Gender differences, UV exposure and risk of lentigo maligna in a nationwide healthcare population cohort study.

BACKGROUND: Our understanding of the relationship between ultraviolet (UV) radiation exposure and lentigo maligna (LM) has been largely derived from epidemiologic/clinical studies based on invasive melanoma. Recent studies have shown gender differences in melanocytic tumours incidence. OBJECTIVE: To examine the association of UV light with LM by gender remains unclear. METHODS: Two prospective cohort study [Nurses' Health Study (1980-2012)] and [Health Professionals Follow-up Study (1986-2010)] were analysed. All participants with LM or MIS, non-LM type were included in analysis. UV index at birth, age 15, and age 30 were calculated by gender. Lifetime UV flux was calculated. Hazard ratios (HRs) were calculated. RESULTS: A total of 110 485 women from NHS and 41 015 men from HPFS were examined. A total of 281 LM and 776 melanoma in situ (MIS), non-LM cases were reported. Risk of LM increased with increasing UV flux exposure in multivariate-adjusted models for men (P for trend = 0.04), but not for women (P for trend = 0.91). CONCLUSIONS: UV flux may be associated with LM in men but not in women.

Interval cancers after skin cancer screening: incidence, tumour characteristics and risk factors for cutaneous melanoma.

BACKGROUND: The rate of interval cancers is an established indicator for the performance of a cancer-screening programme. METHODS: We examined the incidence, tumour characteristics and risk factors of melanoma interval cancers that occurred in participants of the SCREEN project, which was carried out 2003/2004 in Schleswig-Holstein, Germany. Data from 350 306 SCREEN participants, who had been screened negative for melanoma, were linked to data of the state cancer registry. Melanoma interval cancers were defined as melanomas diagnosed within 4-24 months after SCREEN examination. Results were compared with melanomas of the pre-SCREEN era (1999-2002), extracted from the cancer registry. RESULTS: The overall relative incidence of melanoma interval cancers in terms of observed/expected ratio was 0.93 (95% CI: 0.82-1.05; in situ: 1.61 (1.32-1.95), invasive: 0.71 (0.60-0.84)). Compared with melanomas of the pre-SCREEN era, the interval melanomas were thinner and had a slightly greater proportion of lentigo maligna melanomas whereas nodular melanomas were less frequent. INTERPRETATION: The results indicate a moderate performance of the SCREEN intervention with an excess of in situ melanomas. In part, the findings might be due to specifics of the SCREEN project, in particular a short-term follow-up of patients at high risk for melanoma.

Current perspective on actinic keratosis: a review.

Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun-damaged skin. Yearly AK to SCC progression rates of 0·6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5-fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management.

The global burden of melanoma: results from the Global Burden of Disease Study 2015.

BACKGROUND: Despite recent improvements in prevention, diagnosis and treatment, vast differences in melanoma burden still exist between populations. Comparative data can highlight these differences and lead to focused efforts to reduce the burden of melanoma. OBJECTIVES: To assess global, regional and national melanoma incidence, mortality and disability-adjusted life year (DALY) estimates from the Global Burden of Disease Study 2015. METHODS: Vital registration system and cancer registry data were used for melanoma mortality modelling. Incidence and prevalence were estimated using separately modelled mortality-to-incidence ratios. Total prevalence was divided into four disease phases and multiplied by disability weights to generate years lived with disability (YLDs). Deaths in each age group were multiplied by the reference life expectancy to generate years of life lost (YLLs). YLDs and YLLs were added to estimate DALYs. RESULTS: The five world regions with the greatest melanoma incidence, DALY and mortality rates were Australasia, North America, Eastern Europe, Western Europe and Central Europe. With the exception of regions in sub-Saharan Africa, DALY and mortality rates were greater in men than in women. DALY rate by age was highest in those aged 75-79 years, 70-74 years and ≥ 80 years. CONCLUSIONS: The greatest burden from melanoma falls on Australasian, North American, European, elderly and male populations, which is consistent with previous investigations. These substantial disparities in melanoma burden worldwide highlight the need for aggressive prevention efforts. The Global Burden of Disease Study results can help shape melanoma research and public policy.

Temporal trends in healthcare utilization following primary melanoma diagnosis among Medicare beneficiaries.

BACKGROUND: Little is known about the impact of primary melanoma diagnosis on healthcare utilization and changes in utilization over time. OBJECTIVES: To evaluate population-based temporal trends in healthcare utilization following primary melanoma diagnosis. METHODS: We conducted a before-and-after multiple time series study of Medicare beneficiaries aged ≥ 66 years with primary melanoma diagnoses between 2000 and 2009 using the Surveillance, Epidemiology, and End Results Medicare database. Primary exposure was time from primary melanoma diagnosis at 3-6 months and 6-24 months postdiagnosis. Covariates included tumour-, patient- and geographical-level characteristics and healthcare utilization in the 6 months before diagnosis. Poisson regression was used to estimate population-based risk-adjusted utilization rates for skin biopsies, benign skin excisions, internal medicine office visits and dermatology office visits. RESULTS: The study population included 56 254 patients with first diagnoses of primary melanoma. Most patients were ≥ 75 years old (56·8%), male (62·1%), and had in situ melanoma (42·4%) or localized invasive melanoma (45·9%). From 2000 to 2009, risk-adjusted skin biopsy rates 24 months postdiagnosis increased from 358·3 to 541·3 per 1000 person-years (P < 0·001), and dermatology visits increased from 989·0 to 1535·6 per 1000 person-years (P < 0·001). Benign excisions and internal medicine visits remained stable. In 2000, risk-adjusted skin biopsy rates 6 months postdiagnosis increased by 208·5 relative to the 6 months before diagnosis (148·7 vs. 357·2) compared with an observed absolute increase of 272·5 (290·9 vs. 563·1) in 2009. Trends in dermatology visits were similar. CONCLUSIONS: Utilization of skin biopsies and dermatology office visits following primary melanoma diagnosis has increased substantially over time. These results may inform optimization of care delivery for melanoma within the Medicare population.

Skin biopsy utilization and melanoma incidence among Medicare beneficiaries.

BACKGROUND: Melanoma incidence has increased in recent decades in the U.S.A. Uncertainty remains regarding how much of this increase is attributable to greater melanoma screening activities, potential detection bias and overdiagnosis. OBJECTIVES: To use a cross-sectional ecological analysis to evaluate the relationship between skin biopsy and melanoma incidence rates over a more recent time period than prior reports. METHODS: Examination of the association of biopsy rates and melanoma incidence (invasive and in situ) in SEER-Medicare data (including 10 states) for 2002-2009. RESULTS: The skin biopsy rate increased by approximately 50% (6% per year) throughout this 8-year period, from 7012 biopsies per 100 000 persons in 2002 to 10 528 biopsies per 100 000 persons in 2009. The overall melanoma incidence rate increased approximately 4% (< 1% per year) over the same time period. The incidence of melanoma in situ increased approximately 10% (1% per year), while the incidence of invasive melanoma increased from 2002 to 2005 then decreased from 2006 to 2009. Regression models estimated that, on average, for every 1000 skin biopsies performed, an additional 5·2 (95% confidence interval 4·1-6·3) cases of melanoma in situ were diagnosed and 8·1 (95% confidence interval 6·7-9·5) cases of invasive melanoma were diagnosed. When considering individual states, some demonstrated a positive association between biopsy rate and invasive melanoma incidence, others an inverse association, and still others a more complex pattern. CONCLUSIONS: Increased skin biopsies over time are associated with increased diagnosis of in situ melanoma, but the association with invasive melanoma is more complex.

Validation and comparison of quality-of-life measures for topical 5-fluorouracil treatment: results from a randomized controlled trial.

BACKGROUND: Topical 5-fluorouracil (5-FU) is commonly used for high-risk patients with keratinocyte carcinoma (KC). Skindex and Skin Cancer Index (SCI) are validated instruments to measure quality of life (QoL) of patients with KC and those who have had surgical treatment of KCs. AIM: To validate Skindex and SCI for topical 5-fluorouracil (5-FU) application and to compare the two QoL instruments. METHODS: We randomized 932 veterans at high risk for developing a KC to either topical 5-FU or vehicle control cream applied to the face and ears for up to 1 month. We collected their Skindex-29 and SCI scores at baseline and follow-up visits. RESULTS: Compared with controls, 5-FU reduced QoL, measured by the Skindex symptom, Skindex function and SCI social subscales (P < 0.001, P < 0.01, P = 0.02, respectively). At 1 month, significant changes in QoL in the 5-FU group were observed in the Skindex symptom (10.1, 95% CI 0.36-12.6), Skindex function (6.0, 95% CI 4.0-8.0) and SCI social (-3.5, 95% CI -6.2 to -0.8) subscales, while the other subscales of Skindex and SCI did not show significant changes. All three Skindex subscales at 1 month correlated with patient-reported symptom score and photograph-based toxicity score, whereas social subscale was the only one of the SCI subscales that correlated with patient-reported symptom and photograph-based toxicity scores. CONCLUSIONS: Our study validated Skindex symptom, Skindex function and SCI social subscales for QoL measurement during treatment with topical 5-FU. The study could not provide evidence for construct validity of the other subscales. Skindex was more responsive than SCI in the context of 5-FU treatment.

Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

Functional connectivity in prenatally stressed rats with and without maternal treatment with ladostigil, a brain-selective monoamine oxidase inhibitor.

Stress during pregnancy in humans is known to be a risk factor for neuropsychiatric disorders in the offspring. Prenatal stress in rats caused depressive-like behavior that was restored to that of controls by maternal treatment with ladostigil (8.5 mg/kg per day), a brain-selective monoamine oxidase (MAO) inhibitor that prevented increased anxiety-like behavior in stressed mothers. Ladostigil inhibited maternal striatal MAO-A and -B by 45-50% at the time the pups were weaned. Using resting state-functional connectivity magnetic resonance imaging on rat male offspring of control mothers, and mothers stressed during gestation with and without ladostigil treatment, we identified neuronal connections that differed between these groups. The percentage of significant connections within a predefined predominantly limbic network in control rats was 23.3 within the right and 22.0 within the left hemisphere. Prenatal stress disturbed hemispheric symmetry, resulting in 30.2 and 21.6%, significant connections in the right and left hemispheres, respectively, but this was fully restored in the maternal ladostigil group to 24.6% in both hemispheres. All connections that were modified in prenatally stressed rats and restored by maternal drug treatment were associated with the dopaminergic system. Specifically, we observed that restoration of the connections of the right nucleus accumbens shell with frontal areas, the cingulate, septum and motor and sensory cortices, and those of the right globus pallidus with the infra-limbic and the dentate gyrus, were most important for prevention of depressive-like behavior.

Predictors of local adverse effects caused by topical tretinoin cream 0·1% in the Veterans Affairs Topical Tretinoin Chemoprevention trial.

BACKGROUND: Topical tretinoin is commonly prescribed, but its frequent adverse effects are barriers to use. Predictors of resistance or susceptibility to retinoid irritation are not known. OBJECTIVE: To identify baseline patient characteristics associated with adverse effects of topical tretinoin. METHODS: This cohort study used data collected from 324 participants in the Veterans Affairs Topical Tretinoin Chemoprevention trial who were randomized to apply tretinoin cream on the face and ears. Univariate and multivariate logistic regression models were used to examine the associations between baseline characteristics and local adverse effects. RESULTS: One hundred and ninety-seven patients (61% of those randomized to tretinoin) reported local adverse effects within 6 months. Clinical signs of severe photodamage at baseline [odds ratio (OR) 0·15, 95% confidence interval (CI) 0·04-0·54] and history of acne (OR 0·46, 95% CI 0·27-0·77) were associated with a decreased risk of adverse effects to tretinoin. The use of other topical medications at enrolment (OR 1·88, 95% CI 1·15-3·08) predicted an increase in adverse effects. CONCLUSIONS: In this study population, the common indications of topical tretinoin treatment were associated with lower risks of adverse effects. The concurrent use of other topical medications may worsen irritation caused by tretinoin.

Improvement in precision of counting actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) often serve as a primary endpoint for clinical studies. However, reliability of counting these lesions is poor, even among expert dermatologists. OBJECTIVES: To investigate the reliability of counting AKs before and after a yearly consensus meeting, held annually for 4 years. METHODS: As part of the Veterans Affairs (VA) Keratinocyte Carcinoma Chemoprevention Trial, board-certified dermatologists convened annually for 4 years to individually count the number of actinic keratoses on three to five test subjects. The dermatologists then met as a group for a consensus discussion on what constituted an AK lesion on each subject. Afterwards, each dermatologist repeated the independent counting exercise on three to five new subjects. The intraclass correlation coefficient (ICC) was used to analyze the reliability of counting AKs among the dermatologists. RESULTS: Eight dermatologists participated in this exercise for 4 consecutive years. Pre-consensus discussion ICCs over 4 years were 0.18, 0.34, 0.38, 0.75, respectively, showing sustained improvement with each consensus discussion. The greatest improvement in reliability of AK counts was shown during the first year of consensus discussions, when the ICC improved from 0.18 to 0.67. There was no improvement by the fourth year of consensus discussion, with pre- and post-consensus ICCs of 0.75 and 0.75, respectively. CONCLUSIONS: Annual consensus discussions can lead to improvement in reliability of AK counts. This improvement was sustained over 4 years. By the fourth year, the discussion meeting had no effect on improvement in reliability. A consensus meeting discussion may be helpful for improving reliability in other trials.

Reliability of quantification measures of actinic keratosis.

BACKGROUND: Enumerating actinic keratoses (AKs) is highly variable but important to standardize as new therapies are emerging. OBJECTIVES: To assess the reliability of four different methods used to quantify AKs and to investigate whether a consensus meeting affects the reliability. METHODS: This was a single-blinded study of 12 experienced dermatologist raters counting AKs on the face and ears of nine subjects before and after a consensus meeting. Raters were recruited from investigators of a multicentre Veterans Affairs cooperative study. The intraclass correlation coefficient (ICC) among raters for pre- and post-consensus evaluations was the primary outcome measure. RESULTS: Of the four assessment methods, the 'total count' method had the greatest ICC for both pre- (0·18, P = 0·04) and post-consensus (0·66, P = < 0·0001) assessments. Total count was also the only pre-consensus ICC for which the null hypothesis of no association among assessments was rejected. CONCLUSIONS: Total AK count appears to be the most reliable measure of quantifying AKs on the face and ears. Educational consensus discussion prior to assessment improves reliability of this measure.

Skin cancer screening participation and impact on melanoma incidence in Germany--an observational study on incidence trends in regions with and without population-based screening.

BACKGROUND: The SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project involved population-wide skin cancer screening with whole-body examination by general physicians and dermatologists. It was conducted in the German state of Schleswig-Holstein (July 2003-June 2004), but not in the German state of Saarland. METHODS: The population-based registries of Schleswig-Holstein and Saarland provided data on melanoma incidence before, during, and after SCREEN to assess the association of skin cancer screening with incidence. RESULTS: Approximately 19% of the Schleswig-Holstein population participated in SCREEN (women: 27%, men: 10%). A total of 52% of all melanomas diagnosed during SCREEN in Schleswig-Holstein were detected as part of the project. Melanoma incidence increased during SCREEN (invasive melanoma in women: +8.9 per 100,000 (95% confidence intervals (CI): 6.1; 11.7); men: +4.0 per 100,000 (95% CI: 1.6; 6.4)) and decreased afterwards (women: -10.6 per 100,000 (95% CI: -13.3; -7.9); men: -4.1 per 100,000 (95% CI: -6.5; -1.7)). Similar changes were not observed in Saarland that had no such project. The differences between the two states were greatest among women, the group with the greater SCREEN participation. CONCLUSION: The SCREEN project had a substantial impact on melanoma incidence. This is consistent with the impact of effective screening for other cancers.

Clinicopathological comparisons of index and second primary melanomas in paediatric and adult populations.

BACKGROUND: The high incidence of cutaneous melanoma globally has sparked interest in the features associated with second primary melanomas (SPMs). OBJECTIVES: To identify differences and similarities between index and second primary melanomas while comparing the absolute and relative risk of subsequent melanoma development in paediatric and adult patients. METHODS: A retrospective analysis of patients diagnosed with invasive malignant melanoma from 1973 to 2008 inclusive was completed with data obtained from the Surveillance, Epidemiology and End Results (SEER) database. RESULTS: In total, 208,289 patients were diagnosed with invasive melanoma in the SEER database from 1973 to 2008, with subsequent primary melanomas diagnosed in 6888 (3.3%). The incidence of SPMs increased with increasing age of diagnosis of the patient's first melanoma. However, the relative risk of developing a subsequent melanoma was nearly double for patients diagnosed with their first melanoma at the age of 19 years and younger compared with patients greater than the age of 19 years. Compared with a patient's initial invasive melanoma, 44% of the subjects had a different melanoma subtype with their subsequent melanoma. SPMs were located in a different anatomical site from the index malignancy in 55% of patients. Nodular melanomas were more common as index melanomas compared with SPMs. CONCLUSIONS: Although invasive cutaneous melanoma is primarily a malignancy of adulthood, the heightened relative risk of SPMs in the paediatric population calls for careful long-term scrutiny in this latter population following an index melanoma diagnosis.