Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Nanophthalmic uveal effusion managed with scleral windows and topical mitomycin-C.

The authors treated a 38-year-old man with nanophthalmic uveal effusion with scleral windows and local application of mitomycin-C. The patient underwent two separate surgical procedures, involving placement of scleral windows in all four quadrants and topical application of mitomycin-C in one quadrant. Episcleral scarring led to closure of scleral windows in all quadrants except one quadrant where mitomycin-C was applied during the first surgery. The uveal effusion resolved following the second surgery. No complications related to mitomycin-C were observed. Topical mitomycin-C may be a useful adjunct in the surgical management of uveal effusion syndrome.

Ophthalmomyiasis interna posterior. Report of a case with optic atrophy.

PURPOSE: The prognosis for patients with ophthalmomyiasis Interna posterior is variable. In many patients the larva remains in the eye for years without inducing inflammation or loss of vision. Sometimes, however, the migrating larva involves the macula and optic nerve and results in permanent visual loss or even blindness. METHODS: Our patient presented with sudden painless loss of vision in the right eye that was caused by ophthalmomyiasis interna posterior. Hemorrhage of the optic nerve head suggested that the fly larva had entered the vitreous cavity from the optic nerve head. Subretinal tracts were sequelae of the subretinal migration of the organism. Sequential photographs documented the fly larva migration into the optic nerve head head from the vitreous cavity. The organism was removed by pars plana vitrectomy and retinectomy. RESULTS: In spite of the successful removal of the first stage fly larva, the visual acuity remained poor because of optic nerve atrophy. CONCLUSION: We suggest early removal of fly larvae to prevent damage and visual loss in cases of ocular myiasis interna posterior.

Diagnostic indocyanine green angiography in preeclampsia.

PURPOSE: To determine the role of the choroidal vasculature in the pathogenesis of exudative retinal detachments in preeclampsia using indocyanine green angiography. METHODS: We reviewed both fluorescein and indocyanine green angiographic findings for four patients with preeclampsia. RESULTS: Indocyanine green angiographic findings in patients with preeclampsia include nonperfusion in the early phases of the angiogram and staining of the choroidal vasculature with subretinal leakage in the late phases of the angiogram and multiple punctate areas of blocked fluorescence. CONCLUSION: Indocyanine green angiography indicates that damage to the choroidal vasculature leads to many of the retinal changes seen in preeclampsia.

Branch retinal artery occlusion caused by a mitral valve papillary fibroelastoma.

PURPOSE: We studied clinicopathologically a branch retinal artery occlusion caused by an embolus from a mitral valve papillary fibroelastoma. METHODS: At initial examination the patient, a 37-year-old woman, had visual acuity of 20/400 in her left eye, and eight months later her visual acuity improved to 20/20. The diagnosis required echocardiographic and radiologic studies to localize the lesion. RESULTS: The mitral valve papillary fibroelastoma was successfully treated with tumor resection involving the mitral valve. CONCLUSIONS: It is important to diagnose intracardiac papillary fibroelastoma, because it can cause recurrent arterial embolization and because it responds favorably to tumor resection.

Transretinal membrane formation in diffuse unilateral subacute neuroretinitis.

BACKGROUND: Diffuse unilateral subacute neuroretinitis (DUSN) is characterized by unilateral visual loss with vitreous inflammation, optic disc swelling, and the presence of gray-white lesions in the deep retina, and can be associated with intraocular nematode infection. To date, no cases of transretinal membrane formation in DUSN have been reported. METHODS: A 22-year-old woman was examined for a 2-week history of unilateral decreased vision and neuroretinitis. A subretinal nematode was identified and a diagnosis of DUSN was made. The nematode was destroyed with laser photocoagulation. An epiretinal membrane and traction retinal detachment persisted and the membrane was removed surgically, at which time it was noted to be transretinal, passing through a full-thickness retinal defect into the subretinal space. Laser photocoagulation was performed with the argon green laser (400 mW, 400 microns, 100 msec). Subsequent removal of the epiretinal portion of the transretinal membrane was performed via a pars plana approach. The membrane was studied by transmission electron microscopy (TEM). RESULTS: The laser photocoagulation was successful in destroying the nematode. Partial resolution of the neurosensory detachment resulted in marked improvement in visual acuity. The membrane consisted of a pauicellular collagenous stroma with scattered fibroblasts and mononuclear inflammatory cells. CONCLUSION: Removal of membranes affecting the macula may be of benefit in selected patients with DUSN.

Surgery for subfoveal membranes in myopia, angioid streaks, and other disorders.

OBJECTIVE: A retrospective analysis of patients who underwent surgical removal of subfoveal neovascular membranes caused by factors other than age-related macular degeneration (AMD) and presumed ocular histoplasmosis syndrome (POHS) was performed. METHODS: 17 eyes (16 patients) were identified in which subfoveal neovascularization was caused by myopic degeneration (5 eyes), angioid streaks (5 eyes of 4 patients), idiopathic neovascularization (4 eyes), punctate inner choroidopathy (1 eye), multifocal choroiditis (1 eye), or candida chorioretinitis (1 eye). RESULTS: Visual acuity remained stable after surgery in 10 of 17 eyes (59%), improved by 2 or more Snellen lines in 6 eyes (35%) and decreased in 1 eye (6%). Preoperative visual acuity was 20/80 or better in only 1 of 17 eyes (6%), but 5 of 17 eyes (29%) achieved postoperative visual acuity of 20/80 or better. Intraoperative and postoperative complications included peripheral retinal tears (1 eye), peripheral rhegmatogenous retinal detachment (1 eye), and mild cataract formation (1 eye). Subretinal neovascularization recurred after surgical removal in 4 eyes, 2 of which underwent repeat surgery. CONCLUSION: Visual acuity remained stable or improved in 94% of eyes after surgical removal of subfoveal neovascularization, but postoperative visual acuity better than 20/80 was achieved in a minority of eyes.

Abnormalities in color vision and contrast sensitivity in Parkinson's disease.

Dopamine is a neurotransmitter found in the retina. Delays in the visual evoked responses and abnormalities in contrast sensitivity occur in patients with Parkinson's disease. Improvement in the P100 has followed L-dopa therapy. Suspected abnormalities at the retinal level in Parkinson's disease are observed in reductions in photopic, scotopic, and pattern-derived electroretinograms. We studied 35 patients with Parkinson's disease and 26 controls of comparable age and visual acuities using visual evoked responses, color vision, and contrast sensitivity testing. Contrast sensitivity thresholds were significantly different at most frequencies tested, using both stationary and temporally modulated sinusoidal gratings. The total error score of the Farnsworth-Munsell 100 Hue Test revealed significant differences between the patients and controls. The contrast thresholds derived from certain spatial frequencies and the total error in color score were significantly related to the duration of disease. A stepwise discriminant analysis correctly identified 94% of the patients and 94% of the controls. The significant error in chromatic discrimination observed in Parkinson's disease patients may be due to altered intraretinal dopaminergic synaptic activity in these patients.

Mononuclear phagocytes have the potential for sustained hydroxyl radical production. Use of spin-trapping techniques to investigate mononuclear phagocyte free radical production.

Monocytes lack lactoferrin and have much less myeloperoxidase than neutrophils. They also acquire a potential catalyst for .OH production (tartrate-resistant acid phosphatase) as they differentiate into macrophages. Consequently, the nature of free radicals produced by these cells was examined using the previously developed spin-trapping system. When stimulated with either PMA or OZ neither monocytes nor monocyte-derived macrophages (MDM) exhibited spin trap evidence of .OH formation. Pretreatment with IFN-gamma failed to induce MDM .OH production. When provided with an exogenous Fe+3 catalyst, both stimulated monocytes and MDM, but not PMN, exhibited sustained .OH production, presumably due to the absence of lactoferrin in mononuclear phagocytes. Sustained production of .OH could contribute to the microbicidal activity of mononuclear phagocytes as well as inflammatory tissue damage under in vivo conditions where catalytic Fe+3 may be present.

The intravenous fluorescein test: use in timing of groin flap division.

Successful division or delay of the arterial groin flap requires an accurate prediction of viability. The fluorescein dye test is an objective test to determine the earliest possible time a pedicle can be divided. It is an easy, quick, and comfortable test that can be repeated many times without injuring or altering the flap. It consists of an intravenous injection of fluorescein while the pedicle is temporarily and reversibly occluded. All areas with adequate revascularization fluoresce under ultraviolet light. In three groin flaps intended for hand resurfacing, interval fluorescence testing was the sole criterion for successful pedicle division. In an experimental neurovascular island skin flap in the rat, the validity of the fluorescein test was confirmed. In the clinical situation and in the experimental model, fluorescence is an accurate indicator of groin flap revascularization and a predictor for the timing of safe and early groin flap division.