Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers.

Background Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed. Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also reported. Twice daily oral ulixertinib was administered at 10 to 900 mg in the dose escalation cohort (n = 27) and at 600 mg in 21-day cycles in the expansion cohort (n = 108). Results The incidence of ulixertinib-induced dAEs and combined rash were 79% (107/135) and 76% (102/135). The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. The presence of at least 1 dAE was associated with stable disease (SD) or partial response (PR) (OR = 3.64, 95% CI 1.52-8.72; P = .003). Acneiform rash was associated with a PR (OR = 10.19, 95% CI 2.67-38.91; P < .001). Conclusion The clinical spectrum of ulixertinib-induced dAEs was similar to EGFR and MEK inhibitors; dAEs may serve as a surrogate marker of tumor response. We propose treatment algorithms for common ERK inhibitor-induced dAEs to maintain patients' quality of life and dose intensity for maximal clinical benefit. Clinical Trial Registration: NCT01781429.

Fibrovascularization of porous polyethylene (Medpor) orbital implant in a rabbit model.

PURPOSE: To evaluate the porous polyethylene (Medpor) orbital implant in a rabbit model and compare it with three other currently available porous implants: Bio-Eye coralline hydroxyapatite (HA), FCI(3) synthetic HA, and aluminum oxide (Bioceramic). METHODS: The porous polyethylene implant was examined macroscopically and microscopically (with scanning electron microscopy). Implantation was performed in 10 adult male New Zealand albino rabbits. Each animal underwent enucleation of the right globe under general halothane gas anesthesia, followed by placement of a 12-mm porous polyethylene implant. In 5 animals, the implant was encased in polyglactin 910 (Vicryl mesh); in the other 5, it was left unwrapped. The implants were moistened in saline before placement. Implant vascularization was evaluated by histopathology at 4, 8, 12, 16, and 24 weeks. RESULTS: The porous polyethylene implant was found to have a smoother exterior surface than the Bio-Eye, FCI(3) synthetic HA, and aluminum oxide implants. Rather than a uniform interconnected porous architecture, there was an extensive system of interconnected channels through the implant, ranging in size from 125 to 1000 microm. On high-power examination there was a more solid, woven appearance without any sign of the microcrystals seen in the other porous implants. One rabbit had a retrobulbar hemorrhage after surgery and was euthanized. All the other rabbits tolerated the implant well, and there were no complications. On histopathologic examination, fibrovascularization gradually increased over time. One implant was completely vascularized at 12 weeks, and both implants harvested at 16 weeks were completely vascularized. The implant harvested at 24 weeks showed only partial vascularization (14%). CONCLUSIONS: The porous polyethylene orbital implant represents an alternative implant for use after enucleation or evisceration or for secondary implantation. In our rabbit model, the porous polyethylene implant was well tolerated without complication. Complete fibrovascularization was first seen at 12 weeks. Porous polyethylene orbital implants appear to vascularize more slowly than Bio-Eye coralline HA, FCI(3) synthetic HA, and aluminum oxide implants.

Pyogenic granuloma following oculoplastic procedures: an imbalance in angiogenesis regulation?

BACKGROUND: Pyogenic granuloma is a vasoproliferative inflammatory response composed of granulation tissue. The pathogenesis is not entirely clear. We describe a series of patients with pyogenic granulomas occurring following common oculoplastic procedures and propose a common etiology. METHODS: Sixteen cases of pyogenic granuloma that occurred after various oculoplastic procedures from 1991 to 2000 were collected from the files of two oculoplastic surgeons. RESULTS: Pyogenic granulomas were found to occur at surgical and nonsurgical sites associated with tissue irritation or inflammation or both. INTERPRETATION: Capillaries are a predominant component of wound healing and pyogenic granulomas. The growth and development of new capillaries follows an orderly sequence of events that is highly regulated by a variety of angiogenic factors. We postulate an imbalance in angiogenesis regulation as the common pathway for pyogenic granuloma development.

Demonstration of retroiridal extension of an epithelial membrane by ultrasound biomicroscopy: a clinicopathologic correlation.

PURPOSE: To report the utilization of ultrasound biomicroscopy (UBM) in identifying the extension into the posterior segment of an epithelial membrane, as correlated by the histopathologic findings. METHOD: Case report. UBM findings before enucleation with histopathologic correlation. RESULTS: UBM demonstrated a membrane tracking from the posterior iris surface over the ciliary body and towards the retina. Light microscopic examination disclosed the epithelial nature of this membrane. CONCLUSION: UBM can identify extension of an epithelial membrane into the posterior segment and thereby guide the approach to surgical management.

The spectrum of postmortem ocular findings in victims of shaken baby syndrome.

BACKGROUND: Ophthalmologists and ocular pathologists are called on to help identify children who have undergone violent shaking. The objective of this study was to describe the spectrum of postmortem ocular findings in victims of shaken baby syndrome and to correlate the ocular findings with the nonocular features found at autopsy. METHODS: The ocular pathology registry at the University of Ottawa Eye Institute was reviewed to identify all victims of fatal shaken baby syndrome whose eyes had been submitted for examination between Apr. 1, 1971, and Dec. 31, 1995. Autopsy reports were accessed from the hospital charts of the identified patients. RESULTS: Six patients, aged 1 to 34 months, were identified. Intraocular findings ranged from a focal globular hemorrhage at the posterior pole to extensive intraocular hemorrhage involving the entire retina with perimacular folds. All the children had evidence of optic nerve sheath hemorrhage. Nonocular findings included intracranial hemorrhage (in all cases), skull fracture (in two), rib fractures (in three) and high spinal cord hemorrhage (in four). The extent of the intraocular hemorrhage was not consistent with the nonocular findings. INTERPRETATION: Abused children may display a range of postmortem ocular findings, with intraocular hemorrhage varying from minimal to severe. These findings may not correlate with the severity of the child's other injuries. The presence of any retinal or optic nerve sheath hemorrhage in an infant, in the absence of an appropriate explanation for these findings, should raise suspicion of child abuse.

The bioceramic orbital implant: a new generation of porous implants.

PURPOSE: The authors describe a new generation of porous orbital implant made of aluminum oxide (Al2O3) and compare it with the hydroxyapatite orbital implants (Bio-Eye and FCI hydroxyapatite). METHODS: The authors examined the new implant macroscopically, with chemical analysis and microscopically with scanning electron microscopy. Animal implantation studies were performed using six adult male New Zealand albino rabbits. Implant vascularization was evaluated by means of magnetic resonance imaging and histopathologic sectioning. RESULTS: The Bioceramic orbital implant was found to have very uniform pore structure with an average pore size of 500 microm. The implant was 99.9% aluminum oxide on x-ray diffraction. Magnetic resonance imaging in vivo vascularization studies demonstrated enhancement of the implant to its center by 4 weeks after implantation in the rabbit. Histopathologically, fibrovascularization occurred uniformly throughout the implant and was noted by 4 weeks. CONCLUSIONS: The Bioceramic orbital implant represents a new porous orbital implant that has a very regular and extensive interconnected pore system, is as biocompatible as hydroxyapatite, is easy to manufacture, structurally strong, and free of contaminants. It is manufactured with no disruption to marine life ecosystems as may occur in the harvesting of coral for other orbital implants. It is less expensive than currently available hydroxyapatite implants and was approved by the U.S. Food and Drug Administration in April 2000.

The Molteno M-Sphere.

PURPOSE: To analyze a mammalian hydroxyapatite (HA) implant known as the Molteno M-Sphere, recently approved by the Food and Drug Administration of the United States. METHODS: The authors examined the implant macroscopically, with chemical analysis (x-ray powder diffraction, x-ray fluorescence spectrophotometry), and microscopically with scanning electron microscopy. Animal implantation of six Molteno M-Spheres was carried out in six adult male New Zealand albino rabbits. Implant vascularization was evaluated by means of magnetic resonance imaging and histopathologic sectioning. RESULTS: The M-Sphere was found to have multiple interconnected pores throughout with an average pore size of 300 microm to 600 microm. This implant was very light-weight (0.31 g) and fragile. It was made up of pure HA. Magnetic resonance imaging studies showed implant enhancement to its center by 4 weeks after implantation. Histopathologically, fibrovascularization occurred uniformly throughout the 4, 8, and 12-week rabbit implants. CONCLUSIONS: The M-Sphere is an alternative type of HA implant that recently has been reintroduced into the United States for use after enucleation, evisceration, or as a secondary implant. It has multiple interconnected pores allowing central fibrovascularization as early as 4 weeks in a rabbit model. Its light weight and fine trabecular framework, however, are associated with increased implant fragility when compared with other available HA implants (BioEye and FCI3 synthetic HA). The implant requires careful handling because routine handling may damage the implant. The implant is currently approved by the United States Food and Drug Administration.

Brazilian hydroxyapatite implant.

PURPOSE: To evaluate a synthetic hydroxyapatite (HA) (manufactured in Brazil) in a rabbit model. METHODS: Nine New Zealand white rabbits underwent enucleation of one eye followed by implantation of either a 12-mm Brazilian synthetic HA implant or a 12-mm BioEye, wrapped in polyglactin 910 mesh. Magnetic resonance imaging was performed to assess fibrovascular ingrowth 4, 8, and 12 weeks after implantation. Three animals were killed at each of the times for histopathologic examination. The Brazilian implant was also examined chemically and by scanning electron microscopy. RESULTS: The Brazilian HA was found to be heavier than either the BioEye or synthetic FCI3 HA implants. It did not have a visible, regularly arranged interconnected porous architecture. Rather, it had randomly appearing channels apparent on its external and internal surface in addition to large cystic areas within the body of the implant. Scanning electron microscopy revealed the implant to have a microporous architecture in addition to the large channels and cystic cavities. Histopathologically, central vascularization occurred by 4 weeks and was also present at 8 and 12 weeks. In three Brazilian implants an unrecognizable, nonbirefringent material was identified. The cause of it was unclear. Chemical analysis confirmed the implant to consist of pure HA. CONCLUSION: The Brazilian implant is pure HA that appears solid but has randomly arranged channels as well as a microporous architecture that allows vascularization to its center. It is heavier than other available HA implants and has the presence of an unidentified foreign material within it. Although this implant is less expensive and does not require a costly manufacturing process, the structural characteristics of the material do not offer any theoretical or clinical advantages. The implant is only available in Brazil at this time.

Hydroxyapatite implant wrapping materials: analysis of fibrovascular ingrowth in an animal model.

PURPOSE: To compare the influence of seven currently available spherical orbital implant wraps on host fibrovascularization of a hydroxyapatite (HA) orbital implant. METHODS: Five groups of 3 (15 total) adult male New Zealand albino rabbits underwent enucleation with placement of a 12-mm HA implant wrapped in high-porosity expanded polytetrafluoroethylene (e-PTFE), processed bovine pericardium, or processed human pericardium, sclera, or fascia lata. Magnetic resonance imaging before and after the intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (DTPA, 0.1 mol/kg) was performed immediately before exenteration. Five rabbits (one with each of the different implant wraps) were killed at 4, 8, and 12 weeks, and the operated socket was exenterated. Histopathologic sections of the implants were then compared with the results of our previous study using polyglactin 910 mesh and autologous sclera as HA orbital implant wraps. RESULTS: Complete fibrovascularization of all the implants occurred by 12 weeks; however, HA implants wrapped with sclera, polyglactin mesh, and e-PTFE appeared to undergo more rapid fibrovascularization than spheres wrapped with other materials. CONCLUSIONS: Although all of the implant wraps studied may be suitable substitutes for donor sclera, we prefer polyglactin mesh because it is readily available, inexpensive, and without risk of transmissible diseases.

Mucoepidermoid carcinoma of the conjunctiva: a series of three cases.

OBJECTIVE: To detail the clinical presentation and outcomes of currently available treatments for mucoepidermoid carcinoma of the conjunctiva (MCC). DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Three patients ranging from 40 to 63 years of age with MCC participated. INTERVENTION: Excisional biopsies and various therapies were performed. MAIN OUTCOME MEASURES: Clinical and surgical outcomes were measured. RESULTS: Patient 1 is a 55-year-old man with right temporal MCC. He underwent two local excisions with adjuvant cryotherapy and has had no recurrence at 31 months follow-up. Patient 2 is a 63-year-old man with right temporal MCC who underwent fractionated iodine 125 plaque radiotherapy. He had a recurrence approximately 8 months after plaque treatment and subsequently underwent enucleation of the right eye. Clinical follow-up examinations revealed no further recurrence at 17 months. Patient 3 is a 40-year-old woman treated for right MCC with carbon dioxide laser with recurrence at 3 weeks. She subsequently underwent radiation treatment with the development of regional lymph node metastases 16 months later. CONCLUSIONS: MCC is a rare neoplasm that displays an extraordinary capacity for aggressive local invasion. This series of three case reports demonstrates the high recurrence rate of MCC and the response of this tumor to different current modalities of treatment. Extended follow-up is required with this tumor because distant metastases can occur very late.

Epithelioid hemangioma of the orbit.

OBJECTIVE: To describe the histopathologic features of two cases of epithelioid hemangioma occurring in the orbit and to distinguish this condition from Kimura's disease and from other vascular lesions of proliferated endothelium. DESIGN: Two interventional case reports. INTERVENTION: Treatment consisted of orbitotomy with excision of the tumor. MAIN OUTCOME MEASURES: Histopathologic examination including light microscopy, immunohistochemistry, and electron microscopy and clinical follow-up. RESULTS: In one case, there was no local recurrence after 2 years of follow-up. In the other case, local recurrence required re-excision 2 years after surgery with no apparent recurrence 16 years later. Histopathologic examination of both tumors disclosed an epithelioid hemangioma. A characteristic finding was the presence of peculiar plump vacuolated endothelial cells lining the vascular lumina. CONCLUSIONS: Epithelioid hemangioma is an uncommon benign vascular tumor that can occur in the orbit, and surgical excision is usually required. It is the same condition as angiolymphoid hyperplasia with eosinophilia. There are distinct clinical and histopathologic characteristics to distinguish epithelioid hemangioma from Kimura's disease and from other vascular tumors.

A new variety of hydroxyapatite: the Chinese implant.

PURPOSE: This study was designed to evaluate a new type of hydroxyapatite (HA) implant (produced in China) in a rabbit model. METHODS: Three New Zealand white rabbits underwent enucleation of one eye followed by implantation of a 12-mm Chinese HA implant wrapped in Vicryl mesh (polyglactin 910). Magnetic resonance imaging was performed to assess host fibrovascularization of the implant 4, 8, and 12 weeks after implantation. One animal was sacrificed at each of these times for histopathologic examination. The Chinese implant was also examined chemically and by scanning electron microscopy. It was compared to the original BioEye and the third generation synthetic HA implant produced in France by FCI (FCI3). RESULTS: This new variety of HA implant from China is heavier than the FCI3 implant but lighter than the original BioEye. The Chinese implant was easy to work with and not fragile. The pore size was more uniform than the FCI3 implant and similar to the BioEye implant clinically and by scanning electron microscopy. The pores in this implant are unidirectional. Analysis for impurities revealed a calcium oxide (CaO) content of 4.4%. Histopathologically, central vascularization occurred by 4 weeks and was similar in extent to the vascularization seen with the FCI3 implant and the BioEye. CONCLUSIONS: The Chinese implant is less expensive then the BioEye and the FCI3 implants, and appears to be a viable alternative to the BioEye. Further refinements are in progress to eliminate the CaO contaminant.

Complications associated with pegging hydroxyapatite orbital implants.

OBJECTIVE: Prior studies of hydroxyapatite orbital implant complications have primarily focused on complications of the implant itself with only occasional mention of the complications associated with the peg system. This in part may be because of a low rate of pegging and, thus, a small sample size to evaluate. Therefore, a full range of complications that can occur with pegging has not been presented. The objective of this study was to determine the complications associated with pegging and to discuss ways to manage them. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS/INTERVENTION: The authors analyzed all of the complications associated with pegging 165 of a possible 275 hydroxyapatite implants implanted by 2 surgeons over 7 years. MAIN OUTCOME MEASURES: The following data were recorded: type of surgery performed, size of implant used, type of hydroxyapatite used, peg system used, time of pegging, follow-up duration, problems encountered, and treatment. RESULTS: Sixty-two (37.5%) of the 165 patients who had pegged implants were found to have problems with their pegs. Twenty-one (33.8%) of the 62 patients with peg problems had more than 1 peg-related problem. Complications associated with pegging included discharge (37%; 23 of 62), pyogenic granulomas (30.6%; 19 of 62), peg falling out (29%; 18 of 62), poor transfer of movement (11.2%; 7 of 62), clicking (11.2%; 7 of 62), conjunctiva overgrowing peg (4.8%; 3 of 62), poor-fitting sleeve (4.8%; 3 of 62), part of sleeve shaft visible (4.8%; 3 of 62), peg drilled on an angle (4.8%; 3 of 62), hydroxyapatite visible around peg hole (3.2%; 2 of 62), peg drilled off-center (3.2%; 2 of 62), popping peg (3.2%; 2 of 62), and excess movement of peg (3.2%; 2 of 62). The most serious complication occurring in two individuals (3.2%) was implant infection requiring implant removal. CONCLUSION: There are several potential complications that can occur after pegging the hydroxyapatite implant. These problems are generally of a minor nature but often require additional patient visits that would not ordinarily have been required if the peg was not in place. The most serious peg problem is implant infection, which may necessitate implant removal. These potential peg problems should be reviewed with the patient before the procedure is performed.

Clinical experience with passive-fixation coradial bipolar endocardial pacing leads. ThinLine Clinical Investigators.

Bipolar, transvenous, passive-fixation leads (ThinLine, Sulzer Intermedics Inc., Angleton, TX, USA) incorporating coradial individually coated conductor coils, and a redundant external 55D polyurethane insulation sheath were developed. The diameter of the new leads (< 5 Fr) is in the range of available unipolar leads and is considerably smaller than conventional bipolar pacing leads. From January 9, 1994 to November 12, 1996, 1,536 model 432-04 (523 atrial) and 430-10 (1,013 ventricular) leads were implanted in 1,068 patients at 50 US and 5 Canadian centers to evaluate their safety and efficacy. The study included a general phase, with follow-ups at 1, 3, 6, 12, 18, and 24 months; and a randomized intensive phase with collection of more data and additional 2- and 6-week follow-ups. Capture and sensing thresholds, lead impedance, and handling characteristics were evaluated. Clinical events were monitored and performance was compared to that of two commercially available conventional (coaxial) leads: Sulzer Intermedics models 432-03 (atrial) and 430-07 (ventricular). During a total of 17,530 device months, there were two lead failures, no lead related deaths, 32 explants, 37 complications, and no unexpected adverse device effects. Capture thresholds were lower than those for coaxial controls with identical electrodes, sensing was comparable, lead impedances were within clinically acceptable ranges, and investigators found overall handling characteristics good to excellent. ThinLine coradial bipolar leads are safe and effective for cardiac pacing and sensing.