RCS) and macular edema were treated. The first 3-center international trial targets diabetic macular edema and branch vein occlusion. In this review, selective RPE effects are motivated and two modalities to achieve selective RPE effects will be introduced: a pulsed and a continuous wave scanning mode. The mechanism behind selective RPE-effects will be discussed reviewing in vitro results and temperature calculations. So far clinical SRT is performed by applying trains of 30 laser pulses from a Nd:YLF-Laser (527 nm, 1.7 micros, 100 Hz) to the diseased fundus areas. In the range of 450-800 mJ/cm(2) per pulse, RPE-defects in patients were proved angiographically by fluorescein or ICG-leakage. The selectivity with respect to surrounding highly sensitive tissue and the safety range of the treatment will be reviewed. With the laser parameters used neither bleeding nor scotoma, proved by microperimetry, were observed thus demonstrating no adverse effects to the choroid and the photoreceptors, respectively. During and after irradiation, it shows that the irradiated locations are ophthalmoscopically invisible, since the effects are very limited and confined to the RPE, thus a dosimetry control is demanded. We report on a non-invasive opto-acoustic on-line technique to monitor successful RPE-irradiation and compare the data to those achieved with standard angiography one-hour post treatment.

[Selective RPE laser treatment with a scanned cw laser beam in rabbits]. / Selektive Behandlung des RPE unter Verwendung eines gescannten CW-Laserstrahls im Kaninchenmodell.

BACKGROUND: Selective RPE laser therapy with sparing of the neurosensory layer is possible by applying repetitive microsecond laser pulses. Macular diseases such as diabetic maculopathy, soft confluent drusen due to age-related macular degeneration or central serous chorioretinopathy were shown to be treated successfully-without concurrent laser scotoma-by this technique. It was the goal of this study to show, if selectivity could also be achieved using a conventional green cw-laser by scanning the beam across the retina during irradiation. MATERIAL AND METHODS: A cw-laser beam at 532 nm was coupled to a slitlamp via a single mode optical fiber. The spot (18 microm) was scanned across the retina of Dutch-belted rabbits through a contact lens using a two-dimensional acusto-optical deflector. The scan-field was 300 microm x 300 microm in size and consisted of six separate scan lines. The scanning speed was adjusted so as to produce 5 micros exposure at each absorber in the center of the scan line. The entire scan pattern was applied 100 times at each site at a frame rate of 100 Hz. Dose response curve was measured by variation of the laser power. ED(50)-thresholds for RPE damage were calculated by fluorescein angiographic leakage in irradiated areas after exposure to different laser intensities. The extent of selectivity was examined by light microscopy. RESULTS: Clinically the selective laser-induced RPE defect was demonstrated by fluorescein angiographic leakage and concurrent absence of ophthalmoscopic visibility. The angiographic ED(50)-damage threshold was 161 mJ/cm(2) (66 mW). Ophthalmoscopic visibility was not noticed even with the maximum available radiant exposure of 438 mJ/cm(2) (180 mW). Thus the safety range between angiographic and ophthalmoscopic thresholds had a factor of at least 2.7. First histological examinations revealed selective RPE destruction with intact photoreceptors for irradiation at laser power levels 2 times above angiographic threshold. CONCLUSION: Selective RPE targeting is feasible with a conventional green cw-laser when scanning the focused laser beam across the fundus with a speed such that every point in exposed RPE is irradiated for duration of 5 micros.

[Fundus autofluorescence after selective RPE laser treatment]. / Fundus-Autofluoreszenz nach selektiver RPE-Laserbehandlung.

BACKGROUND: The selective RPE laser treatment is a new technique which selectively damages the RPE and avoids adverse effects to the neural retina. A problem is the ophthalmoscopically non-visibility of the laser lesions. The aim of the study was to investigate whether fundus autofluorescence (AF), which is derived from the lipofuscin contained by the RPE cells, is changed due to the RPE damage, and thus may be used for non-invasive treatment control. METHODS: A total of 26 patients with macular diseases, i.e. diabetic maculopathy (DMP), soft drusen maculopathy (AMD) and central serous retinopathy (CSR), were treated with repetitive short laser pulses (800 ns) from a green Nd:YAG laser (parameters: 532 nm, 100 and 50 pulses at 500 and 125 Hz, retinal spot diameter 200 micrometer, pulse energies 70-175 microJ). AF was excited by 488 nm and detected by a barrier filter at 500 nm (HRA, Heidelberg engineering). Patients were examined by ophthalmoscopy, fluorescein angiography and autofluorescence measurements at various times after treatment (i.e. 1 h, 1 and 6 weeks, 3, 6 and 12 months). RESULTS: None of the laser lesions was ophthalmoscopically visible during treatment although fluorescein angiography showed leakage of the irradiated areas. Identification of the lesions was possible by AF imaging showing an intensity decay in the irradiated area in 22 out of 26 patients, predominantly in patients with CSR and AMD. Lesions could be identified as hypoautofluorescent spots 1 h after treatment. During follow-up the laser spots became hyperautofluorescent. In patients with DMP some AF images were less helpful due to diffuse edema and larger retinal thickness. CONCLUSION: Imaging of non-visible selective RPE laser effects can be achieved by AF measurements predominantly in patients without retinal edema. Thus AF may replace invasive fluorescein angiography in many cases to verify therapeutic laser success.

Autofluorescence imaging after selective RPE laser treatment in macular diseases and clinical outcome: a pilot study.

AIM: Selective retinal pigment epithelium (RPE) laser treatment is a new technique which selectively damages the RPE while sparing the neural retina. One difficulty is the inability to visualise the laser lesions. The aim of the study was to investigate whether fundus autofluorescence (AF) is changed because of the RPE damage, and thus might be used for treatment control. Additionally, the clinical course of patients with various macular diseases was evaluated. METHODS: 26 patients with macular diseases (diabetic maculopathy (DMP), soft drusen maculopathy (AMD), and central serous retinopathy (CSR)) were treated and followed up for at least 6 months. Treatment was performed with a train of repetitive short laser pulses (800 ns) of a frequency doubled Nd:YAG laser (parameters: 532 nm, 50 and 500 pulses at 100 and 500 Hz, retinal spot diameter 200 micro m, pulse energies 75-175 micro J). AF was excited by 488 nm and detected by a barrier filter at 500 nm (HRA, Heidelberg Engineering, Germany). Patients were examined by ophthalmoscopy, fluorescein angiography, and autofluorescence measurements at various times after treatment (10 minutes, 1 hour, 1 and 6 weeks, 3, 6, and 12 months). RESULTS: Fluorescein angiography showed leakage from the irradiated areas for about 1 week after treatment. None of the laser lesions was ophthalmoscopically visible during treatment. Identification of the lesions was possible by AF imaging showing an intensity decay in the irradiated area in 22 out of 26 patients, predominantly in patients with CSR and AMD. Lesions could be identified 10 minutes after treatment as hypoautofluorescent spots, which were more pronounced 1 hour later. During follow up the laser spots became hyperautofluorescent. In patients with DMP some AF images were less helpful because of diffuse oedema and larger retinal thickness. In these cases ICG angiography was able to confirm therapeutic success very well. Most of the patients have had benefit from the treatment, with best results obtained for CSR patients. CONCLUSION: Imaging of non-visible selective RPE laser effects can be achieved by AF measurements predominantly in patients without retinal oedema. Therefore, AF may replace invasive fluorescein angiography in many cases to verify therapeutic laser success. Selective laser treatment has the potential to improve the prognosis of macular diseases without the risk of laser scotomas.

The value of radiation therapy in the management of aggressive non-Hodgkin's lymphomas.

Even though chemotherapy plays a major role in the treatment of aggressive non-Hodgkin's lymphomas, the high radiosensitivity of the lymphatic lesions has established radiotherapy as an important component in the management of the disease in localized stages. Nevertheless, the treatment strategies with regard to the stage-adopted indications for radiotherapy, the treatment volume, and the dose remain controversial. This article reviews the available data concerning combined-modality treatment in localized stages and treatment of bulky lesions and residual lymphomas after chemotherapy with emphasis on the role of radiation therapy.