Jose S. Pulido

Malignant Melanoma in the 21st Century, Part 1: Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

Long-term Visual Outcome and Complications Associated with Pars Planitis

PURPOSE To identify the ocular complications and to statistically evaluate the possible association of pars planitis with multiple sclerosis (MS) in a homogeneous population of pars planitis patients. METHODS The authors reexamined 36 patients and reviewed the records of an additional 18 patients (total: 54 patients, 108 eyes) with idiopathic pars planitis. RESULTS The initial mean visual acuity of 20/46 (logMAR: 0.36 +/- 0.50) was not statistically different from the final mean visual acuity of 20/44 (logMAR: 0.34 +/- 0.45; P = 0.73), after a mean follow-up of 89.2 months. Complications included neovascularization with or without associated vitreous hemorrhage (7 eyes, 6.5%), moderate to severe cellophane retinopathy (7 eyes, 6.5%), chronic cystoid macular edema (CME) (9 eyes, 8.3%), visually significant cataracts (16 eyes, 14.8%), and retinal detachment (9 eyes, 8.3%). Significant lens opacification was associated with a greater risk of retinal detachment (P = 0.004). In four patients (7.4%), optic neuritis developed, and in an additional eight patients (14.8%) MS developed. Kaplan-Meier analysis of these data showed a 16.2% +/- 6.2% risk of MS solely developing in patients, and a 20.4% +/- 6.7% risk of either MS or optic neuritis developing, after 5 years of disease. The presence of periphlebitis at the time of pars planitis diagnosis increased the rate of development of these conditions (P = 0.002). Six patients (11.1%) had a family history positive for MS in a first-degree relative. CONCLUSIONS This study demonstrates the overall favorable visual prognosis in patients with pars planitis. Patients with significant cataract formation appear to be at greater risk for retinal detachment. Periphlebitis at the time of diagnosis of pars planitis increases the risk of development of optic neuritis or MS. The strong association demonstrated between pars planitis and MS in this study further supports a link between the two disease states.

Primary Vitreoretinal Lymphoma: A Report from an International Primary Central Nervous System Lymphoma Collaborative Group Symposium

Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.

Rituximab Therapy for Refractory Biliary Strictures in Immunoglobulin G4–Associated Cholangitis

BACKGROUND & AIMS Biliary strictures occur in a third of patients with autoimmune pancreatitis and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC). IAC often responds to steroid therapy. METHODS A patient with autoimmune pancreatitis and (IAC) refractory to steroids and 6-mercaptopurine was treated with rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes. RESULTS The patients biliary strictures improved after rituximab therapy, permitting removal of his biliary stents. Systemic manifestations of IgG4-associated disease also improved. CONCLUSIONS Rituximab may be a treatment option for patients with refractory or recurrent autoimmune pancreatitis or IAC.

The Incidence of Central Serous Chorioretinopathy in Olmsted County, Minnesota, 1980–2002

PURPOSE To determine the incidence of central serous chorioretinopathy (CSC) in Olmsted County, Minnesota from 1980 to 2002, determine the associated risk factors for CSC based on previously reported risk factors, investigate for any new risk factors not previously reported, and determine a population-based recurrence rate. DESIGN Population-based retrospective cohort and case-control study. PARTICIPANTS Cases were all patients with newly diagnosed CSC in Olmsted County Minnesota, from January 1, 1980 through December 31, 2002. Controls were selected from the same general population. Control group 1 patients were matched for age, gender, length of medical follow-up, and index date (corresponding with date of diagnosis for cases). Control group 2 patients were matched for all the same criteria as control group 1, and they had documented normal eye examination results. METHODS Using the Rochester Epidemiology Project medical records linkage system, which captures virtually all medical care provided to residents of Olmsted County, Minnesota, we identified all cases of CSC in county residents between 1980 and 2002. We reviewed the entire medical record of cases and applied standardized criteria for CSC. The medical records of cases and controls were reviewed for the presence of risk factors as well. MAIN OUTCOME MEASURE Incidence of CSC. Secondary outcomes were also evaluated. RESULTS There were 74 cases (63 men, 11 women) of CSC. Mean annual age-adjusted incidences per 100 000 were 9.9 (95% confidence interval [CI], 7.4-12.4) for men and 1.7 (95% CI, 0.7-2.7) for women. The incidence of CSC was approximately 6 times higher in men than in women (P<0.001). There were no significant risk factors identified for CSC. Twenty-three (31%) of the 74 patients with CSC had recurrences. The mean number of recurrences was 1.5 (range, 1-4). Median time from diagnosis to recurrence was 1.3 years (range, 0.4-18.2). CONCLUSION The incidence of CSC has not previously been reported in a population-based study. In accordance with previous studies, we found that CSC occurs more frequently in men than in women.

Improvement in Visual Acuity in Chronic Aphakic and Pseudophakic Cystoid Macular Edema After Treatment With Topical 0.5% Ketorolac Tromethamine

Ketorolac tromethamine 0.5% ophthalmic solution treatment was compared to placebo treatment in 120 patients with chronic aphakic or pseudophakic cystoid macular edema (six-month or more duration of distance visual acuity of 20/40 or less and angiographic evidence of cystoid changes) during a four- to five-month double-masked, multicenter study in which patients were randomly assigned. A statistically significant improvement in distance visual acuity (two lines or more) was observed in the ketorolac-treated group as compared to the placebo-treated group after 30 days (P = .038), 60 days (P = .017), and 90 days (P = .008) of treatment. This improvement in visual acuity remained statistically significant one month after cessation of treatment (P = .001). Nine ketorolac-treated patients and two placebo-treated patients demonstrated a decrease in visual acuity one month after treatment was discontinued. Seven of the nine ketorolac-treated patients experienced an improvement in visual acuity after retreatment as compared to none of the placebo-treated patients. This study offers evidence for a more optimistic outlook in the medical treatment of chronic aphakic and pseudophakic cystoid macular edema.

The Ocular Manifestations of Syphilis in the Human lmmunodeficiency Virus Type 1-infected Host

Nine patients with active ocular or optic nerve involvement by syphilis who also had concurrent human immunodeficiency virus type-1 (HIV-1) infection are described. The ocular manifestations of syphilis led to the discovery of HIV-1 seropositivity in four of nine cases. Fifteen eyes were affected. Ocular manifestations were: iridocyclitis in three eyes, vitreitis in one eye, retinitis or neuroretinitis in five eyes, papillitis in two eyes, optic perineuritis in two eyes, and retrobulbar optic neuritis in two eyes. Three patients diagnosed with acquired immune deficiency syndrome (AIDS) had the worst initial visual acuities. Six of nine patients had evidence of concomitant central nervous syndrome (CNS) involvement with syphilis. Benzathine penicillin was administered intramuscularly to three patients. All three had relapses. Seven of nine patients treated intravenously with high-dose penicillin had dramatic responses to therapy with improvement in vision and serologies and no evidence of relapse. Regimens accepted for the treatment of neurosyphilis appear to be adequate for the treatment of ocular syphilis in HIV-1-infected patients though further long-term follow-up will be required.

Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patients unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.

Malignant Melanoma in the 21st Century, Part 2: Staging, Prognosis, and Treatment

Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patients clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing.

Purpose: To determine the change in anti–vascular endothelial growth factor (VEGF) activity of bevacizumab (Avastin, Genentech, Inc., San Francisco, CA) after refrigeration or freezing. Methods: Samples of bevacizumab were drawn up from new vials into plastic tuberculin syringes and refrigerated at 4°C for 1 week, 3 weeks, 1 month, 3 months, and 6 months. The vials and syringes were stored at 4°C, and the syringes were capped with a needle. One syringe was frozen at −10°C. The bevacizumab concentration was measured, via its binding to VEGF-165. Results: The percentage of degradation of bevacizumab in the previously pierced vials stored at 4°C compared with that in the unpierced vial was 9.6% at 3 months and 12.7% at 6 months. The bevacizumab drawn into the syringe and stored at 4°C was degraded by 1.6% at 1 week, 0% at 3 weeks, 8.8% at 3 months, and 15.9% at 6 months. The bevacizumab frozen in a syringe at −10°C was degraded by 12.0% at 6 months. Conclusion: The anti-VEGF activity of bevacizumab may degrade minimally over time, with storage.