Demonstration of stable, long-term operation of a nanosecond pulsed DPSSL at 10 J, 100 Hz.

We report on stable, long-term operation of a diode-pumped solid-state laser (DPSSL) amplifying 15 ns pulses at 1029.5 nm wavelength to 10 J energy at 100 Hz pulse rate, corresponding to 1 kW average power, with 25.4% optical-to-optical efficiency. The laser was operated at this level for over 45 minutes (∼3 · 105 shots) in two separate runs with a rms energy stability of 1%. The laser was also operated at 7 J, 100 Hz for 4 hours (1.44 · 106 shots) with a rms long-term energy stability of 1% and no need for user intervention. To the best of our knowledge, this is the first time that long-term reliable amplification of a kW-class high energy nanosecond pulsed DPSSL at 100 Hz has been demonstrated.

Improved stability second harmonic conversion of a diode-pumped Yb:YAG laser at the 0.5 kW level.

We report on efficient and stable, type-I phase-matched second harmonic conversion of a nanosecond high-energy, diode-pumped, Yb:YAG laser. With a frequency-doubling crystal in an enclosed, temperature controller with optical windows, 0.5% energy stability was achieved for approximately half an hour. This resulted in 48.9 J pulses at 10 Hz (489 W) and a conversion efficiency of 73.8%. These results are particularly important for stable and reliable operation of high-energy, frequency-doubled lasers.

Generation of Joule-level green bursts of nanosecond pulses from a DPSSL amplifier.

A new approach to generation of a burst of high-energy green pulses by placing a high-energy multi-slab Yb:YAG DPSSL amplifier and SHG crystal inside a regenerative cavity is presented. In a proof-of-concept test, stable generation of a burst of six green (515 nm) pulses, each 10 ns in duration and separated by 29.4 ns (34 MHz), with 2.0 J total energy has been demonstrated at 1 Hz from a non-optimized ring cavity design. A maximum individual green pulse energy of 580 mJ was produced from a 1.78 J circulating infrared (1030 nm) pulse (average fluence 0.9 J/cm2), corresponding to a SHG conversion efficiency of 32%. Experimental results have been compared with predicted performance from a simple model. Efficient generation of a burst of high energy green pulses offers an attractive pump source for Ti:Sa amplifiers, providing the potential to reduce the impact of amplified stimulated emission by reducing instantaneous transverse gain.

Flexible Sigmoidoscopy Utility in the Diagnosis of Pediatric Gastrointestinal Disorders.

AIM:  Although flexible sigmoidoscopy (FS) is utilized in children for the diagnosis of pediatric gastrointestinal conditions, such as inflammatory bowel disease and juvenile polyp disorders, the diagnostic yield of FS in pediatric patients is unknown. MATERIALS AND METHODS:  We retrospectively reviewed FS cases in children under 18 years of age over a five-year period at our institution. Indications for the procedure, endoscopic visual findings, histologic findings, final diagnosis, and any management changes based on FS findings were included. RESULTS:  A total of 354 cases were included in the analysis for which 40 cases (11.3%) had abnormal visual findings, 48 cases (13.6%) had abnormal histologic findings, and 13 cases (3.7%) had both abnormal endoscopic visual and histologic findings. Of the 88 cases with abnormal visual and/or histologic abnormalities, only the results of 34 of these FS cases led to a change in management based on endoscopic findings (9.6%). Most patients with a non-diagnostic FS had a final diagnosis of functional abdominal pain; most patients with a diagnostic FS had a final diagnosis of colitis, not otherwise specified. CONCLUSION:  Our findings suggest that FS is not a helpful diagnostic endoscopic intervention in pediatric patients, especially in children with reassuring history and physical exam findings.

Proactive measurement of infliximab drug levels in children with Crohn's disease.

BACKGROUND: Proactively monitoring infliximab levels is an emerging area of interest in pediatric Crohn's disease. There are only limited data on therapeutic drug monitoring for children with Crohn's disease. The goal of our study was to determine the utility of therapeutic drug monitoring in achieving clinical remission in a cohort of pediatric Crohn's disease patients receiving infliximab. METHODS: This prospective single-center study enrolled 37 patients with Crohn's disease at the start of infliximab infusions and monitored trough levels at 6-month intervals for 18 months. Each participant was matched to a historic control for the modified pediatric Crohn's disease activity index (mPCDAI) at baseline, age and sex. The primary outcome was an mPCDAI score of ≤7.5 at 6, 12 and 18 months. A multivariate logistic regression analysis was performed. RESULTS: Data were available for all 37 cases at 6 and 12 months and for 34 cases at 18 months. Demographics and disease characteristics were similar between groups. All 34 cases demonstrated clinical remission at 18 months (100% vs. 88%, P=0.114). Univariate and multivariate analyses did not show statistical significance. Dose intensification was seen more often in the cases at 18 months. CONCLUSION: All of our moderate-to-severe pediatric Crohn's disease patients who received prospective therapeutic drug monitoring of infliximab were in clinical remission at follow up, but this was not statistically significantly different from the 88% clinical remission rate of the control group.

150 J DPSSL operating at 1.5 kW level.

We report on obtaining output energy of 146 J in 10 ns long pulses at 10 Hz repetition rate from Bivoj, a multi-Joule multi-slab cryogenic gas-cooled diode pumped solid state laser, by overcoming its damage threshold bottleneck. This is a 40% energy and power increase of the laser system in comparison to our previous publication and to the most powerful multi-Joule high power laser system.

Metastatic pediatric sclerosing epithelioid fibrosarcoma.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft-tissue sarcoma thought to originate in fibroblasts of the tissues comprising tendons, ligaments, and muscles. Minimally responsive to conventional cytotoxic chemotherapies, >50% of SEF patients experience local recurrence and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80%-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-yr-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. Finally, we describe the generation of an SEF primary cell line, the first such culture to be reported. The patient described here experienced persistent disease progression despite aggressive treatment including multiple resections, radiotherapy, and numerous chemotherapies and targeted therapeutics. Untreated and locally recurrent tumor and metastatic tissue were sequenced by whole-genome, whole-exome, and deep-transcriptome next-generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1-CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and discuss potential therapeutic strategies for SEF.

Second and third harmonic conversion of a kilowatt average power, 100-J-level diode pumped Yb:YAG laser in large aperture LBO.

We report on the successful demonstration of second and third harmonic conversion of a high pulse energy, high average power 1030 nm diode pumped Yb-doped yttrium aluminum garnet (Yb:YAG) nanosecond pulsed laser in a large aperture lithium triborate (LBO) crystal. We demonstrated generation of 59.7 J at 10 Hz (597 W) at 515 nm (second harmonic) and of 65.0 J at 1 Hz (65 W) at 343 nm (third harmonic), with efficiencies of 66% and 68%, respectively. These results, to the best of our knowledge, represent the highest energy and power reported for frequency conversion to green and UV-A wavelengths.

Modelling and measurement of thermal stress-induced depolarisation in high energy, high repetition rate diode-pumped Yb:YAG lasers.

In this paper, we present a model to predict thermal stress-induced birefringence in high energy, high repetition rate diode-pumped Yb:YAG lasers. The model calculates thermal depolarisation as a function of gain medium geometry, pump power, cooling parameters, and input polarisation state. We show that model predictions are in good agreement with experimental observations carried out on a DiPOLE 100 J, 10 Hz laser amplifier. We show that single-pass depolarisation strongly depends on input polarisation state and pumping parameters. In the absence of any depolarisation compensation scheme, depolarisation varies over a range between 5% and 40%. The strong dependence of thermal stress-induced depolarisation on input polarisation indicates that, in the case of multipass amplifiers, the use of waveplates after every pass can reduce depolarisation losses significantly. We expect that this study will assist in the design and optimisation of Yb:YAG lasers.

Stable high-energy, high-repetition-rate, frequency doubling in a large aperture temperature-controlled LBO at 515 nm.

We report on frequency doubling of high-energy, high-repetition-rate ns pulses from a cryogenically gas cooled, multi-slab Yb:YAG laser system, using a type-I phase-matched lithium triborate (LBO) crystal. Pulse energy of 4.3 J was extracted at 515 nm for a fundamental input of 5.4 J at 10 Hz (54 W), corresponding to a conversion efficiency of 77%. However, during long-term operation, a significant reduction of efficiency (more than 25%) was observed owing to the phase mismatch arising due to the temperature-dependent refractive index change in the crystal. This forced frequent angle tuning of the crystal to recover the second-harmonic generation (SHG) energy. More than a five-fold improvement in energy stability of SHG was observed when the LBO crystal was mounted in an oven, and its temperature was controlled at 27°C. Stable frequency doubling with 0.8% rms energy variation was achieved at a higher input power of 74 W when the LBO temperature was controlled at 50°C.

A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera.

Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF-anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.

Oxidation and other property changes of a remelted highly crosslinked UHMWPE in retrieved tibial bearings.

This study examined retrieved UHMWPE tibial bearings made from a remelted highly crosslinked (HXL) UHMWPE to determine whether the material is chemically stable in vivo. Retrieved tibial components were measured for changes in ketone oxidation and crosslink density. Oxidation increased with in vivo duration, and a significant decrease in crosslink density with increased mean ketone oxidation index was observed. These results suggest that in vivo oxidation is causing material degradation. Furthermore, a subsurface whitened damage region was found below the articular surface of one bearing, indicating the possibility of a clinically relevant decrease in mechanical properties of this component. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 39-45, 2017.

High energy, high repetition rate, second harmonic generation in large aperture DKDP, YCOB, and LBO crystals.

We report on type-I phase-matched second harmonic generation (SHG) in three nonlinear crystals: DKDP (98% deuteration), YCOB (XZ plane), and LBO (XY plane), of 8 J, 10 Hz cryogenic gas cooled Yb:YAG laser operating at 1029.5 nm. DKDP exhibited an efficiency of 45% at a peak fundamental intensity of 0.24 GW/cm2 for 10 Hz operation at 10 ns. At the same intensity and repetition rate, YCOB and LBO showed 50% and 65% conversion efficiencies, respectively. Significant improvement in conversion efficiency, to a maximum of 82%, was demonstrated in LBO at 0.7 GW/cm2 and 10 Hz, generating output energy of 5.6 J at 514.75 nm, without damage or degradation. However, no improvement in conversion efficiency was recorded for YCOB at this increased intensity. Additionally, we present theoretically calculated temperature maps for both 10 J and 100 J operation at 10 Hz, and discuss the suitability of these three crystals for frequency conversion of a 100 J, 10 Hz diode pumped solid state laser (DPSSL).

100 J-level nanosecond pulsed diode pumped solid state laser.

We report on the successful demonstration of a 100 J-level, diode pumped solid state laser based on cryogenic gas cooled, multi-slab ceramic Yb:YAG amplifier technology. When operated at 175 K, the system delivered a pulse energy of 107 J at a 1 Hz repetition rate and 10 ns pulse duration, pumped by 506 J of diode energy at 940 nm, corresponding to an optical-to-optical efficiency of 21%. To the best of our knowledge, this represents the highest energy obtained from a nanosecond pulsed diode pumped solid state laser. This demonstration confirms the energy scalability of the diode pumped optical laser for experiments laser architecture.

DiPOLE: a 10 J, 10 Hz cryogenic gas cooled multi-slab nanosecond Yb:YAG laser.

The Diode Pumped Optical Laser for Experiments (DiPOLE) project at the Central Laser Facility aims to develop a scalable, efficient high pulse energy diode pumped laser amplifier system based on cryogenic gas cooled, multi-slab ceramic Yb:YAG technology. We present recent results obtained from a scaled down prototype laser system designed for operation at 10 Hz pulse repetition rate. At 140 K, the system generated 10.8 J of energy in a 10 ns pulse at 1029.5 nm when pumped by 48 J of diode energy at 940 nm, corresponding to an optical to optical conversion efficiency of 22.5%. To our knowledge, this represents the highest pulse energy obtained from a cryo cooled Yb laser to date and the highest efficiency achieved by a multi-Joule diode pumped solid state laser system. Additionally, we demonstrated shot-to-shot energy stability of 0.85% rms for the system operated at 7 J, 10 Hz during several runs lasting up to 6 hours, with more than 50 hours in total. We also demonstrated pulse shaping capability and report on beam, wavefront and focal spot quality.

Oxidation and other property changes of retrieved sequentially annealed UHMWPE acetabular and tibial bearings.

This investigation analyzed retrieved sequentially crosslinked and annealed (SXL) ultra-high molecular weight polyethylene bearings to determine whether the material is chemically stable in vivo. A series of retrieved tibial and acetabular components were analyzed for changes in ketone oxidation, crosslink density, and free radical concentration. Oxidation was observed to increase with in vivo duration, and the rate of oxidation in tibial inserts was significantly greater than in acetabular liners. SXL acetabular bearings oxidized at a rate comparable to gamma-sterilized liners, while SXL tibial inserts oxidized at a significantly faster rate than their gamma-sterilized counterparts. A significant decrease in crosslink density with increased mean ketone oxidation index was observed, suggesting that in vivo oxidation may be causing material degradation. Furthermore, a subsurface whitened damage region was also found in a subset of the bearings, indicating the possibility of a clinically relevant decrease in mechanical properties of these components.

Outcomes of proton therapy for the treatment of uveal metastases.

PURPOSE/OBJECTIVE(S): Radiation therapy can be used to treat uveal metastases with the goal of local control and improvement of quality of life. Proton therapy can be used to treat uveal tumors efficiently and with expectant minimization of normal tissue injury. Here, we report the use of proton beam therapy for the management of uveal metastases. METHODS AND MATERIALS: A retrospective chart review was made of all patients with uveal metastases treated at our institution with proton therapy between June 2002 and June 2012. Patient and tumor characteristics, fractionation and dose schemes, local control, and toxicities are reported. RESULTS: Ninety patients were identified. Of those, 13 were excluded because of missing information. We report on 77 patients with 99 affected eyes with available data. Patients were 68% female, and the most common primary tumor was breast carcinoma (49%). The median age at diagnosis of uveal metastasis was 57.9 years. Serous retinal detachment was seen in 38% of treated eyes. The median follow-up time was 7.7 months. The median dose delivered to either eye was 20 Gy(relative biological effectiveness [RBE]) in 2 fractions. Local control was 94%. The median survival after diagnosis of uveal metastases was 12.3 months (95% confidence interval, 7.7-16.8). Death in all cases was secondary to systemic disease. Radiation vasculopathy, measured decreased visual acuity, or both was observed in 50% of evaluable treated eyes. The actuarial rate of radiation vasculopathy, measured decreased visual acuity, or both was 46% at 6 months and 73% at 1 year. The 6 eyes with documented local failure were successfully salvaged with retreatment. CONCLUSIONS: Proton therapy is an effective and efficient means of treating uveal metastases. Acutely, the majority of patients experience minor adverse effects. For longer-term survivors, the risk of retinal injury with vision loss increases significantly over the first year.