Impact of High Age and Comorbidity on Management Decisions and Adherence to Guidelines in Patients with Keratinocyte Skin Cancer.

Appropriate medical decision-making in patients with keratinocyte skin cancer (KSC) can be challenging, especially in those with a limited life expectancy (LEx). Treatment should be beneficial for the individual patient, the risk of both over- and under-treatment should be carefully considered, and deviation from guideline recommendations may be necessary. In this study retrospective analysis was performed to determine the influence of age and comorbidity, both factors strongly related to limited LEx, on KSC management in daily practice. After analysis of 401 patients it was found that management in patients with KSC is not influenced, or is only minimally influenced, by high age and comorbidity. Better integration of aspects related to a limited LEx in KSC management might optimize care and prevent overtreatment. Future research on the general prognostication, prediction of the patient burden caused by tumour and treatment, and time-to-benefit in KSC management is strongly recommended.

Comparison of "Lesion-by-Lesion" and Field Photodynamic Therapy in the Prevention of Actinic Keratoses: A Randomized, Split-Face, Single-Blind Pilot Study.

BACKGROUND: Actinic keratoses (AKs) are often treated separately, lesion by lesion. However, in the past years, AKs have been described as a field disease and not limited to single clinically apparent lesions. Treatment should therefore target an area of field change which may reduce the risk of development of further AKs, second tumours, and local recurrence. OBJECTIVE: The primary objective was to determine the number of new lesions at 9 months after methyl aminolevulinate photodynamic therapy (MAL-PDT). Secondary objectives were to determine the number of new lesions at 3 and 6 months after treatment and the percentage reduction of AKs from baseline at 3, 6, and 9 months after MAL-PDT. METHODS: This was a single-centre, prospective, randomized, split-face, investigator-blinded pilot study with a study duration of 1 year. The study population comprised patients with AKs on the face or scalp, with a maximum of 10 AKs on each side. One side was treated with 1 session of "lesion-by-lesion" MAL-PDT (LT side) and the other side with 1 session of field MAL-PDT (FT side). RESULTS: At 9 months the FT demonstrated significantly fewer new lesions. At every time point during the follow-up, we found a significant reduction in the number of AKs in the LT as well as in the FT sides. After 3 and 6 months we did not observe significant differences between the sides. However, after 9 months, the LT area showed significantly fewer remaining AKs, whereas the FT area demonstrated significantly fewer new lesions. CONCLUSIONS: Field treatment results in significantly fewer new AK lesions compared with lesion-by-lesion treatment.

Real-life Data on Patient Characteristics, Cost and Effectiveness of Field-directed Treatment for Actinic Keratoses: An Observational Study.

Actinic keratoses (AK) occur frequently; however, real-life clinical data on personalized treatment choice and costs are scarce. This multicentre one-year observational study investigated patient-characteristics, cost and effectiveness of methylaminolaevulinate photodynamic therapy (MAL-PDT), imiquimod (IMI) and 5-fluorour-acil (5-FU) in patients with AKs on the face/scalp. A total of 104 patients preferred MAL-PDT, 106 preferred IMI and 110 preferred 5-FU. At baseline, significant differences between treatment groups were found; most patients were severely affected (mean 32.5 AK in PDT-group, 20.2 in IMI-group, 22.8 in 5-FU-group). A mean reduction in lesions of 81% after MAL-PDT, 82% after IMI and 88% after 5-FU was found after one year. Annual costs were €1,950 for MAL-PDT, €877 for IMI and €738 for 5-FU. These results show that, compared with clinical trials, in the real-life clinical setting AK patients are usually more severely affected and treatment costs are much higher. Furthermore, patient characteristics are important factors in treatment choice.

Skin tumour surgery in primary care: do general practitioners need to improve their surgical skills?

BACKGROUND: Due to a rapid increase in the incidence of skin cancer, it seems inevitable that general practitioners (GPs) will play a larger role in skin cancer care. OBJECTIVES: To assess surgical procedures used by GPs in skin tumour management. METHODS: We performed a retrospective study of 1,898 pathology reports of skin tumours excised by GPs in 2009. RESULTS: In 22.9% no diagnosis was provided on the application form. Mostly, once-off excisions (no preceding biopsy) were performed, 7% of the excised lesions were malignant, and 35% of incisions were incomplete. Excisions in the face and neck region were incomplete in 65.4%; 22% of melanomas were biopsied or shaved. CONCLUSION: This study underlines the difficulties in skin tumour management in primary care. To stimulate adequate resource use, the number of excisions of benign lesions could be lowered, and pretreatment biopsy in non-melanoma skin cancer management should be encouraged. GPs should be aware of their limitations and consider referral of high-risk malignancies.

Establishing the dynamics of neutrophil accumulation in vivo by reflectance confocal microscopy.

Reflectance confocal microscopy (RCM) is an imaging tool, which visualizes the epidermal skin layers in vivo with a cellular resolution. Neutrophil accumulation is a characteristic feature in psoriasis and is thought to play a role in the pathophysiology of psoriasis. Until now, imaging of neutrophil accumulation in vivo is not performed. We evaluated the dynamics of neutrophil migration in active psoriatic lesions by non-invasive RCM imaging. Additionally, we evaluated the time phasing and duration of neutrophil trafficking. We performed RCM imaging prior to the start of topical treatment and for seven consecutive days with a 24-h time interval at the Radboud University Medical Center, Nijmegen, the Netherlands. Twelve psoriatic lesions in three patients with a severe exacerbation of psoriasis were included. The four most active lesions were selected in each patient based on the highest degree of redness, induration and expansion in the previous 2 weeks. In all lesions, a cyclic pattern of neutrophil migration was observed, consisting of squirting papillae, transepidermal migration, accumulation in the stratum spinosum, accumulation in the stratum corneum and degeneration of the abscesses. The time interval of a neutrophil-trafficking cycle was 5-7 days and showed a synchronic time phasing. This study is the first to establish the dynamics and time phasing of neutrophil migration in vivo in psoriatic lesions. Previously reported theories were confirmed by these novel in vivo data. RCM might distinguish between active or chronic psoriatic areas, which might contribute to new insights into the pathogenesis of psoriasis.

Referrals by general practitioners for suspicious skin lesions: the urgency of training.

Skin cancer is common among white populations and rapid increases in incidence are being observed in many countries, leading to a large burden on healthcare systems. Unnecessary referrals from general practitioners (GPs) may contribute to this burden. The aim of this study was to analyse the quality of referrals from GPs of patients with skin tumours. Referral letters for 734 patients were collected. The proposed diagnoses were compared with definitive diagnosis made by dermatologists. In 44.5%, lesions appeared to be benign. Malignant skin tumours were poorly recognised by GPs and seborrheic keratoses were often mistaken for naevi (33.6%). Furthermore, with total body examination, dermatologists found 111 additional malignant lesions. We discussed several recommendations to minimise unnecessary referrals as well as the future role of GPs in skin cancer care.

In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy.

BACKGROUND: Reflectance confocal microscopy (RCM) is a noninvasive imaging technique. Currently, RCM is mainly used for the diagnosis of melanoma and nonmelanoma skin cancer including basal cell carcinoma (BCC). Until now, it has not been possible to distinguish between subtypes of BCC using RCM. OBJECTIVE: To establish the RCM features for subtypes of BCC. METHODS: 57 lesions were selected for RCM imaging. Clinical and dermatoscopic pictures were taken and a 3-mm biopsy was obtained. RESULTS: It was demonstrated that tumor nests with peripheral palisading, branch-like structures, fibrotic septa and increase in vascular diameter were characteristic RCM features for nodular and micronodular BCC. The size and shape of the tumor nests allowed further distinction between these BCCs. Solar elastosis and tumor nests connected with the basal cell layer characterize superficial BCC. CONCLUSION: This study presents RCM features for BCC, which might allow in vivo diagnosis of the nodular, micronodular and superficial subtype of BCC. This could prevent a skin biopsy, resulting in direct proper treatment. Further, RCM allows to evaluate the total lesion, which makes it possible to detect mixed-type BCCs.

Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used.

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide-MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1(+) melanoma patients were vaccinated intravenously (on average 25 × 10(6) DC) and intradermally (on average 11 × 10(6) DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses.

Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma.

Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model.

Fluorescence diagnosis in keratinocytic intraepidermal neoplasias.

BACKGROUND: As different tissue types have distinct capabilities to accumulate protoporphyrin-IX, fluorescence diagnosis with aminolevulinic acid-induced porphyrin (FDAP) could be used to discriminate between different tissue types. OBJECTIVE: Protoporphyrin-IX accumulation and proliferation were studied in cutaneous squamous (pre)malignancies to see whether FDAP could be used to discriminate between different stages of keratinocytic intraepidermal neoplasia or proliferative status. METHODS: FDAP was performed in 14 patients (86 lesions) and biopsy specimens were taken, on which (immuno)histochemistry was performed for histopathologic classification and assessment of Ki67-antigen expression. Stratum corneum thickness was also measured. RESULTS: The fluorescence ratio (lesional:nonlesional skin) showed neither significant differences between the different keratinocytic intraepidermal neoplasia stages, nor between different levels of Ki67-antigen expression. Macroscopic fluorescence intensity and stratum corneum thickness were negatively correlated. LIMITATIONS: Relatively few malignancies were biopsied. CONCLUSIONS: With FDAP we were not able to discriminate between keratinocytic intraepidermal neoplasia lesions or proliferative activity. However, hyperkeratosis appeared to be an important determinant in variations in macroscopic fluorescence intensity.

The Epidemiology and Clinicopathological Features of Basal Cell Carcinoma in Patients 80 Years and Older: A Systematic Review.

Importance: The number of very elderly (≥80 years) is rapidly growing worldwide. Basal cell carcinoma (BCC) are common in this age group and treatment is often challenging in this population. Objective: Obtaining an overview of the epidemiology and clinicopathological features of BCC in the very elderly to guide clinicians and policy makers. Evidence Review: A systematic review of literature was performed using PubMed, Excerpta Medica Database (EMBASE), and the Cochrane Library. Study selection, quality assessment, and data extraction was performed by 2 independent reviewers. For quality assessment (including the risk of bias) the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist was used, combined with the Quality Rating Scheme for Studies and Other Evidence. Data were described though a narrative synthesis and tabulation. Findings: Of 13 628 studies identified, 83 studies were included and quality assesment was performed for 76 studies; 27 studies (representing >350 000 patients) were found that included age-specific incidence rates of BCC in the very elderly. High and increasing incidence rates of BCC in the very elderly were found ranging from 13 to 12 112 per 100 000 person-years, strongly depending on factors like study population and clinical setting. Basal cell carcinoma in the very elderly were more common in men, mostly of the nodular subtype, and located in the head and neck region. Interpretation and generalization of the data was limited by the heterogeneity of study populations, methods, and outcomes. Data concerning impact on health-related quality of life (HRQoL) and prognostication were scarce. Conclusions and Relevance: The incidence of BCC among the very elderly is high and increasing. Epidemiologic and clinicopathological data from current literature provide only limited guidance in clinical decision making owing to heterogeneity and scarcity. Future research should focus more specifically on BCC in the very elderly, together with prognostication and their relation with HRQoL in both the short and longer term.

Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome.

PURPOSE: Tumor-specific immunomonitoring is essential to evaluate the efficacy of vaccination against cancer. In this study, we investigated the predictive value of the presence or absence of antigen-specific T cells in biopsies from delayed-type hypersensitivity (DTH) sites. PATIENTS AND METHODS: In our ongoing clinical trials, HLA-A2.1+ melanoma patients were vaccinated with mature dendritic cells (DC) pulsed with melanoma-associated peptides (gp100 and tyrosinase) and keyhole limpet hemocyanin. RESULTS: After intradermal administration of a DTH challenge with gp100- and tyrosinase peptide-loaded DC, essentially all patients showed a positive induration. In clinically responding patients, T cells specific for the antigen preferentially accumulated in the DTH site, as visualized by in situ tetramer staining. Furthermore, significant numbers of functional gp100 and tyrosinase tetramer-positive T cells could be isolated from these DTH biopsies, in accordance with the applied antigen in the DTH challenge. We observed a direct correlation between the presence of DC vaccine-related T cells in the DTH biopsies of stage IV melanoma patients and a positive clinical outcome (P = .0012). CONCLUSION: These findings demonstrate the potency of this novel approach in the monitoring of vaccination studies in cancer patients.

Topical macrolide immunomodulators: a role in the treatment of vitiligo?

Recently, topical macrolide immunomodulators have been successfully introduced in the treatment of atopic dermatitis. With the growing interest in this new line of topical immunosuppressants, research into the efficacy of these medicines in other T-cell-mediated skin diseases, such as psoriasis, lichen planus, and even vitiligo, is expanding rapidly. It is generally accepted that autoimmune factors play an important role in vitiligo. In this article, the possible use and mechanism of topical macrolide immunomodulators in the treatment of vitiligo are discussed, together with the current state of clinical studies and case reports. These limited reports indicate that topical macrolide immunomodulators may play a role in the treatment of vitiligo, particularly in areas where use of potent corticosteroids is contraindicated.

Current and future treatment options for acne.

Acne is a frequent skin disease with abnormalities in the process of keratinization, sebaceous gland functioning and inflammation. In this review, our understanding of the pathogenesis of acne has been updated. An overview of efficacy and side effects of available anti-acne treatments is presented. Based on the present overview a recommendation for the treatment of various manifestations of acne is provided, also reconciling beneficial combinations of treatments. It is attractive to speculate that the increased insight into the pathogenesis of acne will create new treatment options. Challenging new options comprise blue light, photodynamic therapy, retinoic acid metabolism blocking agents and inhibitors of Th-1 cytokines.

The current role of in vivo reflectance confocal microscopy within the continuum of actinic keratosis and squamous cell carcinoma: a systematic review.

BACKGROUND: Clinical differentiation between actinic keratosis (AK), squamous cell carcinoma (SCC) in situ, and invasive SCC and its variants may be difficult. Reflectance confocal microscopy (RCM) is a non-invasive technique for in vivo skin imaging. OBJECTIVES: To explicate the diagnostic and monitoring use of RCM within the spectrum of AK and SCC, and evaluate the accuracy of RCM for these diagnoses relative to histopathology. MATERIALS & METHODS: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, and Web of Science databases. The quality was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. RESULTS: Twenty-five eligible studies were included. Different diagnostic RCM features have been described for AK, actinic cheilitis (AC), erythroplasia of Queyrat, Bowen disease, invasive SCC, and keratoacanthoma (KA). The overall range of sensitivity and specificity of RCM for the diagnosis of SCC, AK, SCC in situ, and KA was 79-100% and 78-100%, respectively. CONCLUSION: The current literature describes the use of RCM for diagnosing AK, AC, erythroplasia of Queyrat, Bowen disease, invasive SCC, and KA, as well as for monitoring treatments of AK, with good accuracy. Unfortunately, studies with high methodological quality are lacking. Pre-treatment of hyperkeratotic lesions and uniform definitions of RCM features are required to simplify the differentiation between AKs, SCC in situ, and SCC and its variants in clinical practice.

Diagnosis of Basal Cell Carcinoma by Reflectance Confocal Microscopy: Study Design and Protocol of a Randomized Controlled Multicenter Trial.

BACKGROUND: Skin cancer, including basal cell carcinoma (BCC), has become a major health care problem. The limitations of a punch biopsy (at present the gold standard) as diagnostic method together with the increasing incidence of skin cancer point out the need for more accurate, cost-effective, and patient friendly diagnostic tools. In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has great potential for skin cancer diagnosis. OBJECTIVE: To investigate whether in vivo RCM can correctly identify the subtype of BCC and to determine the cost-effectiveness of RCM compared with punch biopsy (usual care). STUDY DESIGN: Randomized controlled multicenter trial. METHODS: On the basis of 80% power and an alpha of 0.05, 329 patients with lesions clinically suspicious for BCC will be included in this study. Patients will be randomized for RCM or for a punch biopsy (usual care). When a BCC is diagnosed, surgical excision will follow and a follow-up visit will be planned 3 months later. Several questionnaires will be filled in (EQ-5D, EQ-5D VAS, iMTA PCQ, and TSQM-9). We will perform statistical analysis, cost-effectiveness, and patient outcome analysis after data collection. RESULTS: This research started in January 2016 and is ethically approved. We expect to finish this study at the end of 2018. CONCLUSIONS: In this study, we will investigate whether RCM is at least as good in identifying BCC subtypes as conventional pathological investigation of skin biopsies. Anticipating that RCM is found to be a cost-effective alternative, it saves on direct medical consumption like labor of the pathologist and other medical personnel as well as materials related to treatment failure with at least equal effectiveness. TRIAL REGISTRATION: Clinicaltrials.gov NCT02623101; https://clinicaltrials.gov/ct2/show/NCT02623101 (Archived by WebCite at http://www.webcitation.org/6id54WQa2).

Correlation between macroscopic fluorescence and protoporphyrin IX content in psoriasis and actinic keratosis following application of aminolevulinic acid.

In fluorescence diagnosis with 5-aminolevulinic acid (ALA)-induced porphyrins (FDAP), protoporphyrin IX (PpIX) accumulation can be macroscopically visualized. Interpretation of these data is still problematic because of the low reproducibility of the procedure and poor understanding of the mechanisms involved in PpIX tumor selectivity. In this study, PpIX accumulation is investigated in patients with psoriasis and actinic keratosis (AK) following FDAP. For this purpose, desquamated lesional and non-lesional skin were incubated with 20% ALA ointment for 3 h, FDAP was performed, and highly fluorescing lesional skin and non-lesional skin were biopsied. In extracts from these biopsies, PpIX, protein, and dsDNA were quantified by spectrofluorometry. Digital images acquired with FDAP were analyzed using image analysis software. PpIX per biopsy in lesional skin in both psoriasis and AK was significantly higher than in non-lesional skin (p < 0.05). When corrected for epidermal involvement, only lesional psoriatic skin showed significantly higher PpIX levels than non-lesional skin. The PpIX-ratio lesional:non-lesional skin (mean(pmol per mL)+/-SEM) was 4.12+/-0.91 in psoriasis and 1.96+/-0.24 in AK. In FDAP, the ratio of lesional:non-lesional skin was 1.77+/-0.06 in psoriasis and 1.37+/-0.07 in AK. Macroscopic fluorescence and PpIX content appeared to be well correlated (r = 0.73), thus making FDAP a good predictor of PpIX content.