The COMS Randomized Trial of Iodine 125 Brachytherapy for Choroidal Melanoma: IV. Local Treatment Failure and Enucleation in the First 5 Years after Brachytherapy. COMS Report No. 19.

OBJECTIVE: To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I125) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN: Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS: I125 brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES: Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS: As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS: Local treatment failure and enucleation were relatively infrequent events after I125 brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death.

The ε4 allele of the apolipoprotein E (ApoE) gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment, and death in a large, well-characterized study sample. A total of 2846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus.

The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning.

Both human immunodeficiency virus (HIV)-1 infection and illicit stimulant use can adversely impact neurocognitive functioning, and these effects can be additive. However, significant variability exists such that as-of-yet unidentified exogenous and endogenous factors affect one's risk for neurocognitive impairment. Literature on both HIV and stimulant use indicates that host genetic variants in immunologic and dopamine-related genes are one such factor. In this study, the individual and interactive effects of HIV status, stimulant use, and genotype upon neurocognitive functioning were examined longitudinally over a 10-year period. Nine hundred fifty-two Caucasian HIV+ and HIV- cases from the Multicenter AIDS Cohort Study were included. All cases had at least two comprehensive neurocognitive evaluations between 1985 and 1995. Pre-highly active antiretroviral therapy (HAART) data were examined in order to avoid the confounding effect of variable drug regimens. Linear mixed models were used, with neurocognitive domain scores as the outcome variables. No four-way interactions were found, indicating that HIV and stimulant use do not interact over time to affect neurocognitive functioning as a function of genotype. Multiple three-way interactions were found that involved genotype and HIV status. All immunologically related genes found to interact with HIV status affected neurocognitive functioning in the expected direction; however, only C-C chemokine ligand 2 (CCL2) and CCL3 affected HIV+ individuals specifically. Dopamine-related genetic variants generally affected HIV-negative individuals only. Neurocognitive functioning among HIV+ individuals who also used stimulants was not significantly different from those who did not use stimulants. The findings support the role of immunologically related genetic differences in CCL2 and CCL3 in neurocognitive functioning among HIV+ individuals; however, their impact is minor. Being consistent with findings from another cohort, dopamine (DA)-related genetic differences do not appear to impact the longitudinal neurocognitive functioning of HIV+ individuals.

Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here, we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies. Data from 1,287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis. No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated NCI, and HAD were not validated. In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.

Platelet decline as a predictor of brain injury in HIV infection.

An association between platelet decline and increased risk of progression to dementia has been observed in an advanced HIV infection cohort study. This investigation evaluated the prognostic significance of platelet decline for dementia, for psychomotor slowing, and for brain injury, as quantified in vivo, in a much larger population of HIV+ men. Platelet counts and neurocognitive data were available from biannual visits of 2,125 HIV+ men participating in the prospective, Multicenter AIDS Cohort Study from 1984 to 2009. Brain volumetric data were also available from an imaging substudy of 83 seropositive participants aged 50 and older. The association of platelet counts with neurocognitive outcome was assessed using Cox proportional hazard models where change in platelet count from baseline was a time-updated variable. Marked platelet decline was associated with increased risk of dementia in univariate analysis (hazard ratio [HR] = 2.5, 95% confidence interval [CI] = 1.8-3.5), but not after adjustment for CD4 cell count, HIV viral load, age, study site, hemoglobin, race, education, smoking, and alcohol use (HR = 1.4, 95% CI = 0.78-2.5). Platelet decline did not predict psychomotor slowing in either univariate (HR = 0.79, 95% CI = 0.58-1.08) or multivariate (HR = 1.10, 95% CI = 0.73-1.67) analysis. Analysis of brain volumetric data, however, indicated a relationship between platelet decline and reduced gray matter volume fraction in univariate (p = 0.06) and multivariate (p < 0.05) analyses. Platelet decline was not an independent predictor of dementia or psychomotor slowing, after adjusting for stage of disease. Findings from a structural brain imaging substudy of older participants, however, support a possible relationship between platelet decline and reduced gray matter.

Addressing the well-being of Aboriginal children in out-of-home care: are we there yet?

AIM: Children in out-of-home care (OOHC) have well-documented health and developmental needs. In Australia, Aboriginal children have significantly worse health outcomes than non-Aboriginal children. We wanted to identify the health and well-being of Aboriginal children entering OOHC, placed with an Aboriginal organisation, who accessed a specialised multidisciplinary clinic in south-western Sydney. We wanted to identify children entering care who were doing well and who improved in care. We also wanted to identify enablers and barriers to care. METHODS: We analysed records of the first 100 children attending the OOHC clinic in south-western Sydney. Measures included clinical outcomes and recommendations at first and subsequent visits. Descriptive statistics were calculated using SPSS 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Key stakeholders from the relevant agencies were interviewed about enablers and barriers to care by independent evaluators. RESULTS: A significant proportion of children had health needs identified including speech delay (54%), under-immunisation (50%), behaviour problems (45%), hearing problems (44%), visual problems (35%) and dental problems (36%). Sixteen per cent of the children were doing well at first visit; a third improved in care, and a third remained stable. Significant differences were identified in health and educational needs between the under-5 year olds and the 5-13 year olds. Key barriers identified were systemic issues and lack of resources for intervention. CONCLUSIONS: Children attending this clinic had similar rates of problems identified as other studies. School-age children appear to have significant additional health needs. Targeted developmentally and culturally appropriate interventions need to be provided to address the identified barriers to care.

Selective expression of a sodium pump isozyme by cough receptors and evidence for its essential role in regulating cough.

We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na(+)-K(+) ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the alpha(3) subunit of Na(+)-K(+) ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation.

I-125 brachytherapy for choroidal melanoma photographic and angiographic abnormalities: the Collaborative Ocular Melanoma Study: COMS Report No. 30.

OBJECTIVES: (1) To summarize the protocol used for grading features of postradiation abnormalities from fundus photographs and fluorescein angiograms of patients enrolled in the Collaborative Ocular Melanoma Study (COMS); (2) to document the prevalence of features of interest in the posterior pole of these eyes during 8 years of follow-up; and (3) to investigate baseline patient, tumor, and treatment characteristics associated with posterior pole features. DESIGN: Observational case series within a randomized, multicenter clinical trial. PARTICIPANTS: We evaluated 650 patients who were assigned to and received iodine-125 brachytherapy in the COMS for medium-sized tumors. METHODS: Color fundus photographs and fluorescein angiograms were taken at baseline and 2, 5, and 8 years; 30 features were graded according to a standard protocol. MAIN OUTCOME MEASURES: Prevalence at selected time intervals of fundus photographic features associated with retinopathy and optic neuropathy. RESULTS: The percentage of patients with >/=1 feature of interest was 49.2% at baseline, 84.4% at 2 years, 91.2% at 5 years, and 90.7% at 8 years. The most frequent findings across all follow-up examinations were macular microaneurysms (75.6% of examinations), macular angiographic leakage (75.1%), and optic disc hyperfluorescence (62.8%). The median number of features present increased significantly with each follow-up to a maximum of 7 features at 8 years. The prevalence of neovascularization of the disc at 5 years was 5.2%. The prevalence of optic neuropathy at 5 years was 27.4%. Prognostic factors for more prevalent and severe posterior pole abnormalities were diabetes, tumor location close to both optic nerve and foveal avascular zone, and greater dose of radiation to the foveola and optic nerve head. CONCLUSIONS: The amount and severity of retinopathy and optic neuropathy after iodine-125 brachytherapy increased through 8 years of follow-up. Assessment of photographs and angiograms taken in accord with a standard protocol provided reliable estimates of rates of development of features of retinopathy and optic neuropathy in eyes treated using the COMS brachytherapy protocol. Our findings support earlier reports that tumor factors in addition to radiation treatment may contribute to posterior pole abnormalities. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Histopathologic characteristics of choroidal melanoma in eyes enucleated after iodine 125 brachytherapy in the collaborative ocular melanoma study.

OBJECTIVE: To describe the histopathologic findings in eyes with uveal melanoma that had secondary enucleation after failed brachytherapy plaque treatment. METHODS: Histopathologic findings in eyes that had secondary enucleation after plaque radiation therapy in the Collaborative Ocular Melanoma Study (COMS) were reported on a standardized data form. The findings were compared with eyes that had primary enucleation for uveal melanoma. RESULTS: Seventy-five eyes that had secondary enucleation were studied. Compared with primary enucleations, tumors in the irradiated eyes had lower mitotic activity, a smaller proportion of histologically intact tumor, more inflammation, more fibrosis, and more vascular damage within the tumor. In addition, compared with primary enucleations, eyes previously irradiated had a higher frequency of retinal invasion by the tumor and greater damage to the retinal vasculature, consistent with radiation retinopathy; neovascularization of the iris; and vitreous hemorrhage. Tumor growth or extrascleral extension was confirmed histopathologically in 25 of 42 eyes (60%) enucleated because of a reported failure of local control. CONCLUSIONS: Eyes with secondary enucleation after brachytherapy differ histopathologically from eyes with primary enucleation for uveal melanoma. These histopathologic differences may be due to the effects of radiation, tissue conditions related to plaque failure, and, in some cases, tumor growth. In 40% of eyes enucleated because of suspected failure of local control, increased tumor size could not be histologically confirmed.

Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A1 receptor-dependent mechanism.

Adenosine induces dyspnea, cough, and airways obstruction in asthma, a phenomenon that also occurs in various sensitized animal models in which a neuronal involvement has been implicated. Although adenosine has been suggested to activate cholinergic nerves, the precise mechanism has not been established. In the present study, the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) induced a cholinergic reflex, causing tracheal smooth muscle contraction that was significantly inhibited by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 100 microg/kg) (P < 0.05) in anesthetized animals. Furthermore, the adenosine A(2) agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) induced a small reflex, whereas the A(3) selective agonist N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) was without effect. The tracheal reflex induced by CPA was also inhibited by recurrent nerve ligation or muscarinic receptor blockade (P < 0.001), indicating that a cholinergic neuronal mechanism of action accounted for this response. The cholinergic reflex in response to aerosolized CPA was significantly greater in passively sensitized compared with naive guinea pigs (P < 0.01). Chronic capsaicin treatment, which inhibited sensory nerve function, failed to inhibit CPA-induced reflex tracheal contractions in passively sensitized guinea pigs, although the local anesthetic lidocaine inhibited CPA-induced tracheal contractions. The effects of CPA on the reflex response was not dependent on the release of histamine from tissue mast cells or endogenous prostaglandins as shown by the lack of effect of the histamine H(1) receptor antagonist pyrilamine (1 mg/kg) or the cyclooxygenase inhibitor meclofenamic acid (3 mg/kg), respectively. In conclusion, activation of pulmonary adenosine A(1) receptors can stimulate cholinergic reflexes, and these reflexes are increased in allergic guinea pigs.

The impact of depressive symptoms and chronic diseases on active life expectancy in older Americans.

OBJECTIVES: The authors prospectively examined whether depressive symptoms (DS) in older adults negatively affected active live expectancy (ALE), or remaining years free of disability, and mortality, independently and in the presence of chronic diseases, and after stratification by gender. DESIGN: Prospective cohort study, first three waves (1993-1998) of the Asset and Health Dynamics Among the Oldest Old. DATA COLLECTION: University of Michigan; analysis: University of South Florida. PARTICIPANTS: Nationally representative sample of community-dwelling adults age 70 and older (N = 7,381). MEASUREMENTS: DS (Center for Epidemiological Studies Depression, 8-item version), self-reported cancer, diabetes, heart disease, or stroke, difficulty with activities of daily living, death, and estimates of total, active, and disabled life expectancy. RESULTS: DS reduced ALE by 6.5 years for young-old men (age 70), 3.2 years for old-old men (age 85), 4.2 years for young-old women, and 2.2 years for old-old women, and these effects remained significant at all ages and across gender even after controlling for chronic disease, the one exception being DS and cancer in old-old women. DS also reduced total life expectancy significantly, although controlling for some chronic diseases (particularly cancer and stroke) eliminated the effect of DS across age and gender groups. CONCLUSION: Depressive symptoms represent a serious and distinct threat to independent functioning in older adults. Whether experienced alone, or in combination with chronic diseases, depressive symptoms shorten ALE substantially. Timely diagnosis and treatment of depressive symptoms in older adults may delay the onset of disability and improve the quality of life.

A tale of two countries--the United States and Japan: are differences in health due to differences in overweight?

BACKGROUND: Despite similar standards of living and health care systems for older persons, there are marked differences in the relative health of the elderly populations in the United States (US) and Japan. We explore the association of overweight and obesity with these health disparities. METHODS: Data on older adults from the US National Health Interview Survey (1994) and the Longitudinal Study of Aging II (1994) were compared to similar data from the 1999-2001 Nihon University Japanese Longitudinal Study of Aging. Regression analyses for the 2 countries were conducted to examine the correlates of being overweight and obese, and the relationships of overweight and obesity with activities of daily living functioning, heart disease, arthritis, and diabetes. RESULTS: The prevalence of overweight and obesity is higher in the US than in Japan, as is the prevalence of heart disease, diabetes, arthritis, and functioning problems. Education level and marital status are predictors of overweight for older Americans but not for older Japanese people. Health behaviors affect weight in all groups. The prevalence of functioning problems and disease are more likely to be associated with being overweight in US men and women than in Japanese women, and are not associated with being overweight in Japanese men. CONCLUSION: Despite similar standards of living and health care systems for older persons, the conditions associated with poor health differ in the US and Japan. Being overweight or obese appears to be related to more functioning problems and arthritis in the US than in Japan.

Cohort differences in adult obesity in the United States: 1982-2002.

OBJECTIVE: To examine the relative importance of broad social change, cohort-specific change, and population composition on trends in adult obesity over the past two decades. METHODS: Using the National Health Interview Study from 1982 through 2002, 5-year birth cohorts are examined for differential trends in obesity. Logistic regression is used to separate out the effects of population composition from broad social change and cohort-specific change. RESULTS: Results confirm that age-specific obesity rates have been increasing for successively born cohorts, indicating broad social change. There is little evidence for cohort-specific change, and only small effects of compositional change. DISCUSSION: Although increasing diversity in the older population will probably result in higher rates of obesity in the future, increasingly sedentary lives and the uncertain impact of smoking cessation on weight outweigh population composition effects. More research is needed on the impact of lifestyle behaviors on the American population.

Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study.

BACKGROUND: The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment. METHODS: With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data. FINDINGS: 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0·0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0·002), executive function (p<0·0001), motor function (p<0·0001), and working memory (p=0·001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0·03) and motor function (p=0·02). INTERPRETATION: A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains. FUNDING: National Institute of Mental Health.

Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS Report No. 3.

OBJECTIVE: To describe health- and vision-targeted quality of life following treatment with iodine 125 brachytherapy vs enucleation for choroidal melanoma in a subgroup of patients who were treated and observed prospectively as part of a large randomized clinical trial. MAIN OUTCOME MEASURES: Difficulty with driving, near vision activities, and activities using stereopsis or binocularity; anxiety; and depression. PARTICIPANTS: Two hundred nine patients who enrolled in the Collaborative Ocular Melanoma Study trial for medium-sized tumors between March 1995 and July 1998 and gave informed consent prior to randomization to participation in an ancillary study of quality of life. METHODS: Patients were interviewed by telephone by a trained interviewer from the Collaborative Ocular Melanoma Study Coordinating Center at baseline (prior to randomization), at 6 months, and on annual anniversaries of enrollment. The questionnaire battery included the Medical Outcomes Study Short Form 36, the Activities of Daily Vision Scale, the National Eye Institute Visual Function Questionnaire, and the Hospital Anxiety and Depression Scale. Additional questions concerning satisfaction with posttreatment appearance and concerns about cancer recurrence also were included in posttreatment interviews. RESULTS: There was a significant increase in both treatment groups in levels of reported difficulty for most vision-oriented activities, and in bodily and ocular pain, 6 months following treatment. Differences in visual function between treatment groups reported during follow-up were relatively small, but significant differences favoring brachytherapy-treated patients were observed for driving during the first year of follow-up and for peripheral vision during the first 2 years of follow-up. Anxiety levels in both groups decreased significantly following treatment, but patients treated with brachytherapy with symptoms of anxiety were less likely to report later resolution of symptoms than patients with symptoms of anxiety who were treated with enucleation. This study was unable to assess impact of treatment on satisfaction with appearance and concern about cancer recurrence during the first year after treatment, but no treatment-related differences were found on these measures at 2 years and later follow-up times. CONCLUSIONS: Patients treated with brachytherapy reported significantly better visual function than patients treated with enucleation with respect to driving and peripheral vision for up to 2 years following treatment. Differences between treatments in visual function diminished by 3 to 5 years posttreatment, paralleling decline in visual acuity in brachytherapy-treated eyes. Patients treated with brachytherapy were more likely to have symptoms of anxiety during follow-up than patients treated with enucleation. APPLICATION TO CLINICAL PRACTICE: Given that no significant differences in survival between enucleation and brachytherapy have been found, the differences demonstrated here for driving and anxiety will allow the individual patient and physician to make informed choices regarding treatment based on personal preferences.

Presence and prognostic significance of melanoma-associated antigens CYT-MAA and HMW-MAA in serum of patients with melanoma.

With the goal of finding serological markers to monitor patients with early- as well as late-stage melanoma, we compared the levels of the cytoplasmic melanoma-associated antigens (CYT-MAA) and high-molecular-weight melanoma-associated antigen (HMW-MAA) in the sera of melanoma patients and controls. Using double-sandwich ELISA, we measured levels of both antigens in 117 patients and in 62 age- and sex-matched controls. Patients were stratified into four risk group based on stage of the disease. Serum levels of both markers were significantly higher in melanoma patients than in controls. CYT-MAA was the more sensitive marker, with 61% of patients showing elevated levels regardless of the stage of disease. HMW-MAA was elevated in 29%. Elevated CYT-MAA was also significantly correlated with poorer clinical outcome. By multivariate analysis (adjusting for stage and age), patients who had elevated CYT-MAA were 81% more likely to recur than patients with undetectable levels (hazard ratio=1.81, 95% CI=[1.07, 3.06], p-value=0.03). Elevated levels of HMW-MAA did not correlate with poor prognosis. These results suggest that both CYT-MAA and HMW-MAA are serum markers for residual melanoma in patients with resected disease. Furthermore, CYT-MAA appears to be a prognostic marker of clinical outcome in melanoma vaccine-treated patients.

Screening for metastasis from choroidal melanoma: the Collaborative Ocular Melanoma Study Group Report 23.

PURPOSE: To describe the predictive value of liver function tests (LFTs), chest x-ray, and diagnostic imaging for detecting melanoma metastasis during routine follow-up after treatment for choroidal melanoma. MATERIALS AND METHODS: Prospective longitudinal follow-up of patients enrolled onto two randomized trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group. Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2320 patients enrolled on the COMS. RESULTS: COMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or imaging test to confirm or rule out cancer recurrence. Of 714 patients with clinical reports of metastasis, 675 patients died. Of these 675 patients, all but four had either histopathologically confirmed or clinically suspected metastatic melanoma present at the time of death. Among all patients, the 5-year cumulative diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all patients with reported metastasis, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively. CONCLUSION: Use of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity. Better tests are needed to identify earlier metastatic disease associated with choroidal melanoma.

The pharmacology of cough.

Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as to this article.

Second primary cancers after enrollment in the COMS trials for treatment of choroidal melanoma: COMS Report No. 25.

OBJECTIVE: To report sites of second primary cancer and the time to first diagnosis during routine follow-up after treatment for choroidal melanoma. DESIGN: Prospective longitudinal follow-up of patients enrolled in 2 randomized trials conducted by the Collaborative Ocular Melanoma Study (COMS) Group. METHODS: Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2320 patients enrolled in the COMS without evidence of melanoma metastasis or other primary cancer at baseline. Deaths were coded by a mortality coding committee. RESULTS: Subsequent to treatment for choroidal melanoma, a total of 222 patients were diagnosed with a second primary cancer other than basal or squamous cell skin cancer (5-year rate of 7.7% [95% confidence interval, 6.6%-9.0%]). The most common sites were prostate (23% of reported cases) and breast (17%); 12 of these 222 patients were diagnosed simultaneously with second primary cancers in 2 or more sites. Of these 222 patients, 113 died; 37 (33%) were coded as dead with melanoma metastasis, 33 (29%) as dead with a malignant tumor other than metastatic melanoma, and 13 (11%) as dead with a malignancy of uncertain origin. Radiotherapy did not significantly increase the development of second primary cancers. The rate of diagnosis of second primary cancer did not differ significantly by smoking status, although the rate in former smokers was increased vs that observed in either current smokers or those who never smoked. CONCLUSION: Routine medical surveillance for development of second primary cancers among patients treated for choroidal melanoma is important, especially for those with a history of smoking, regardless of the size of choroidal melanoma at the time of treatment.

Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26.

OBJECTIVE: To describe the time between treatment for choroidal melanoma and first diagnosis of metastatic disease, sites of metastasis, treatments for metastasis, and time between diagnosis of metastasis and death. DESIGN: Prospective, longitudinal follow-up of patients diagnosed with choroidal melanoma who were enrolled in 2 randomized trials conducted by the Collaborative Ocular Melanoma Study Group. METHODS: Systemic and laboratory evaluations were performed during follow-up according to a standard protocol for 2320 patients enrolled in the Collaborative Ocular Melanoma Study trials without evidence of melanoma metastasis or other primary cancer at baseline. RESULTS: Seven hundred thirty-nine patients were diagnosed with at least 1 site of metastasis during follow-up after treatment for choroidal melanoma. Five- and 10-year cumulative metastasis rates were 25% (95% confidence interval, 23%-27%) and 34% (95% confidence interval, 32%-37%), respectively. Liver was the most common site (89%). The death rate following the report of melanoma metastasis was 80% at 1 year (95% confidence interval, 77%-83%) and 92% at 2 years (95% confidence interval, 89%-94%). Overall survival after metastasis did not vary by baseline size of primary tumor nor treatment for metastasis (when known). Long-term survival after diagnosis of metastasis was uncommon; only 8 patients survived 5 or more years. CONCLUSION: Metastasis rate increased significantly with increasing primary tumor dimensions at time of patient enrollment. Prognosis after metastatic disease remains poor. Effective methods are needed to prevent, diagnose, and treat metastasis from choroidal melanoma.