Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma.

The MYC proto-oncogenes (c-MYC, MYCN , MYCL ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN -amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine ß-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1 + somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of δ cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC-overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.

C4-T3 Replacement Laminoplasty and Microsurgical Resection of Ependymoma: 2-Dimensional Operative Video.

Spinal ependymomas are the most common intramedullary spinal cord tumors in adults.1-4 They are benign histologically, and maximum safe surgical resection should be pursued with the goal of maintaining neurological integrity.4 Spinal ependymoma resections have been described in the operative video literature, including those using techniques of laminoplasty to prevent postlaminectomy kyphosis.1-3,5 Defining the planes between tumor and normal spinal cord is critical to achieving safe maximum resection.3 This video will illustrate the microsurgical techniques used in the resection of a large spinal cord ependymoma in a patient who presented with progressive lower extremity paraparesis and incontinence and was found to have a large intradural, intramedullary C4-T3 lesion with a rostral glial tumor cyst. The patient consented to surgical intervention. The patient was placed prone in MAYFIELD 3-point pin fixation (Integra LifeSciences, Plainsboro Township, New Jersey). Intraoperative neurophysiological electrodes were placed for somatosensory evoked potentials, motor evoked potentials, and D-wave monitoring of corticospinal tracts.6,7 C3-T4 replacement laminoplasties were performed. A midline dural incision spanning C4-T4 was made. A midline myelotomy preserving the pial venous plexus was performed with a 69 Beaver blade.2 The attachments of the tumor to the normal white matter of the spinal cord were microsurgically defined, coagulated, and divided. Tumor debulking was performed with an ultrasonic aspirator. Once gross total resection was achieved, the pial edges of the spinal cord were reapproximated. The dura was closed in a watertight fashion. The patient recovered from surgery well with preservation of her motor function with a continued T7 sensory level.

High vacuum and aspiration on phacoemulsification efficiency and chatter for Centurion.

OBJECTIVE: To compare relative efficiency and chatter of high aspiration and vacuum settings. DESIGN: In vitro laboratory study. METHODS: The John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, was the study setting. Porcine nuclei were fixed in formalin and cut into 2.0 mm cubes. Lens cubes were phacoemulsified with Balanced tips at 50 and 60 mL/min aspiration with 500, 600, and 700 mm Hg vacuum with monitored forced infusion. Experiments were conducted at constant torsional power, longitudinal power, and intraocular pressure. RESULTS: No significant change was observed in average chatter across each tested setting. Increasing aspiration rate did not increase efficiency. Increasing vacuum up to 600 mm Hg from 500 mm Hg did not change efficiency. However, increasing vacuum to 700 mm Hg decreased efficiency (p = 0.008 for 500 mm Hg vs 700 mm Hg and p = 0.05 for 600 mm Hg vs 700 mm Hg). Increasing aspiration and increasing vacuum did not significantly improve chatter. CONCLUSIONS: Increasing aspiration above 50 mL/min did not improve phacoemulsification efficiency. Increasing vacuum settings to 700 mm Hg decreases efficiency. Chatter did not significantly change with increasing aspiration and vacuum settings.

Long-term capsule clarity with a disk-shaped intraocular lens.

PURPOSE: To evaluate long-term capsular clarity with a modified disk-shaped 1-piece hydrophilic acrylic monofocal intraocular lens (IOL) (Zephyr) suspended between 2 complete haptic rings connected by a pillar of the haptic material. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Study and control (1-piece hydrophobic acrylic) IOLs were implanted into the right and left eyes, respectively, of 8 New Zealand rabbits. Eyes were examined at the slitlamp at set intervals for 6 months. At the end of the clinical follow-up, the globes were enucleated and capsular clarity was scored from the posterior view (Miyake-Apple technique). Then, all the eyes were processed for a complete histopathological evaluation. RESULTS: At 6 months, the slitlamp evaluation showed a posterior capsule opacification score of 0.28 ± 0.26 (SD) in the study group and 4 ± 0 in the control (P < .0001, paired t test). The anterior capsule was generally clear in the study group. This parameter was difficult to analyze in the control group because of synechiae formation and poor pupil dilation. CONCLUSIONS: The degree of capsular bag clarity observed at 6 months postoperatively in the study eyes in this rabbit model was exceptional. It was likely because of the IOL design, keeping the capsular bag open and expanded, and minimizing contact between the IOL and the anterior capsule.

Intraocular lens power adjustment by a femtosecond laser: In vitro evaluation of power change, modulation transfer function, light transmission, and light scattering in a blue light-filtering lens.

PURPOSE: To evaluate intraocular lens (IOL) power, modulation transfer function (MTF), light transmission, and light scattering of a blue light-filtering IOL before and after power adjustment by a femtosecond laser obtained through increased hydrophilicity of targeted areas within the optic, creating the ability to build a refractive-index-shaping lens within an existing IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Ten CT Lucia 601PY single-piece yellow hydrophobic acrylic IOLs were used in this study. The IOL power and MTF were measured with a power and modulation transfer function device. Light transmission was measured using a Lambda 35 UV-VIS spectrophotometer. Backlight scattering was assessed with a Scheimpflug camera within the IOL substance. All measurements were done with hydrated IOLs. The IOLs were also evaluated under light microscopy (LM) before and after laser adjustment. RESULTS: After laser adjustment, a mean power change of -2.037 diopters was associated with a MTF change of -0.064 and a light transmittance change of -1.4%. Backlight scattering increased within the IOL optic in the zone corresponding to the laser treatment at levels that are not expected to be clinically significant. Treated areas within the optic could be well appreciated under LM without damage to the IOLs. CONCLUSION: Power adjustment of a commercially available hydrophobic acrylic blue light-filtering IOL by a femtosecond laser produced an accurate change in dioptric power while not significantly affecting the quality of the IOL.

Long-term uveal and capsular biocompatibility of a novel modular intraocular lens system.

BACKGROUND: We evaluated the long-term biocompatibility and safety of a new modular posterior chamber intraocular lens (IOL) system in rabbit eyes. METHODS: Seven New Zealand rabbits underwent bilateral phacoemulsification with placement of the modular IOL in OD and a control IOL (SA60AT) in OS. Slit-lamp examinations were performed at postoperative weeks 1, 2, 3, 4, 6 and 8 and months 3 and 6. All rabbits were then sacrificed and eyes enucleated. The eyes were examined grossly from the Miyake-Apple view. Selected IOLs were explanted and underwent surface staining for implant cytology. All globes were then sectioned and processed for histopathological examination. RESULTS: The modular IOL remained stable in all seven rabbits through the entire follow-up period. Biocompatibility was better than the control lens at six months postoperatively, on account of less extensive synechiae formation as assessed by slit-lamp examination. At the six-week examination, posterior capsule opacification (PCO) was significantly better in the test group (scored as 1.71 ± 0.8 versus 3.28 ± 0.48 in the control group, p = 0.0008). On gross examination with the Miyake-Apple view, Soemmering's ring formation was significantly better in the test group, (5.14 ± 1.57 versus 10.85 ± 1.95 in the control group, p = 0.002). CONCLUSION: Previous studies showed that explantation/exchange of the modular system optic was safer and easier than with a standard IOL. The new modular IOL system has demonstrated better long-term biocompatibility compared to the control lens at six months postoperatively in the rabbit model.

Optimization of transversal phacoemulsification settings in peristaltic mode using a new transversal ultrasound machine.

PURPOSE: To determine the optimum bottle height, vacuum, aspiration rate, and power settings in the peristaltic mode of the Whitestar Signature Pro machine with Ellips FX tip action (transversal). SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Porcine lens nuclei were hardened with formalin and cut into 2.0 mm cubes. Lens cubes were emulsified using transversal and fragment removal time (efficiency), and fragment bounces off the tip (chatter) were measured to determine optimum aspiration rate, bottle height, vacuum, and power settings in the peristaltic mode. RESULTS: Efficiency increased in a linear fashion with increasing bottle height and vacuum. The most efficient aspiration rate was 50 mL/min, with 60 mL/min statistically similar. Increasing power increased efficiency up to 90% with increased chatter at 100%. CONCLUSION: The most efficient values for the settings tested were bottle height at 100 cm, vacuum at 600 mm Hg, aspiration rate of 50 or 60 mL/min, and power at 90%.

Biocompatibility of intraocular lens power adjustment using a femtosecond laser in a rabbit model.

PURPOSE: To evaluate the biocompatibility (uveal and capsular) of intraocular lens (IOL) power adjustment by a femtosecond laser obtained through increased hydrophilicity of targeted areas within the optic, creating the ability to build a refractive-index shaping lens within an existing IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Six rabbits had phacoemulsification with bilateral implantation of a commercially available hydrophobic acrylic IOL. The postoperative power adjustment was performed 2 weeks after implantation in 1 eye of each rabbit. The animals were followed clinically for an additional 2 weeks and then killed humanely. Their globes were enucleated and bisected coronally just anterior to the equator for gross examination from the Miyake-Apple view to assess capsular bag opacification. After IOL explantation for power measurements, the globes were sectioned and processed for standard histopathology. RESULTS: Slitlamp examinations performed after the laser treatments showed the formation of small gas bubbles behind the lenses that disappeared within a few hours. No postoperative inflammation or toxicity was observed in the treated eyes, and postoperative outcomes and histopathological examination results were similar to those in untreated eyes. The power measurements showed that the change in power obtained was consistent and within ±0.1 diopter of the target. CONCLUSIONS: Consistent and precise power changes can be induced in the optic of commercially available IOLs in vivo by using a femtosecond laser to create a refractive-index shaping lens. The laser treatment of the IOLs was biocompatible.