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.

Transgenic mice carrying the mouse mammary tumor virus ras fusion gene: distinct effects in various tissues.

Transgenic mice carrying the v-Ha-ras oncogene under the control of the mouse mammary tumor virus long terminal repeat were produced. These mice exhibit several phenotypes: mammary tumors, bilateral hyperplasia of the harderian lacrimal gland, primary bronchio-alveolar lung adenocarcinoma, and splenomegaly. High levels of the transgene RNA were detected in mammary, harderian, and lung tumors. Accumulation of cells of the myeloid lineages was found in enlarged spleens. This phenotype may represent an indirect effect of v-Ha-ras expression on myeloid progenitors. Our data illustrate the cell-specific effects of v-Ha-ras.

Endocardial pacing, cardioversion and defibrillation using a braided endocardial lead system.

The clinical efficacy and safety of a second-generation braided endocardial pacing, cardioversion and defibrillation lead system was evaluated in 25 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF). The lead system consisted of two 8Fr active fixation endocardial leads each with pacing and defibrillation electrodes and a thoracic patch electrode. Monophasic and biphasic shocks were delivered using a triple-electrode configuration with a right ventricular common cathode and right atrial and thoracic patch anodes. VT and VF were electrically induced. Rapid VT (rate > or = 180 beats/min) and VF were initially terminated by 20 J (550 V) shocks and slow VT (rate < 180 beats/min) by 10 J (400 V) shocks. One hundred fourteen episodes (rapid VT/VF 73, slow VT 41) were treated with 128 shocks (monophasic 80, biphasic 48). Mean ventricular pacing threshold was 0.7 +/- 0.5 ms before and 0.9 +/- 0.5 ms after endocardial shock delivery (p > 0.2). Mean ventricular electrogram amplitude in sinus rhythm was 11.9 +/- 5.7 mV before and 11.4 +/- 5.1 mV after shock delivery (p > 0.2). Simultaneous monophasic endocardial shocks terminated 53% of VF episodes at < or = 20 J. Simultaneous biphasic shocks terminated 94% of all VF episodes at < or = 20 J (p < 0.03). Efficacy of > or = 10 J shocks for rapid VT/VF was greater for biphasic (92%) versus monophasic (74%) shocks (p < 0.05) at lower average shock energy (15 +/- 7 J vs 19 +/- 7 J, respectively, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of isoproterenol in facilitating atrioventricular nodal reentry tachycardia during electrophysiologic testing.

In some patients with documented atrioventricular (AV) nodal supraventricular tachycardia (SVT), the arrhythmia is not inducible during a standard stimulation protocol. In these patients the level of sympathetic activity may be an important factor. This study evaluates the influence of isoproterenol on anterograde and retrograde pathway properties in patients with AV nodal SVT and the mechanism by which this SVT is facilitated. Group 1 consisted of 8 consecutive patients, ages 23 to 85 years (mean +/- standard error, 57 +/- 8) who had no inducible AV nodal SVT during electrophysiologic testing until isoproterenol (0.5 to 3.0 micrograms/min) was infused. These patients were compared with 6 patients in the same age range (45 to 78 years, mean +/- standard error, 64 +/- 5) who had inducible AV nodal SVT without isoproterenol and who comprised group 2. In comparing group 1 (before isoproterenol) with group 2, there was no significant difference in the refractory periods of the anterograde slow and fast pathways, although the anterograde block cycle length was longer in group 1 patients (421 +/- 18 vs 362 +/- 14 ms, p less than 0.05). The retrograde block cycle length was also longer in 7 of the 8 group 1 (before isoproterenol) patients in whom it could be measured versus those in group 2 (411 +/- 14 vs 318 +/- 27 ms, p less than 0.05). During isoproterenol, the anterograde and retrograde block cycle lengths in group 1 were not different from group 2. Therefore, AV nodal SVT may not be inducible in some patients during routine electrophysiologic testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Trisomy 22 and facioauriculovertebral (Goldenhar) sequence.

We report on an infant girl born with complete trisomy 22 and left hemifacial microsomia, ear anomaly, and limbal and epibulbar complex choristoma. Trisomy 22 was confirmed by prometaphase chromosome analysis and in situ hybridization. This patient extends the list of chromosome abnormalities associated with apparent Golenhar sequence and emphasizes the importance of chromosome analysis in the investigation of patients with this condition. A detailed ophthalmopathological investigation is reported.

Cystoid macular edema with equatorial choroidal melanoma.

Symptoms and signs related to cystoid macular edema were the initial findings in a patient with a choroidal malignant melanoma located in the equatorial region of the globe. Histopathologic findings included retinal perivasculitis and cystoid macular edema. There was no evidence of a serous detachment of the macula. Patients with cystoid macular edema should be carefully examined for tumors or other pathological findings in the peripheral fundus.

Eccrine sweat gland carcinoma of the eyelid with orbital involvement.

A 70-year-old man had a sweat gland carcinoma in his right upper eyelid that was slowly growing, but it clinically remained confined to the lid tissues for a period of 25 years. The tumor ultimately extended deeper into the orbit and invaded the sclera, the optic nerve sheath, and the ethmoidal sinuses. Histopathologic examination disclosed malignant features with a variety of cellular patterns. The results of electron microscopic studies confirmed the origin of the tumor from the eccrine sweat glands.

Sebaceous carcinoma of the eyelid masquerading as superior limbic keratoconjunctivitis.

A 49-year-old woman had been treated for 18 months for superior limbic keratoconjunctivitis of the right eye. Pathologic examination of a biopsy specimen of the superior perilimbal conjunctiva disclosed intraepithelial carcinoma of sebaceous gland origin. Because of the extensive involvement of the conjunctival epithelium by tumor, a subtotal orbital exenteration was performed. To our knowledge, this is the first report of sebaceous carcinoma masquerading as superior limbic keratoconjunctivitis.

Bilateral blindness in temporal arteritis with skip areas.

A 73-year-old woman received systemic corticosteroids for suspected temporal arteritis after blindness developed in the right eye during the previous day. Because a right temporal artery biopsy specimen was reported as normal, a diagnosis of arteriosclerotic ischemic optic neuropathy was made and the corticosteroid therapy was discontinued. Two weeks later the patient rapidly lost vision in her left eye. A left temporal artery biopsy specimen showed granulomatous arteritis adjacent to normal artery (skip area). Deeper sections of the original right temporal artery biopsy specimen also demonstrated a small focus of granulomatous arteritis adjacent to normal artery. In patients with suspected temporal arteritis, numerous step sections of a long segment of temporal artery should be examined; if the results are normal, the contralateral temporal artery should be studied. A nonspecific inflammatory reaction within or adjacent to the artery should alert the pathologist to the possible presence of a nearby focus of granulomatous arteritis.

Ocular Candida with pale-centered hemorrhages.

A 54-year-old man with severe thermal burns had Candida corneal ulcers and Candida septicemia develop, and he died 39 days after admission to the hospital. At autopsy examination, fungi were noted in the cornea to extend across the intact Descemet's membrane and were also found within foci of retinitis and choroiditis. Also, hemorrhages (some of which had pale centers) were present in both retinas. Histopathologic examination of these hemorrhages disclosed that the pale centers were comprised of a disrupted small blood vessel surrounded by an acellular material that most likely represented fibrin-platelet aggregates.

Nonglaucomatous cavernous degeneration of the optic nerve. Report of two cases.

The globes from two elderly women who underwent enucleation for malignant melanoma of the choroid showed cavernous degeneration of the optic nerve. Both individuals had prominent optic cups and a strong family history of severe cardiovascular disease; one patient also had mild anemia and substantial arteriosclerotic heart disease. Neither patient showed any clinical or histologic evidence of glaucoma. It is proposed that cavernous degeneration of the optic nerves in some patients may represent an aging change associated with generalized arteriosclerosis. Individuals with large optic cups may be more at risk of developing this condition.

Sandhoff's disease (GM2 gangliosidosis type 2). Histopathology and ultrastructure of the eye.

Sandhoff's disease (GM2 gangliosidosis type 2) was diagnosed in an infant in whom a progressive neurologic disorder and cherry-red foveal spots developed. At autopsy, ultrastructural examination of the retina and optic nerve disclosed abundant pleomorphic storage cytosomes in all neurons of the retina, including the inner segments of the photoreceptor cells, and in glial cells of the optic nerve. Electron microscopy of the cornea showed, within the keratocytes, distended clear lysosomes that contained some fibrillogranular material and an occasional collection of lamellae. We discuss the pathogenesis of the clinical and pathologic ocular findings with regard to the inherited absence of the enzymes hexosaminidase A and B and an accumulation of the substrates, GM2 ganglioside and asialo GM2, in the nervous system (including retina and optic nerve) and globoside and other hexosamine-containing substances in the viscera (including cornea).

Optic nerve in globoid leukodystrophy (Krabbe's disease). Ultrastructural changes.

Globoid leukodystrophy (Krabbe's disease) was diagnosed in an infant in whom a progressive neurological disorder and optic atrophy developed. At autopsy, ultrastructural examination of the optic nerves and cerebral white matter revealed characteristic tubular inclusions in globoid-epithelioid cells. Thinning of the nerve fiber and ganglion cell layers of the retina appeared to be due to retrograde degeneration of the optic nerve related to the abnormal metabolism of myelin. We discuss the pathogenesis of the clinical and pathological ocular findings, with regard to the inherited absence of the enzyme galactocerebroside beta-galactosidase and the accumulation in the optic nerve and brain of its substrates, galactocerebroside and psychosine.

Trilateral retinoblastoma. Report of two cases.

Two children had bilateral retinoblastoma and a morphologically similar intracranial neoplasm localized to the region of the pineal gland as shown on computed tomography and at postmortem examination. The first child's intracranial malignant neoplasm produced symptoms that indicated its probable presence when the ocular tumors were first diagnosed. With the second child, there was a latent period of more than three years between the diagnosis and initial management of the ocular neoplasms and the onset of symptoms from the pineal tumor. We diagnosed both cases as trilateral retinoblastoma, which in our experience is a relatively frequent cause of mortality in patients with heritable retinoblastoma.

Combined surgery and cryotherapy for diffuse malignant melanoma of the conjunctiva.

Two patients who had refused exenteration for widespread conjunctival melanoma were treated by a combination of cryotherapy and surgical excisions. Cryotherapy was delivered only to the extensive areas of flat intraepithelial melanocytic proliferation (precancerous melanosis), while the surgical excisions were performed on the focal nodules, representing localized invasive melanoma. In our two patients, the invasive nodules measured, respectively, 1.2 and 1.5 mm in greatest thickness, placing them in a low to borderline risk group for metastasis. Repeated cryoapplicatons were required to control the widespread flat intraepithelial disease. The conjunctiva tolerated these procedures well because the substantia propria is not sacrificed as it must be in surgical conjunctivectomy, allowing comparatively normal reepithelialization to occur from adjacent zones, after the treated epithelium containing the melanocytes sloughs. No evidence of invasive melanoma (cancerous melanosis) has developed in any of the cryotreated areas of intraepithelial disease (precancerous melanosis); sequential biopsies have established that the atypical melanocytes have disappeared from the epithelium.

Cryotherapy for precancerous melanosis (atypical melanocytic hyperplasia) of the conjunctiva.

Two patients with progressive, diffuse precancerous melanosis (intraepithelial atypical melanocytic hyperplasia or melanocytic dysplasia) of the conjunctiva were treated with cryotherapy. In one patient, the contiguous cutaneous portions of both eyelids were involved and received the same therapy; the extensive disease of the patient was managed by two cryotherapy sessions during a period of 21/2 months. The melanocytic process in both patients showed a good response to this therapy, which resulted in a slough of the superficial conjunctiva with reepithelialization from adjacent areas. Neither patients has shown recurrent disease in more than seven months of follow-up, although one patient had incomplete regression of the melanocytic condition in the perilimbal region, which was subsequently treated by an excisional biopsy. Serious complications occurred in one patient who had corneal and lenticular opacities; this patient had severe extensive disease for which exenteration was considered the only feasible alternative therapy to control the melanocytic proliferation disorder adequately. Less severe complications also developed, including trichiasis, ptosis, transient hypotony, and macular edema. In this article, we discuss the clinical and histologic features of acquired pigmentations of the conjunctiva, the criteria for their management, and the approaches to minimize the complications that we have encountered with cryotherapy.

Congenital hereditary (juvenile X-linked) retinoschisis. Histopathologic and ultrastructural findings in three eyes.

One surgically enucleated and two postmortem eyes were obtained from two related men with congenital hereditary retinoschisis. A periodic acid-Schiff-positive amorphous material was identified within the retina adjacent to the schisis cavities. Ultrastructural examination of this material showed numerous extracellular filaments, measuring approximately 11 nm in diameter. Similar filaments were found in the vitreous in all three globes and in a normal globe. We believe that the intraretinal filaments are produced by defective Müller cells and that their extracellular accumulation may lead to degeneration of cells and subsequent schisis formation.

The prevalence of macular drusen in postmortem eyes.

In a histologic study of 46 eyes from 23 consecutive autopsy cases (mean age, 67 years; range, 36 to 94 years) with no previously documented ocular disease, drusen were identified in the macula of 87% (40 of 46 eyes), with hard drusen in 83% (38 of 46 eyes) and soft drusen in 39% (18 of 46 eyes). Soft drusen were found without hard drusen in two maculas. In 14 of the 16 eyes that contained both hard and soft drusen, the hard drusen outnumbered the soft drusen. The number of macular drusen in the right eye generally approximated that in the left eye for both hard drusen (r = 0.959; P less than .001) and soft drusen (r = 0.754; P less than .001). There was no correlation (t = 0.538; P greater than .05) between the number of hard drusen and increasing age. However, there was a significant correlation (t = 2.54; P less than .02) between the number of soft drusen and increasing age.

Fungal invasion of seven hydrophilic contact lenses.

In six patients we reviewed the clinical, microbiologic, and histopathologic findings of seven hydrophilic contact lenses that had been infiltrated by fungi. Three patients had visual blurring or irritation and redness while wearing a contaminated lens; of these, two were unaware of any lens deposits. Three of the lenses from two patients were spares kept in storage for six months and one year, respectively. One contaminated lens had been torn and was kept in a case while a loaner lens was worn. Culture of this lens grew Cladosporium species. The contact lens case from one patient grew Penicillium species. Gross pathologic inspection disclosed multiple brown deposits in five lenses, multiple gray infiltrates in one lens, and a white infiltrate in one lens. Light microscopic examination disclosed partial-thickness (three lenses) or full-thickness (four lenses) invasion of the lens matrix by fungi, which contained granular, brown pigment in six lenses.

Pseudomonas aeruginosa scleritis.

In two patients Pseudomonas aeruginosa scleral infection led to ocular perforation. In one patient, a scleral abscess was identified anteriorly. A scleral perforation occurred at a more posterior focus, but the eye was salvaged with minimal residual visual function. In the other patient, perforation at the corneoscleral limbus occurred after initial corneal improvement with antibiotic therapy; histopathologic examination of the enucleated globe disclosed an abscess extending from the corneoscleral limbus to the equator superiorly.