Peritoneal Dialysis Technique Survival: A Cohort Study.

RATIONALE & OBJECTIVE: Reasons for transfer from peritoneal dialysis (PD) to hemodialysis (HD) remain incompletely understood. Among incident and prevalent patients receiving PD, we evaluated the association between prior treatment with HD and PD technique survival. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults who initiated PD at a Dialysis Clinic, Inc. (DCI) outpatient facility between January 1, 2010 and September 30, 2019. EXPOSURES: The primary exposure of interest was timing of PD start, categorized as PD-first, PD-early, or PD-late. Other covariates included demographics, clinical characteristics, and routine laboratory results. OUTCOMES: Modality switch from PD to HD sustained for more than 90 days. ANALYTICAL APPROACH: Multivariable Fine-Gray models with competing risks and time-varying covariates, stratified at 9 months to account for lack of proportionality. RESULTS: Among 5224 patients who initiated PD at a DCI facility, 3174 initiated dialysis with PD ("PD-first"), 942 transitioned from HD to PD within 90 days ("PD-early"), and 1108 transitioned beyond 90 days ("PD-late"); 1472 (28%) subsequently transferred from PD to HD. PD-early and PD-late patients had higher risk of transfer to HD as compared to PD-first patients [adjusted hazard ratio (aHR) 1.51 (95% CI: 1.17-1.96) and 2.41 (1.94-3.00), respectively, in the first 9 months and aHR 1.16 (0.99-1.35) and 1.43 (1.24-1.65), respectively, after 9 months]. More peritonitis episodes, fewer home visits, lower serum albumin, lower residual kidney function, and lower peritoneal clearance calculated with weekly Kt/V were additional risk factors for PD-to-HD transfer. LIMITATIONS: Missing data on dialysis adequacy and residual kidney function, confounded by short PD technique survival. CONCLUSIONS: Initiating dialysis with PD is associated with greater PD technique survival, though many of those who initiate PD late in their dialysis course still experience substantial time on PD. Peritonitis, lower serum albumin, and lower Kt/V are risk factors for PD-to-HD transfer that may be amenable to intervention.

Comparison of Dialysis Unit and Home Blood Pressures: An Observational Cohort Study.

RATIONALE & OBJECTIVE: Prior studies of patients receiving maintenance hemodialysis have shown that, on average, blood pressure (BP) measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BP that is higher when measured at home than when measured predialysis and this subgroup of patients has a higher prevalence of left ventricular hypertrophy. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP ≤140/90 to 155-165/90 mm Hg. EXPOSURE: Differences between predialysis and next-day home systolic BP measured ≥6 times over 1 year. OUTCOME: Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging. ANALYTICAL APPROACH: A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI. RESULTS: Mean differences between predialysis and home systolic BP were 19.1 (95% CI, 17.0 to 21.1) mm Hg for cluster 1 ("home lower"), 3.7 (95% CI, 1.6 to 5.8) mm Hg for cluster 2 ("home and predialysis similar"), and -9.7 (95% CI, -12.0 to -7.4) mm Hg for cluster 3 ("home higher"). Systolic BP declined during dialysis in clusters 1 and 2 but increased in cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in cluster 3 than in clusters 1 and 2: differences in means of 10.6 ± 4.96 (SE) g/m2 (P = 0.04) and 12.0 ± 5.08 g/m2 (P = 0.02), respectively. LIMITATIONS: Limited statistical power. CONCLUSIONS: Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home, indicating that their BP may have been undertreated.

Association of Intradialytic Hypertension with Left Ventricular Mass in Hypertensive Hemodialysis Patients Enrolled in the Blood Pressure in Dialysis (BID) Study.

BACKGROUND/AIMS: Intradialytic hypertension (IDH), or paradoxical rise in blood pressure (BP) during hemodialysis (HD) is associated with increased morbidity and mortality. The association between IDH and increased left ventricular mass (LVM), a well-known risk factor for adverse cardiovascular outcomes in HD patients, has not been studied. The aim of our study is to evaluate the cross-sectional association of intradialytic change in BP with cardiac structure and function measured by cardiac MRI in hypertensive HD patients enrolled in the multi-center Blood Pressure in Dialysis (BID) clinical trial. METHODS: Participants in the BID study were categorized into 3 groups based on average change (Δ) in systolic blood pressure (SBP) (post-HD SBP minus pre-HD SBP) during HD over a 1 month period: group 1 - patients with an increase in SBP ≥ 10mm Hg during HD (IDH); group 2 -patients with SBP decrease of greater ≥10mm Hg during HD; group 3 - patients with SBP increase or decrease by < 10mm Hg during HD. LVM index (LVMI) was measured using cardiac MRI, which were centrally read. Baseline characteristics were compared in the 3 groups and multivariable regression models were fitted for the adjusted association of IDH with LVMI. RESULTS: Among the 80 participants, 7 (8.8%) had IDH and had average Δ SBP 17.0 ± 10.1 mmHg during HD. Patients with IDH were less likely to be diabetic, had lower pre-dialysis SBP and lower percent interdialytic weight gain as compared to the other 2 groups (p=0.02, p< 0.001 and p=0.02 respectively). In multivariable regression analyses, IDH was significantly associated with LVMI (adjusted mean difference relative to SBP decreased group [95% confidence interval (CI)] = 12.5 [3.6, 21.5], p=0.01) after adjusting for age, sex, diabetes, IDWG%, pre-HD SBP and beta blocker use. Every 1 mm rise in ΔSBP during HD was associated with 0.2 g/m2 increase in LVMI in adjusted models (p=0.04). CONCLUSION: IDH is independently associated with higher LVMI in hypertensive HD patients and may contribute to increased cardiovascular events.

BP in Dialysis: Results of a Pilot Study.

The optimal BP target for patients receiving hemodialysis is unknown. We randomized 126 hypertensive patients on hemodialysis to a standardized predialysis systolic BP of 110-140 mmHg (intensive arm) or 155-165 mmHg (standard arm). The primary objectives were to assess feasibility and safety and inform the design of a full-scale trial. A secondary objective was to assess changes in left ventricular mass. Median follow-up was 365 days. In the standard arm, the 2-week moving average systolic BP did not change significantly during the intervention period, but in the intensive arm, systolic BP decreased from 160 mmHg at baseline to 143 mmHg at 4.5 months. From months 4-12, the mean separation in systolic BP between arms was 12.9 mmHg. Four deaths occurred in the intensive arm and one death occurred in the standard arm. The incidence rate ratios for the intensive compared with the standard arm (95% confidence intervals) were 1.18 (0.40 to 3.33), 1.61 (0.87 to 2.97), and 3.09 (0.96 to 8.78) for major adverse cardiovascular events, hospitalizations, and vascular access thrombosis, respectively. The intensive and standard arms had similar median changes (95% confidence intervals) in left ventricular mass of -0.84 (-17.1 to 10.0) g and 1.4 (-11.6 to 10.4) g, respectively. Although we identified a possible safety signal, the small size and short duration of the trial prevent definitive conclusions. Considering the high risk for major adverse cardiovascular events in patients receiving hemodialysis, a full-scale trial is needed to assess potential benefits of intensive hypertension control in this population.

Low dialysate potassium concentration is associated with prolonged recovery time.

INTRODUCTION: Modifiable hemodialysis treatment parameters may impact patient reported outcomes, including recovery time. Answers to the recovery question may predict the impact of treatment parameters on clinical outcomes and health related quality of life. However, the reliability of answers to the recovery question after consecutive and nonconsecutive dialysis treatments in diverse populations has not been established. OBJECTIVE: To assess the reliability of this instrument and to determine if recovery time was associated with modifiable dialysis parameters, we conducted a quality assurance project in which we asked, "How long did it take you to recover from your last dialysis session?" after consecutive and nonconsecutive treatments. METHODS: We asked patients the recovery question ≤ seven times. We computed polychoric correlations to assess within patient correlations. We used random intercept ordinal logistic regression models to test for associations of recovery time with patient variables. RESULTS: We obtained answers to the recovery question in association with 1572 treatments in 364 patients. Recovery time was <2 hours in 52.1%; 2 to 7 hours in 20.9%; and >7 hours in 27.0% of treatments. Polychoric correlations demonstrated highly reliable responses within individual patients between consecutive and nonconsecutive treatments. Prolonged recovery was associated with a dialysate potassium of 1 vs. 2 mEq/L (odds ratio [OR] 2.25 {95% confidence interval [CI] 1.43-3.55}) and 1 vs. 3 mEq/L (OR 1.88 [95% CI 1.06-3.33]); vintage >6 months (OR 2.43 [95% CI 1.42-4.16]), body mass index >35 kg/m2 (OR 1.94 [95% CI 1.18-3.20]), post-dialysis systolic blood pressure (SBP) <115 mmHg (OR 1.57 [95% CI 1.04-2.37]) and intradialytic cramps (OR 1.76 [95% CI 1.09-2.86]). There were no associations with gender, race, age, ESRD etiology, intradialytic SBP <90 mmHg, serum sodium or potassium, dialysate sodium, bicarbonate or temperature, blood flow rate, or ultrafiltration rate. CONCLUSIONS: Responses to the recovery question were reliable and low dialysate potassium was associated with prolonged recovery.

Skin self-examination and long-term melanoma survival.

To evaluate the effect of skin self-examination (SSE) on melanoma mortality, we estimated the survival for individuals performing SSE compared with those who did not. Participants were from a previously carried out case-control study, who were newly diagnosed melanoma cases in 1987-1989. A 20-year survival analysis was carried out using death (event) and other causes of death (competing). Cumulative incidence functions were evaluated using Gray's test and proportional subdistribution hazards regression models were fitted to study the effect of SSE and other covariates on melanoma survival. Forty-five percent of patients died, with 48.4% melanoma deaths. Individuals who did not perform SSE experienced a continuous increase in the risk of melanoma death trending toward significance for nearly 20 years after diagnosis, whereas melanoma deaths in skin self-examiners plateaued before 10 years after diagnosis (P=0.32). Univariate analyses suggested a 25% lower risk of melanoma death for those who performed SSE [hazard ratio (HR)=0.75, 95% confidence interval (CI)=0.43-1.32, P=0.32]. After adjusting for competing risks, the multivariate risk estimate was above one (HR=1.12, 95% CI=0.61-2.06, P=0.71). Skin awareness (HR=0.46, 95% CI=0.28-0.75, P≤0.01) was associated independently with a decreased risk of melanoma death. Although we did not find a significant association between melanoma mortality and SSE when adjusting for competing mortality and other covariates, we extended previous findings that increased skin awareness and tumor thickness are strongly inversely related to survival. Research is needed to continue developing best practices for melanoma screening and to further explore the components of SSE and long-term melanoma survival.

Comparison of Prescribed and Measured Dialysate Sodium: A Quality Improvement Project.

BACKGROUND: There is controversy regarding the optimal dialysate sodium concentration for hemodialysis patients. Dialysate sodium concentrations of 134 to 138 mEq/L may decrease interdialytic weight gain and improve hypertension control, whereas a higher dialysate sodium concentration may offer protection to patients with low serum sodium concentrations and hypotension. We conducted a quality improvement project to explore the hypothesis that prescribed and delivered dialysate sodium concentrations may differ significantly. STUDY DESIGN: Cross-sectional quality improvement project. SETTING & PARTICIPANTS: 333 hemodialysis treatments in 4 facilities operated by Dialysis Clinic, Inc. QUALITY IMPROVEMENT PLAN: Measure dialysate sodium to assess the relationships of prescribed and measured dialysate sodium concentrations. OUTCOMES: Magnitude of differences between prescribed and measured dialysate sodium concentrations. MEASUREMENTS: Dialysate sodium measured pre- and late dialysis. RESULTS: The least square mean of the difference between prescribed minus measured dialysate sodium concentration was -2.48 (95% CI, -2.87 to -2.10) mEq/L. Clinics with a greater number of different dialysate sodium prescriptions (clinic 1, n=8; clinic 2, n=7) and that mixed dialysate concentrates on site had greater differences between prescribed and measured dialysate sodium concentrations. Overall, 57% of measured dialysate sodium concentrations were within ±2 mEq/L of the prescribed dialysate sodium concentration. Differences were greater at higher prescribed dialysate sodium concentrations. LIMITATIONS: We only studied 4 facilities and dialysate delivery machines from 2 manufacturers. Because clinics using premixed dialysate used the same type of machine, we were unable to independently assess the impact of these factors. Pressures in dialysate delivery loops were not measured. CONCLUSIONS: There were significant differences between prescribed and measured dialysate sodium concentrations. This may have beneficial or deleterious effects on clinical outcomes, as well as confound results from studies assessing the relationships of dialysate sodium concentrations to outcomes. Additional studies are needed to identify factors that contribute to differences between prescribed and measured dialysate sodium concentrations. Quality assurance and performance improvement (QAPI) programs should include measurements of dialysate sodium.

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.

Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma.

IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN, SETTING, AND PARTICIPANTS: A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher­AJCC stage primary melanomas.

Satisfaction with Care of Patients on Hemodialysis.

BACKGROUND AND OBJECTIVES: Little is known about patients receiving dialysis who respond to satisfaction and experience of care surveys and those who do not respond, nor is much known about the corollaries of satisfaction. This study examined factors predicting response to Dialysis Clinic, Inc. (DCI)'s patient satisfaction survey and factors associated with higher satisfaction among responders. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENT: A total of 10,628 patients receiving in-center hemodialysis care at 201 DCI facilities between January 1, 2011, and December 31, 2011, aged ≥18 years, treated during the survey administration window, and at the facility for ≥3 months before survey administration. Primary outcome was response to at least one of the nine survey questions; secondary outcome was overall satisfaction with care. RESULTS: Response rate was 77.3%. In adjusted logistic regression (odds ratios with 95% confidence intervals), race other than black (white race, 1.23 [1.10 to 1.37]), missed treatments (1.16 [1.02 to 1.32]) or shortened treatments (≥5 treatments, 1.40 [1.22 to 1.60]), more hospital days (>3 days in the last 3 months, 1.89 [1.66 to 2.15]), and lower serum albumin (albumin level <3.5 g/dl, 1.4 [1.28 to 1.73]) all independently predicted nonresponse. In adjusted linear regression, the following were more satisfied with care: older patients (age ≥63 years, 1.84 [1.78 to 1.90]; age <63 years, 1.91 [1.86 to 1.97]; P<0.001), white patients (1.76 [1.71 to 1.81]) versus black patients (1.93 [1.88 to 1.99]) or those of other race (1.93 [1.83 to 2.03]) (P<0.001), patients with shorter duration of dialysis (≤2.5 years, 1.79 [1.73 to 1.84]; >2.5 years, 1.96 [1.91 to 2.02]; P<0.001), patients who had missed one or fewer treatments (1.83 [1.78 to 1.88]) versus those who had missed more than one treatment (1.92 [1.85 to 1.98]; P=0.002) and those who had shortened treatment (for one treatment or less, 1.84 [1.77 to 1.90]; for two to four treatments, 1.87 [1.81 to 1.93]; for five or more treatments, 1.92 [1.87 to 1.98]; P=0.004). CONCLUSIONS: Survey results represent healthier and more adherent patients on hemodialysis. Shorter survey administration windows were associated with higher response rates. Older, white patients with shorter dialysis vintage were more satisfied.

Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project.

The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10(-7)) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10(-6)) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.

Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study.

IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

Sun exposure and melanoma survival: a GEM study.

BACKGROUND: We previously reported a significant association between higher UV radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure before diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information. METHODS: We conducted a multicenter, international population-based study in four countries-Australia, Italy, Canada, and the United States-with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient ultraviolet B (280-320 nm) dose, histologic solar elastosis, and season of diagnosis. RESULTS: Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in 1 year within 10 years of diagnosis was inversely associated with survival; solar elastosis-a measure of lifetime cumulative exposure-was not. In addition, none of the intermittent exposure measures-water-related activities and sunny holidays-were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival. CONCLUSION: Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure before diagnosis is associated with greater melanoma-specific survival. IMPACT: This study adds to the evidence that sun exposure before melanoma diagnosis has little effect on survival with melanoma.

Design of the Blood Pressure Goals in Dialysis pilot study.

BACKGROUND: Cardiovascular disease (CVD) is markedly increased among hemodialysis (HD) patients. Optimizing blood pressure (BP) among HD patients may present an important opportunity to reduce the disparity in CVD rates between HD patients and the general population. The optimal target predialysis systolic BP (SBP) among HD patients is unknown. Current international guidelines, calling for a predialysis SBP < 140 mm Hg, are based on the opinion and extrapolation from the general population. Existing randomized controlled trials (RCTs) were small and did not include prespecified BP targets. METHODS: The authors described the design of the Blood Pressure in Dialysis (BID) Study, a pilot, multicenter RCT where HD patients are randomized to either a target-standardized predialysis SBP of 110 to 140 mm Hg or 155 to 165 mm Hg. This is the first study to randomize HD patients to 2 different SBP targets. RESULTS: Primary outcomes are feasibility and safety. Feasibility parameters include recruitment and retention rates, adherence with prescribed BP measurements and achievement and maintenance of selected BP targets. Safety parameters include rates of hypotension and other adverse and serious adverse events. The authors obtained preliminary data on changes in left ventricular mass, aortic pulse wave velocity, vascular access thromboses and health-related quality of life across study arms, which may be the secondary outcomes in the full-scale study. CONCLUSIONS: The data acquired in the pilot RCT will determine the feasibility and safety and inform the design of a full-scale trial, powered for hard outcomes, which may require 2000 participants.

Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study.

PURPOSE: Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. PATIENTS AND METHODS: On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. RESULTS: Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. CONCLUSION: At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

DNA repair variants, indoor tanning, and risk of melanoma.

Although ultraviolet radiation (UV) exposure from indoor tanning has been linked to an increased risk of melanoma, the role of DNA repair genes in this process is unknown. We evaluated the association of 92 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes with the risk of melanoma and indoor tanning among 929 patients with melanoma and 817 controls from the Minnesota Skin Health Study. Significant associations with melanoma risk were identified for SNPs in ERCC4, ERCC6, RFC1, XPC, MGMT, and FBRSL1 genes; with a cutoff of P < 0.05. ERCC6 and FBRSL1 gene variants and haplotypes interacted with indoor tanning. However, none of the 92 SNPs tested met the correction criteria for multiple comparisons. This study, based on an a priori interest in investigating the role of DNA repair capacity using variants in base excision and nucleotide excision repair, identified several genes that may play a role in resolving UV-induced DNA damage.

Vitamin D receptor polymorphisms in patients with cutaneous melanoma.

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

Sun exposure, vitamin D receptor polymorphisms FokI and BsmI and risk of multiple primary melanoma.

BACKGROUND: Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one. METHODS: We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed. RESULTS: Only the BsmI variant was associated with multiple primary melanoma (OR=1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high. CONCLUSION: These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR.

Associations of cumulative sun exposure and phenotypic characteristics with histologic solar elastosis.

BACKGROUND: Solar elastosis adjacent to melanomas in histologic sections is regarded as an indicator of sun exposure, although the associations of UV exposure and phenotype with solar elastosis are yet to be fully explored. METHODS: The study included 2,589 incident primary melanoma patients with assessment of histologic solar elastosis in the population-based Genes, Environment, and Melanoma study. Ambient erythemal UV (UVE) at places of residence and sun exposure hours, including body site-specific exposure, were collected. We examined the association of cumulative site-specific and non-site-specific sun exposure hours and ambient UVE with solar elastosis in multivariable models adjusted for age, sex, center, pigmentary characteristics, nevi, and, where relevant, body site. RESULTS: Solar elastosis was associated most strongly with site-specific UVE [odds ratio (OR) for top exposure quartile, 5.20; 95% confidence interval (95% CI), 3.40-7.96; P for trend <0.001] and also with site-specific sun exposure (OR for top quartile, 5.12; 95% CI, 3.35-7.83; P for trend <0.001). Older age (OR at >70 years, 7.69; 95% CI, 5.14-11.52; P for trend < 0.001) and having more than 10 back nevi (OR, 0.77; 95% CI, 0.61-0.97; P = 0.03) were independently associated with solar elastosis. CONCLUSION: Solar elastosis had a strong association with higher site-specific UVE dose, older age, and fewer nevi. IMPACT: Solar elastosis could be a useful biomarker of lifetime site-specific UV. Future research is needed to explore whether age represents more than simple accumulation of sun exposure and to determine why people with more nevi may be less prone to solar elastosis.