Mechanism of Indirect Photon-Induced Desorption at the Water Ice Surface.

Electronic excitations near the surface of water ice lead to the desorption of adsorbed molecules, through a so far debated mechanism. A systematic study of photon-induced indirect desorption, revealed by the spectral dependence of the desorption (7-13 eV), is conducted for Ar, Kr, N_{2}, and CO adsorbed on H_{2}O or D_{2}O amorphous ices. The mass and isotopic dependence and the increase of intrinsic desorption efficiency with photon energy all point to a mechanism of desorption induced by collisions between adsorbates and energetic H/D atoms, produced by photodissociation of water. This constitutes a direct and unambiguous experimental demonstration of the mechanism of indirect desorption of weakly adsorbed species on water ice, and sheds new light on the possibility of this mechanism in other systems. It also has implications for the description of photon-induced desorption in astrochemical models.

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.

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.

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).

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.

Dermatologic care of institutionalized elderly patients: a survey among dermatologists in the Netherlands.

BACKGROUND: dermatologists are expected to be increasingly confronted with institutionalized elderly patients, due to the rapidly ageing world population. OBJECTIVES: to determine the proportion of dermatologists visiting patients in nursing homes, together with the reasons for consultation, barriers to perform these visits and diagnostic and treatment patterns. MATERIALS & METHODS: a web-based questionnaire regarding dermatologic care in nursing home patients was developed by a multidisciplinary group of dermatologists, residents and elderly care physicians. A cover letter containing a link to the final questionnaire was sent by e-mail to all 661 dermatologists and dermatology residents in the Netherlands. RESULTS: a total of 130 eligible questionnaires were returned (19.7%). Most respondents (79.2%) never had contact with an elderly care physician concerning a nursing home patient. However, only 30.0% of the respondents ever visited a patient within a nursing home. The most common reasons for nursing home visits were cutaneous (pre)malignancies (51.4%), eczema/dermatitis (25.7%) and (pressure) ulcers (8.6%). The most important barriers mentioned to perform nursing home visits were a lack of time and indistinct and/or inadequate financial compensation. Diagnostic and treatment patterns often differed from the outpatient clinic due to various patient-related and logistic factors. CONCLUSION: dermatologists are frequently confronted with nursing home patients but only a minority visits patients within nursing homes. Lack of time and/or financial compensation seem important barriers.

Current Dermatologic Care in Dutch Nursing Homes and Possible Improvements: A Nationwide Survey.

OBJECTIVES: To assess the provision and need of dermatologic care among Dutch nursing home patients and to obtain recommendations for improvement. DESIGN: Cross-sectional nationwide survey. SETTING: All 173 nursing home organizations in the Netherlands. PARTICIPANTS: Physicians working in nursing homes. MEASUREMENTS: Web-based questionnaire concerning the burden of skin diseases in nursing home patients, diagnostic procedures and therapy, collaboration with dermatologists, physicians' level of education, and suggestions for improvement. RESULTS: A total of 126 (72.8%) nursing home organizations, with 1133 associated physicians participated in our study and received the questionnaire. A total of 347 physicians (30.6%) completed the questionnaire. Almost all respondents (99.4%) were recently confronted with skin diseases, mostly (pressure) ulcers, eczema, and fungal infections. Diagnostic and treatment options were limited because of a lack of availability and experience of the physicians. More live consultation of dermatologists was suggested as being important to improve dermatologic care. Other suggestions were better education, more usage of telemedicine applications, and better availability of diagnostic and/or treatment procedures like cryotherapy. CONCLUSION: Physicians in nursing homes are frequently confronted with skin diseases. Several changes in organization of care and education are expected to improve dermatologic care in nursing home patients.

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.

In vivo Reflectance Confocal Microscopy: A Useful Tool to Select the Location of a Punch Biopsy in a Large, Clinically Indistinctive Lesion.

Reflectance confocal microscopy (RCM) is a noninvasive technique for in vivo imaging of the skin that allows evaluation of the total lesion area. This case report about a 66-year-old patient with a clinically indistinctive, previously treated erythematous lesion on the frontal part of the face demonstrates the use of RCM to select the proper biopsy location.

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.

In situ expression of tumor antigens by messenger RNA-electroporated dendritic cells in lymph nodes of melanoma patients.

Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) for cancer immunotherapy has been proved efficient and clinically safe. It obviates prior knowledge of CTL and Th epitopes in the antigen and leads to the presentation of multiple epitopes for several HLA alleles. Here we studied the migration capacity and the antigen expression of mRNA-electroporated DC (mRNA-DC) in lymph nodes after vaccination in melanoma patients. DC were electroporated with mRNA encoding gp100 or tyrosinase, labeled with indium-111 and superparamagnetic iron oxide particles, and injected intranodally in melanoma patients 24 to 48 hours before scheduled dissection of regional lymph nodes. Immunohistochemical analysis of the lymph nodes after surgery revealed that mRNA-DC migrated from the injection site into the T-cell areas of the same and subsequent lymph nodes, where they expressed the antigen encoded by the electroporated mRNA. Furthermore, vaccine-related CD8(+) T-cell responses could be detected in 7 of 11 patients vaccinated with mRNA-DC. Together these data show that mature DC electroporated with mRNA encoding TAA migrate and express antigens in the lymph nodes and induce specific immune responses.