Results of a 10-year web-based health promotion campaign against skin cancer in Switzerland.

Skin cancer is the most common malignancy with rising incidence. Although early detection can be lifesaving, prevention programmes are under-utilized. In 2008, a group of board-certified dermatologists in Switzerland established a website aimed at educating about skin cancer risk factors and providing guidance on self-assessment. To present the data of this programme over the last 10 years with regards to representation of the targeted groups and sustained impact on primary skin cancer prevention. A comprehensive web-based health promotion campaign was established for education and guidance on self-assessment. Teledermatological evaluation was offered and participants were then interviewed. In total, 11,171 digital photos were evaluated during 2008-2018; 54.3% (n = 6,067) from females and 45.7% (n = 5,104) from males. In 26.7% (n = 2,983), clinical examination was recommended. Of the participants, 1,874 replied revealing 103 malignancies (9.2% of the lesions were presented to a physician): 34 melanomas in situ, six squamous cell carcinomas, 53 basal cell carcinomas and 10 malignant lesions (not further specified). Of the participants, 40.5% (n = 683) changed their attitude towards sun exposure, 48.7% (n = 820) used more sunscreen, and 57.5% (n = 966) improved sunscreen measures. Web-based educational programmes raise public awareness, enhance prevention, and support early diagnosis of skin cancer. Teledermatology might contribute to reducing skin cancer mortality rates.

Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis.

Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs), which may result in treatment discontinuation. We sought to describe the onset, frequency, and kinetics of irAEs in melanoma patients in a real-life setting and to further investigate the prognostic role of irAEs in treatment outcomes. In this retrospective single-center cohort study, we included 249 melanoma patients. Onset, grade, and resolution of irAEs and their treatment were analyzed. A total of 191 (74.6%) patients in the non-adjuvant and 65 (25.3%) in the adjuvant treatment setting were identified. In the non-adjuvant setting, 29 patients (59.2%) with anti-CTLA4, 43 (58.1%) with anti-PD1, and 54 (79.4%) with anti-PD1/anti-CTLA4 experienced some grade of irAE and these had an improved outcome. In the adjuvant setting, the frequency of irAEs was 84.6% in anti-CTLA4 and 63.5% in anti-PD1, but no correlation with disease relapse was observed. Patients with underlying autoimmune conditions have a risk of disease exacerbation. Immunomodulatory agents had no impact on treatment efficacy. IrAEs are correlated with increased treatment efficacy in the non-adjuvant setting. Application of steroids and immunomodulatory agents, such as anti-TNF-alpha or anti-IL6, did not affect ICI efficacy. These data support irAEs as possible prognostic markers for ICI treatment.

Ectopic axillary breast cancer in a male patient.

Ectopic breast tissue can persist in the axilla due to lack of involution of mammary glands along the mammary lines. It is rare in men, and the malignant transformation to breast cancer has occasionally been described. Differential diagnosis of any axillary tumor should include breast cancer arising at ectopic sites.

Retrospective Analysis of Treatment and Complications of Immune Checkpoint Inhibitor-Associated Colitis: Histological Ulcerations as Potential Predictor for a Steroid-Refractory Disease Course.

BACKGROUND/AIMS: Among the severe immune-related adverse events (irAEs) that occur with immune checkpoint inhibitor (ICI) therapy, colitis is the most frequent one. This study aimed at describing the experience from the largest gastroenterology unit in Switzerland with immune checkpoint inhibitor-associated colitis (ICIAC), its clinical presentation, management, and outcomes. METHODS: We performed a retrospective review of patients who were referred for the evaluation of ICIAC between January 2011 and October 2018 to the Division of Gastroenterology and Hepatology, University Hospital Zurich. RESULTS: Thirty-three patients with immune-related colitis grade 3 or 4 met the inclusion criteria and were analyzed in detail: All patients had diarrhea, 64% had abdominal pain, 42% had bloody stool, 27% had emesis, and 18% developed fever. In total, 33% were successfully treated with corticosteroids alone; 66% were steroid-refractory and treated with infliximab or vedolizumab. Two of these patients developed severe complications requiring surgery. All patients reached complete remission of ICIAC and its symptoms. At colonoscopy, ulcerations were seen in 37% of steroid-refractory versus 63% of steroid-responsive cases. Deep histological ulcerations invading the submucosa were only present in steroid-refractory cases. CONCLUSION: ICIAC is a severe irAE which frequently requires high-dose steroids and a close follow-up due to deleterious complications. The detection of histologically diagnosed deep ulcerations may predict a steroid-refractory course and may warrant early application of infliximab. However, larger studies are required to confirm our findings.

How I treat metastatic melanoma.

Tremendous progress in basic and clinical research has completely revolutionised the management of advanced melanoma, and this dramatic development is still ongoing. In this environment, state-of-the-art patient care is a major challenge. We describe how patient-centred medicine is organised in a leading referral centre that is also involved in early and late clinical trials and is part of a worldwide network for translational research.

Single-center real-life experience with low-dose ipilimumab monotherapy in adjuvant setting for patients with stage III melanoma.

Ipilimumab is approved for adjuvant melanoma treatment at a dose of 10 mg/kg, but its use is limited owing to high toxicity and treatment-associated costs. We retrospectively analyzed 29 patients who underwent complete resection of stage IIC-III melanoma and were treated with ipilimumab 3 mg/kg in an adjuvant setting. The aim was to assess development of adverse events (primary endpoint) and to evaluate survival outcomes (secondary endpoint) under adjuvant treatment with ipilimumab in a real-life setting. Immune-related adverse events (irAE) of all grades were reported in 72.4% of patients, grade 3 in 5.3% (n = 2), and none for grade 4 or 5. Immune-related hypophysitis resolved in 3/8 (37.5%) and immune-related thyroiditis in 7/10 (70%) cases, whereas the others remained on substitution drugs. The rest irAEs affected the gut (n = 8), skin (n = 5), liver (n = 2), and uvea (n = 2) and resolved completely. Only one patient required tumor necrosis factor-α owing to grade 3 colitis. Hospitalization was required in five cases owing to irAE (four colitis and one hypophysitis). At a median follow-up of 9.7 (1.7-16.8) months, 65.5% of the patients were free of disease. Median progression-free survival was 15.1 months, and median overall survival was not reached yet. Ipilimumab 3 mg/kg for the adjuvant treatment of high-risk patients with fully resected melanoma favors a better safety profile compared with the approved dose of 10 mg/kg in the same setting. Although its limited application owing lately promising data of antiprogrammed cell death protein-1 treatment, it may be considered as additional option or second-line treatment after fully resected disease recurrence under antiprogrammed cell death protein-1 treatment.

The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe.

PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments.

A Prospective Trial Comparing Q-Switched Ruby Laser and a Triple Combination Skin-Lightening Cream in the Treatment of Solar Lentigines.

BACKGROUND: Quality-switched (QS) laser therapy is a safe and well-established treatment option for removing solar lentigines. Triple combination therapy (TCT) with the active pharmaceutical ingredients hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03% is often used for skin-lightening. OBJECTIVE: This prospective, open-label trial compares the efficacy and safety of a QS Ruby laser (QSRL) and a TCT in the treatment of solar lentigines. METHODS: In total, 15 patients with symmetrically distributed solar lentigines on the back of both hands were included. The lesions on the back of the right hand were treated in one or 2 sessions with a QSRL, the ones on the back of the left hand with a TCT for 7 weeks accompanied by UV protection. Clinical results were evaluated 4 weeks, 8 weeks, and 20 weeks after baseline. RESULTS: Treatment with QSRL provided significant lightening (p = .01) compared with TCT. Both procedures were generally well-tolerated. Comparing the side effects, the laser produced significantly more crusting and hyperpigmentation than the TCT. CONCLUSION: Both QSRL and TCT were capable in reducing solar lentigines in Fitzpatrick skin Type I to IV with an acceptable side effect profile. The QSRL provides faster, superior, and long lasting lightening compared with TCT.

Topical Timolol for Infantile Hemangiomas: Evidence for Efficacy and Degree of Systemic Absorption.

BACKGROUND: Topical use of timolol for infantile hemangiomas has recently emerged with promising results. It is unknown whether topical ß-blockers act locally or if their effect is partly due to systemic absorption. This study investigates whether topically applied timolol is absorbed and reports on the efficacy of this treatment. METHODS: We treated 40 infants with small proliferating hemangiomas with topical timolol gel 0.5% twice daily and assessed urinary excretion and serum levels in a proportion of patients. Clinical response was evaluated on a visual analog scale of standardized photographs after 1, 2, 3, and 5 months. RESULTS: Forty infants with a median age of 18 weeks (range 2-35 wks) were included; 23 (58%) had superficial and 17 (42%) mixed-type hemangiomas. The median size was 3 cm(2) (range 0.1-15 cm(2) ) and nine hemangiomas were ulcerated. The hemangiomas improved significantly during treatment, with a median increase in visual analog scale of 7 points after 5 months (p < 0.001). Urinalysis for timolol was performed in 24 patients and was positive in 20 patients (83%). In three infants, serum levels of timolol were also measured and were all positive (median 0.16 ng/mL [range 0.1-0.18 ng/mL]). No significant side effects were recorded. CONCLUSION: Topical therapy with timolol is effective for infantile hemangiomas, but systemic absorption occurs. Serum levels in our patients were low, suggesting that using timolol for small hemangiomas is safe, but caution is advised when treating ulcerated or large hemangiomas, very young infants, or concomitantly using systemic propranolol.

In vivo profiling reveals immunomodulatory effects of sorafenib and dacarbazine on melanoma.

Sorafenib is a multi-kinase inhibitor used alone or in combination with dacarbazine to treat metastasized melanoma. Our study investigated the relationship between metabolic response assessed by PET-CT and global transcriptome changes during sorafenib and dacarbazine therapy in patients with advanced melanoma. We conducted an open-label, investigator-initiated study that enrolled 13 sorafenib-naïve Stage IV melanoma patients, whose metastases were accessible for repeated biopsies. Treatment regimen included orally administered sorafenib and intravenous dacarbazine. Biopsies of skin or superficial lymph node metastases were taken before treatment (baseline), during sorafenib and after dacarbazine therapy and used for transcriptional profiling and validation experiments. Serum samples were evaluated for cytokine production. Metabolic response to therapy was observed in 45.5% of patients. The study drugs were well tolerated. We observed a clear upregulation of interferon (IFN)-stimulated immune response genes in profiled metastases. The IFNγ-induced gene signature seemed to be enhanced after addition of dacarbazine to sorafenib. Serum IFNγ also increased during therapy, particularly after addition of dacarbazine. Induction of IFNγ stimulated genes correlating with increased serum IFNγ was predictive of better clinical outcome and responders who had significantly higher serum IFNγ levels lived longer. Our data reveal in situ changes in melanoma metastases during treatment with sorafenib and dacarbazine and suggest an additional mechanism of action through immunomodulation.

Coexpression of SOX10/CD271 (p75(NTR)) and ß-Galactosidase in Large to Giant Congenital Melanocytic Nevi of Pediatric Patients.

BACKGROUND: Congenital melanocytic nevi (CMNs) are melanocytic neoplasms that can transform into melanoma. However, this development is impeded in the majority of cases and mostly affects patients with large or giant CMNs. METHODS: To elucidate mechanisms that keep CMNs from malignant transformation, CMN tissue biopsies were investigated for p-ERK and senescence markers by immunohistochemistry and for SOX10/CD271 (p75(NTR)) by immunofluorescence. CMN cells were cultivated, and MTT assays were performed for evaluating cell viability. Mutation status for NRAS and BRAF was performed by real-time PCR. RESULTS: 13 CMNs (from patients aged 0.5-11.8 years, mean: 2.7) showed immunoreactivity for SOX10/CD271 (p75(NTR)) in 34.2%. p-ERK was immunoreactive in 80% (4/5); ß-galactosidase was significantly stronger expressed in CMNs compared to melanocytic nevi of patients over 70 years (p = 0.0085). The 5 CMN cultures were immunoreactive for SOX10/CD271 (p75(NTR)) in 36.7%. By silencing SOX10 by siRNA in 2 CMN cell cultures, cell viability decreased significantly. NRAS(Q61K) mutation was found in 91.7% (11/12) and BRAF(V600E) in 6.3% of all analyzable CMNs (1/16). CONCLUSIONS: Oncogene-induced senescence might prevent malignant transformation through activation of the mitogen-activated protein kinase pathway. SOX10 is necessary for the viability of human CMN cell cultures and may be responsible for clinical changes during aging.

Management of split-thickness skin graft donor sites: a randomized controlled trial of calcium alginate versus polyurethane film dressing.

BACKGROUND: Split-thickness skin graft (STSG) donor sites sometimes cause more postoperative morbidity for patients than the wound covered with the graft. Yet, there is no consensus on which dressings are best suited to treat these donor sites. OBJECTIVE: To evaluate two commonly used modern wound dressings in the postoperative healing of STSG donor sites in a prospective randomized controlled trial. METHODS: 38 patients were randomly assigned to treatment of an STSG donor site with an alginate dressing or a polyurethane film dressing. The primary outcome measures were postoperative pain scores, secondary outcome variables were time to epithelialization, dressing changes and complications. RESULTS: Postoperative pain on day 1 was significantly lower in the polyurethane film group (2.05 vs. 0.79, p = 0.035) as compared to the alginate group. This difference was not detected on day 5 (0.89 vs. 0.53, p = 0.52). Time to epithelialization did not differ significantly between the two dressing groups. There were more dressing changes in the polyurethane film group and problems with leakage. CONCLUSION: Whereas film dressings resulted in initially lower pain scores, alginate dressings caused fewer additional dressing changes and less leakage.

Phototherapy with UVB narrowband, UVA/UVBnb, and UVA1 differentially impacts serum 25-hydroxyvitamin-D3.

BACKGROUND: Ultraviolet (UV) B radiation increases serum 25-hydroxyvitamin-D3 [25(OH)D], but the influence of UVA1 and UVA/narrowband UVB (UVBnb) phototherapy on serum vitamin D is unknown. OBJECTIVE: We sought to investigate the influence of UVBnb, UVA1, and UVA/UVBnb phototherapy on serum levels of 25(OH)D and related parameters in patients with an inflammatory skin condition. METHODS: 25(OH)D, as well as calcium, parathormone, phosphate, and albumin were measured before therapy, 2 weeks after start, and after completion of the phototherapy. Diagnoses were divided in 4 groups: atopic dermatitis, psoriasis, morphea, and others. RESULTS: We surveyed 116 dermatologic patients undergoing phototherapy with UVA1 (n = 38), UVA/UVBnb (n = 30), or UVBnb (n = 48) 2 to 3 times a week for 53 to 90 days. UVBnb phototherapy increased serum 25(OH)D from 22.1 to 39.5 ng/mL after the therapy (P < .001). The lower the baseline 25(OH)D level was, the steeper the increase in 25(OH)D was upon application of UVBnb phototherapy. UVA/UVBnb therapy also increased serum 25(OH)D, from 23.9 to 50.3 ng/mL (P = .003). Conversely, in the UVA1 therapy group, 25(OH)D serum levels decreased significantly from 21.9 to 19.0 ng/mL (P < .001). LIMITATIONS: The study design was open trial without randomization. An influence of a precise skin disease cannot be excluded because of the heterogeneous diagnoses. Bias may have arisen from patient preference for treatment at our center, referral, unrecognized differences in underlying skin disease, and other factors. CONCLUSION: Phototherapy with UVBnb and UVA/UVBnb increased 25(OH)D serum level significantly. UVA1 therapy alone induced a reduction in serum 25(OH)D concentrations.

Dermatofibrosarcoma protuberans in childhood treated with slow Mohs micrographic surgery.

Dermatofibrosarcoma protuberans (DFSP) in childhood is a rare tumor with high recurrence rates. Wide local excision can result in disfiguring mutilation, whereas Mohs micrographic surgery (MMS) reduces surgical margins. MMS in children is not performed routinely, as the required infrastructures such as a histopathology lab in close proximity to the operating room is often lacking. We retrospectively reviewed children diagnosed with DFSP treated at our hospital over 2 years. We recorded surgical treatment details, including margins, duration of inpatient stay, outcome, follow-up, and molecular genetic tumor tissue analysis. Four children with a median age of 6.8 years (range 6.0-8.8 years) were identified who had a diagnostic delay of a median of 2.5 years (range 0.5-4.0 years); all underwent complete tumor excision using the slow MMS technique using vacuum-assisted closure systems between repeated excisions and before wound closure. The median maximal safety margins were 1.5 cm (range 1.0-3.0 cm). By using vacuum-assisted closure systems, no dressing changes were needed, pain was limited, and full mobility was maintained in all children. The median total time in the hospital was 11 days (range 10-14 days). No relapses occurred during a median follow-up of 25.8 months (range 11.3-32.6 months). Collagen 1A1/platelet-derived growth factor B (COL1A1/PDGFB) translocation on chromosomes 17 and 22 was detected in all three analyzable specimens. Lesions suspected of being DFSP warrant prompt histologic evaluation; interdisciplinary management is mandatory in particular for children. Micrographic surgery allows smaller surgical margins than wide excision and should be considered as the treatment of choice in children with DFSP. The interim usage of vacuum-assisted closure systems increases patient comfort. Translocations in the COL1A1/PDGFB gene imply susceptibility to targeted treatment modalities for therapy-resistant cases.

Long-term recurrence rate of large and difficult to treat cutaneous squamous cell carcinomas after superficial radiotherapy.

BACKGROUND: Surgical excision is the gold standard for cutaneous squamous cell carcinoma (cSCC), however its application is limited in specific cases. Superficial radiotherapy (RTx) is an alternative treatment option, but long-term follow-up data are limited. OBJECTIVE: To determine the outcome of superficial RTx of cSCC in correlation to histological differentiation grade and tumor localization. METHODS: The outcome of 180 large cSCCs after superficial RTx between 1960 and 2004 was retrospectively reviewed. RESULTS: Mean tumor size was 3.5 cm(2) (SD 7.5) and mean follow-up period was 4.9 years (SD 4.7). Relapse-free survival was 95.8 and 80.4% after 1 and 10 years. Two-year relapse-free survival was 94.8% for good, 88.9% for moderate and 85.7% for poor differentiated tumors. Five-year relapse-free survival was highest in cSCCs located around the eyes (100%) and cheeks (90.9%). CONCLUSION: Superficial RTx is an effective alternative for cSCC if surgery is difficult due to localization or concomitant disease.

Intense pulsed light.

In addition to lasers, intense pulsed light (IPL) sources are widely used in medicine to treat various indications, such as vascular lesions, irregular pigmentation and hypertrichosis. In contrast to lasers, IPL systems are broadband flash lamps that emit polychromatic incoherent light ranging from visible to infrared (500-1,300 nm). Optical filters are used to tailor the polychromatic light to specific needs. As a broad range of wavelengths are delivered, treatment of multiple chromophores--including melanin, hemoglobin, water and collagen--within the same exposure is possible.

Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions.

We have investigated the staining patterns of primary and metastatic melanoma lesions using F8, L19 and F16. These three clinical-stage antibodies are currently being studied in clinical trials for the pharmacodelivery of cytokines or therapeutic radionuclides to neoplastic sites in patients with cancer. Frozen sections of 24 primary and 29 metastatic melanoma lesions were stained, using immunofluorescence procedures, with biotinylated preparations of the F8, L19 and F16 antibodies, which are specific to the alternatively spliced extra domain A and extra domain B domains of fibronectin and A1 domain of tenascin-C, respectively. Blood vessels were costained using von Willebrand factor-specific antibodies. In primary cutaneous melanoma lesions, F16 and F8 (but not L19) strongly stained the basal lamina at the interface between epidermis and dermis, with a strikingly complementary pattern. By contrast, metastatic melanoma lesions displayed a strong and diffuse pattern of immunoreactivity with all three antibodies. It was found that the extracellular matrix in melanoma undergoes extensive remodelling during the transition from primary to metastatic lesions. The intense staining of metastatic melanoma lesions by the F8, L19 and F16 antibodies provides a strong rationale for the use of these antibodies and their derivatives for the treatment of melanoma patients and possibly for the personalized choice of the best performing antibody in individual patients.

Facial blaschkitis: case and review.

We report on a 15-year-old female with a 3-month history of a pruritic, erythematous cutaneous eruption on the right cheek and perioral area. The lesion had a linear distribution following the lines of Blaschko. Histopathological findings and direct immunofluorescence were compatible with chronic cutaneous lupus erythematosus (LE). Treatment with topical steroids and systemic antimalarial agents over 2 months showed hardly any improvement contrary to similar cases reported in the literature in the past. Histological findings move this case close to LE. However, the unusual clinical presentation as well as the resistance to antimalarial drugs do not fully allow to confirm this suspicion. Therefore, we recommend to call this new entity LE-like facial Blaschkitis of the adult.

Spitzoid melanoma and micrometastases in two lymph node regions: a critical situation.

Atypical Spitz tumors can hardly be differentiated from spitzoid melanoma. CGH might help in the differential diagnosis. An 8 year old child with an atypical Spitz tumor (with a CGH pattern compatible with melanoma) of 8.0 mm Breslow thickness and micrometastases in two lymph node regions was seen at our department. The management and prognosis of atypical Spitz tumors is controversial, and aggressive procedural steps similar to melanoma are usually not recommended. Even performing sentinel lymph node biopsy has been questioned. After extensive interdisciplinary consultations, we did not recommend resection of both lymph node regions and chose instead to follow-up with regular whole-body MRI and adjuvant treatment with pegylated interferon. Treatment decisions for atypical Spitz tumors are a major medical and ethical challenge due to the limited available data.

Cancer-testis antigens and immunosurveillance in human cutaneous squamous cell and basal cell carcinomas.

PURPOSE: Nonmelanoma skin cancer is the most common cancer and comprises basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The incidence of SCC increases drastically in immunosuppressed individuals, suggesting a critical role of the immune system in controlling SCC. To find an explanation for the selective immunosurveillance of SCC, we investigated the expression of cancer-testis (CT) antigens and MHC class I (MHC-I) and the infiltration by immune cells in BCC and SCC. EXPERIMENTAL DESIGN: We determined the expression of 23 different CT-antigens in 63 BCC and 40 SCC biopsies of immunocompetent and in 20 biopsies of immunosuppressed SCC patients by reverse transcription-PCR and immunohistochemistry. IgG responses to 36 tumor antigens were measured by Western blotting and ELISA. MHC-I expression and CD8(+) T-cell infiltration were analyzed by immunohistochemistry in BCC and SCC of immunocompetent and immunosuppressed patients and in imiquimod-treated BCC patients. RESULTS: We found expression of at least one CT-antigen in 81% of BCC and in 40% of SCC. We did not detect CT-antigen-specific serum IgG. Most SCC, but not BCC, expressed MHC-I and were infiltrated with CD8(+) cells. Imiquimod-treated BCC expressed MHC-I and were infiltrated by CD8(+) T cells. CONCLUSIONS: We propose that immunosurveillance controls SCC, but not BCC, because the latter lacks MHC-I. This fits with the increased incidence of SCC in immunosuppressed individuals and may explain the relatively low prevalence of CT-antigen expression in SCC as a result of CD8(+) T-cell-driven immunoediting.