Mobile health technologies in an interventional hybrid study on actinic keratosis: Results from an early phase randomized controlled trial investigating the safety and efficacy of a cytosolic phospholipase A2 inhibitor gel in photodamaged skin.

Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0-5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0-4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety.

Diagnostic flow of patients in a national fast-track referral system for malignant melanoma.

INTRODUCTION. Timely diagnosis of malignant melanoma (MM) is crucial for optimal patient outcomes. Thus, the Danish Health Authority implemented a fast-track referral system (FTRS) comprising a clinical diagnostic filter function (CDFF) and a cancer package. This study aimed to characterise the flow of patients with a tentative MM diagnosis referred through the CDFF to a department of dermatology. METHODS. Retrospective data from the Danish patient and pathology file system were analysed for patients referred to the Department of Dermato-Venereology at Bispebjerg Hospital, Denmark, via the CDFF, with suspected MM in a one-year period. RESULTS. Among 860 patients with 895 skin lesions, 283 (31.6%) were discharged with a clinical benign diagnosis after their initial consultation, whereas treatment of another 77 (8.6%) patients concluded following a three-month observation period. One-year follow-up of these 360 (283 + 77) clinically benign skin lesions showed no malignancy. Among 100 MM-suspicious lesions promptly referred for excision to a department of plastic surgery, 48% were MM. CONCLUSIONS. In a Danish population with tentative MM diagnosis referred through the CDFF to a dermatological hospital department, one-third of patients were discharged with a clinically benign diagnosis. Half of the skin lesions referred for excision to the department of plastic surgery were MM. This indicates a decreased burden of overdiagnosis and a potential reduction of unnecessary surgical scars when dermatologists serve as gate keepers of the FTRS for MM. FUNDING. None TRIAL REGISTRATION. Data obtained with permission from BBH j. no. 20078406.

Feasibility of Intratumoral Anti-PD1 as Treatment of Human Basal Cell Carcinoma: An Explorative Study with Adjuvant Ablative Fractional Laser.

The use of immune checkpoint inhibitors (ICI) is expanding with the approval for advanced/metastatic keratinocyte carcinoma; however, most tumors are non-aggressive. Local administration could broaden ICI, but adequate immune response might require an immune-attractive adjuvant such as ablative fractional laser (AFL). Accordingly, this study aimed to explore intratumoral injection of anti-PD1 with and without AFL in basal cell carcinoma (BCC), exploring anti-PD1 concentration, immune cell infiltration, tumor response, and safety. This open-label, proof-of-concept trial investigated intratumoral anti-PD1 + AFL combination therapy versus anti-PD1 or AFL monotherapy in 28 BCC patients. The primary endpoints were immune cell infiltration evaluated immunohistochemically and clinical tumor response after 3 months. The secondary outcomes were tumoral drug concentration and safety. The most robust response was obtained following intervention with combined anti-PD1+AFL, leading to a ~2.5-fold increase in CD3+ cells (p = 0.027), and tumor reduction ≥25% in 73%, including two tumors with complete remission. Upon anti-PD1 monotherapy, a slight decrease in CD3+ cells was observed while a non-significant increase following AFL was seen. Tumor reduction ≥25% was seen in 45% and 50%, respectively, after anti-PD1 and AFL monotherapy. The CD8/CD3 ratio remained unchanged after anti-PD1+AFL and anti-PD1 monotherapy, while AFL led to a decreased ratio. A non-significant decline in the Foxp3/CD3 ratio was observed for all groups. Side-effects were mild with no systemic drug concentration detected. Intratumoral anti-PD1 injection is feasible, and a single exposure to locally injected anti-PD1 with adjuvant AFL increased immune cell infiltration and reduction in BCC with limited side-effects.

Laser Immunotherapy: A Potential Treatment Modality for Keratinocyte Carcinoma.

The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT.

Risk of skin cancer in patients with HIV: A Danish nationwide cohort study.

BACKGROUND: The risk of skin cancer in patients with HIV has not been extensively studied. OBJECTIVE: We sought to determine the risk of skin cancer in patients with HIV and compare it with the risk in the background population. METHODS: In a matched, nationwide, population-based cohort study, we compared the risk of skin cancer in 4280 patients with HIV from the Danish HIV cohort study with a background population cohort, according to the level of immunosuppression and route of transmission. Primary outcomes were time to first basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or malignant melanoma. RESULTS: Patients with HIV had an increased risk of BCC and SCC with incident rate ratios of 1.79 (95% confidence interval 1.43-2.22) and 5.40 (95% confidence interval 3.07-9.52), respectively, compared with the background population. We observed no increased risk of malignant melanoma. Low nadir CD4 cell count was associated with an increased risk of SCC. The increased risk of BCC among patients with HIV was restricted to men who had sex with men. LIMITATIONS: This study was observational and included a small number of patients with melanoma. CONCLUSION: Patients with HIV have an increased risk of BCC and SCC. Low nadir, but not current, CD4 cell count as a marker of immunosuppression was associated with an increased risk of SCC.

Correction to: Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin.

After publication of the original article [1] it was identified that order of the author list had been presented incorrectly. The author Robert Gniadecki's surname was also incorrect in the original article.

Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin.

BACKGROUND: Cutaneous basal cell carcinoma (BCC) is the commonest cancer worldwide. BCC is locally invasive and the surrounding stromal microenvironment is pivotal for tumourigenesis. Cancer associated fibroblasts (CAFs) in the microenvironment are essential for tumour growth in a variety of neoplasms but their role in BCC is poorly understood. METHODS: Material included facial BCC and control skin from the peritumoural area and from the buttocks. With next-generation sequencing (NGS) we compared mRNA expression between BCC and peritumoural skin. qRT-PCR, immunohistochemical and immunofluorescent staining were performed to validate the NGS results and to investigate CAF-related cyto-and chemokines. RESULTS: NGS revealed upregulation of 65 genes in BCC coding for extracellular matrix components pointing at CAF-related matrix remodeling. qRT-PCR showed increased mRNA expression of CAF markers FAP-α, PDGFR-ß and prolyl-4-hydroxylase in BCC. Peritumoural skin (but not buttock skin) also exhibited high expression of PDGFR-ß and prolyl-4-hydroxylase but not FAP-α. We found a similar pattern for the CAF-associated chemokines CCL17, CCL18, CCL22, CCL25, CXCL12 and IL6 with high expression in BCC and peritumoural skin but absence in buttock skin. Immunofluorescence revealed correlation between FAP-α and PDGFR-ß and CXCL12 and CCL17. CONCLUSION: Matrix remodeling is the most prominent molecular feature of BCC. CAFs are present within BCC stroma and associated with increased expression of chemokines involved in tumour progression and immunosuppression (CXCL12, CCL17). Fibroblasts from chronically sun-exposed skin near tumours show gene expression patterns resembling that of CAFs, indicating that stromal fibroblasts in cancer-free surgical BCC margins exhibit a tumour promoting phenotype.

Local immune response in cutaneous basal cell carcinoma.

BCC is an immunogenic tumor highlighted by the increased risk in immunosuppressed individuals and the frequent occurrence of tumor infiltrating lymphocytes (TILs) in the tumor surroundings. Immunotherapy is evolving as a promising treatment strategy for several cancer types where topical immunostimulators are among the possibilities for superficial BCC. The overall aim of this thesis is to characterize the immunologic response upon BCC as well as characterizing the surrounding tumor stroma. The aim was achieved by the use of a variety of laboratory techniques; immunohistochemistry, immunoflourescence, qRT-PCR and NGS. Tumor microenvironment: T-regs are a subpopulation of the CD4 positive T-cells normally comprising around 5-10% of the peripheral T-cells and up to 20% of the skin resident T-cells. In the healthy individual they are crucial in hindering autoimmune diseases whereas the role in cancer is less advantageous with association to tumor progression for a variety of cancer types. By investigating the presence of T-regs in BCC by immunohistochemistry in study I, it was found that T-regs comprised 45% in mean of the total CD4 positive cells in BCC. The increased T-reg concentration was confirmed with qRT-PCR showing increased Foxp3 expression levels in BCC as well as in the peritumoral skin. In the normal non-UV exposed buttock skin, no Foxp3 expression was found. Hence, T-regs seem to play a role both in BCC but also in the tumor surroundings. Tumor surroundings are essential in terms of the ability for a tumor to grow. Apart from interaction between immune and cancer cells, also crosstalk with cells of the connective tissue such as CAFs is essential. In study II, NGS revealed increased expression of the CAF-markers P4H and PDGFR-ß in BCC. Subsequent qRT-PCR confirmed this and also showed increased expression in the peritumoral skin whereas no expression was found in the normal buttock skin. FAP-α expression was seen only within BCC. CAFs are thus highly present within BCC and we further hypothesize that fibroblasts in the peritumoral skin acquire a phenotype intermediate between normal fibroblasts and CAFs in BCC. This intermediate phenotype might be induced by chronic UV-exposure mediated by increased IL6 expression. This corresponds to our findings of highly increased IL6 expression primarily in the peritumoral skin and to previous literature describing CAF-induced tumor-promoting IL6 expression upon UV-exposure in cutaneous SCC. Recruitment of TILs to BCC: mRNA expression levels of the chemokines CCL17, CCL18, CCL22 and CXCL12, involved in T-reg attraction to tumor sites were increased both in tumor and peritumoral skin with lack of expression in the normal skin. Correlation between the chemokines CCL17 and CXCL12 and CAF markers was found by IF establishing a role for CAFs in attracting T-regs to tumor sites. Efficient immunologic anti-tumor response could be provided by clonal expansion of T-cells directed against tumor-antigens. If this was the case, then restricted TCR-repertoire in BCC compared with surrounding skin would be seen. Analysis of the α and ß- chain of the TCR was performed showing a high diversity of TCR repertoire in BCC and lack of predominant V(D)J-gene usage, no preferential VJ pairing or specific CDR3 length distribution. Therefore, no support of antigen-driven clone selection was found. This corresponds with lack of obvious anti-tumor skewing towards a Th1, Th2 or Th17 polarization. CONCLUSION: To summarize it has been shown, with these studies on the local immune response upon BCC development, that an immunologic response is generated in line with BCC being an immunogenic tumor. This response is not specific, though. Additionally, BCC is capable of generating a protective niche in the microenvironment composed of both T-regs and CAFs breeding local immunosuppression and hindering of adequate anti-tumor response. In a clinical perspective, further research in improving immunotherapy for BCC is promising since an immunological response is present but needs to be reactivated.

[Mohs surgery for basal cell carcinoma].

Micrographic surgery is currently the only technique which ensures complete removal of basal cell carcinomas. The major limitation is the high set-up cost, which is particularly connected with specialized training of surgeons, technicians and the set-up of a histology facility for frozen tissue sectioning and staining. In the long run, however, the cost of Mohs surgery per patient does not exceed that of conventional surgery. The technique is very safe and has multiple advantages over any other treatment modality. It achieves the highest cure rates, it is minimally invasive, it is tissue-sparing and it enables the optimal closure of the surgical defect. Mohs surgery is cost-effective, especially when dealing with poorly demarcated, high-risk, facial tumours, where it should be considered as the first choice of treatment.

[Dermatological laser- and light treatments of scars].

Many patients struggle with tender, rigid and erythematous scars. Various modalities are used to treat cutaneous scars and in recent years, laser treatments are emerging as promising procedures. This article describes laser systems used for scar treatment according to scar type, evaluates the highest available level of evidence from randomized controlled trials (RCTs) and introduces a guideline for laser treatment of scars. Twelve RCTs documented effect on acne, burn and surgical scars. It is recommended that laser- and light-based treatments are considered according to the scar type.

[Basal cell carcinoma surgery].

Basal cell carcinoma (BCC) is the most common type of cancer in humans. The lifetime risk of developing BCC is 30%. The scope of the treatment is total eradication of the tumour followed by preservation of functionality and optimal cosmetic results. The risk of recurrence after treatment is highest in the tumours with aggressive growth patterns, in tumours located in the facial H-zone and in recurrent tumours. The optimal treatment of high-risk BCCs is surgical excision or radiotherapy. Low-risk tumours may be treated with cryotherapy, curettage, photodynamic therapy or topical agents.

Skin Cancer Risk in Hematopoietic Stem-Cell Transplant Recipients Compared With Background Population and Renal Transplant Recipients: A Population-Based Cohort Study.

IMPORTANCE: While a high risk of nonmelanoma skin cancer is well recognized in solid-organ transplant recipients, the risk of skin cancer in hematopoietic stem-cell transplant (HSCT) recipients has not been extensively studied. OBJECTIVE: To determine the risk of cutaneous cancer in HSCT recipients and compare it with the risk in renal transplant recipients (RTRs) and individuals who have not received any transplant. DESIGN, SETTING, AND PARTICIPANTS: A nationwide population-based cohort study from the Danish National Hospital Register including 3302 patients who underwent HSCT (1007 allogeneic, 2295 autologous) from 1999 through 2014, 4789 RTRs from 1976 through 2014, and 10 age- and sex-matched nontransplanted individuals for each of the groups from the background population. Person-years at risk were calculated from the time of study inclusion until first cutaneous cancer. To compare the risk of skin cancer between transplant recipients and background population, we used a stratified proportional hazard regression model for hazard ratio (HR) estimations. By use of the cumulative incidence, we estimated 5- and 10-year risks of skin cancers. All RTR and HSCT recipients were treated and followed up in specialized hospital departments in Denmark (total population 5.7 million). MAIN OUTCOMES AND MEASURES: Primary outcomes were time to first appearance of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or malignant melanoma (MM) and comparative risk estimates of cutaneous cancers in HSCT recipients and RTRs. The hypothesis was tested during data collection. RESULTS: Allogeneic HSCT recipients had an increased risk of BCC, SCC, and MM, with respective HRs of 3.1 (95% CI, 1.9-5.2), 18.3 (95% CI, 4.1-81.8), and 5.5 (95% CI, 1.7-17.7) compared with the background population. Compared with RTRs, allogeneic HSCT recipients had a 3-fold higher risk of MM. The risk of BCC after allogeneic HSCT was seen only in patients conditioned with total-body irradiation (HR, 3.9 [95% CI, 2.6-6.8]). The risk of BCC was similar for allogeneic HSCT recipients and RTRs, while the risk of SCC was highest for RTRs. Autologous HSCT recipients had no increased risk of skin cancer. CONCLUSIONS AND RELEVANCE: Allogeneic HSCT recipients have an increased risk of BCC, SCC, and MM. Total-body irradiation was a major determinant for BCC. Our findings indicate the relevance of dermatologic follow-up in HSCT recipients.

Favourable results of Mohs micrographic surgery for basal cell carcinoma.

INTRODUCTION: Basal cell carcinoma (BCC) is the most common malignant neoplasm with an annual incidence approaching 200/100,000 person-years. Mohs micrographic surgery (MMS) is widely used in North America and in Europe for treatment of BCC. This technique ensures radical tumour removal, sparing of the surrounding healthy skin, and it also offers higher cure rates than standard tumour excision with a predefined margin of healthy skin. The superiority of MMS relies on the fact that the entire (100%) margin of the excised tissue is examined microscopically for residual tumour in contrast to the traditional histopathological examination, in which 2% of the margin is examined. METHODS: In Denmark, MMS was first introduced by us in 2012. In the present study, we retrospectively included all patients who underwent MMS from May 2012 to June 2015. RESULTS: A total of 231 patients with 263 BCC were included. The mean age was 66.1 years. The most common localisations were the forehead (31.3%), the nose (31.0%) and the cheek (14.7%). Primary BCC comprised 54.0%; the remaining cases were relapses, most frequently after curettage (36.9%), radiotherapy (18.9%) and photodynamic therapy (11.7%). MMS leads to 40% smaller skin defects than standard excisions with 4 or 6 mm margins. Closure of skin defects was achieved by side-to-side closure in 49% and by local flaps in 40%. There were no relapses during the observation time. The safety, cosmetic and functional outcome were excellent. CONCLUSIONS: We recommend that MMS be included in the Danish BCC treatment guidelines, especially for high-risk BCC in the face, in line with standard practice in Europe and the United States. FUNDING: none. TRIAL REGISTRATION: not relevant.

Psoriasis inversa: A separate identity or a variant of psoriasis vulgaris?

Psoriasis is a chronic skin disorder affecting approximately 2% of the European and American population. The most common form of psoriasis is the chronic plaque type. Inverse psoriasis, also named flexural or intertriginous psoriasis, is not considered a separate disease entity but rather a special site of involvement of plaque psoriasis, characterized by its localization to inverse/intertriginous/flexural body sites. We review current evidence and establish whether inverse psoriasis is a separate disease entity based on characteristics in terms of epidemiology, pathogenesis, clinical and histologic presentation, microbiology, and treatment.

Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients.

TL1A is a TNF-like cytokine which has been shown to co-stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF-α are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti-TNF-α blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large-scale studies are warranted to investigate TL1A as a biomarker.

The successful use of extracorporeal photopheresis in a 12-year-old patient with refractory epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita is a rare autoimmune bullous disease of the mucosa and skin characterized by the presence of anti-collagen VII antibodies at the dermoepidermal junction. Most patients respond to immunosuppressive or antiinflammatory agents, although patients whose condition is refractory to these therapies will require more aggressive treatment. We present a 12-year-old girl with refractory epidermolysis bullosa acquisita who responded to extracorporeal photopheresis.

Subtyping of nonsmall cell lung cancer on cytology specimens: reproducibility of cytopathologic diagnoses on sparse material.

Cytologic examination of fine-needle aspiration (material is increasingly used in diagnosing lung cancer. High interobserver agreement in distinguishing small-cell lung cancer from nonsmall-cell lung cancer (NSCLC) on cytologic material has been demonstrated. Because of new treatment-modalities, subclassification of NSCLC into squamous cell carcinoma (SQC) and non-SQC has clinical impact. Subclassification based on morphology alone may be difficult, but applying immunohistochemistry (IHC) to clot-material has proved helpful. When insufficient material is available to make a clot from the aspirate, cytoscrape (CS) can convert cytologic material into tissue fragments useful for IHC. The purpose of this study was to test the reproducibility of pulmonary malignant diagnoses, in particular distinction between subgroups of NSCLC, based on smeared material and IHC on CS. A consecutive series of May-Grunwald-Giemsa (MGG) stained smears and CS with IHC on material from 79 patients suspected of having lung cancer was included. The material was circulated twice to four pathologists. The diagnoses were categorized in five groups: SQC, adenocarcinoma of the lung, non-SQC, benign lesion and other forms of malignancy, including metastases. Reproducibility was analyzed using Kappa statistics. Interobserver reproducibility of the diagnoses in round 1 was good to very good (kappa 0.57-0.71) and very good in round 2 (0.63-0.80). Reproducibility of subclassification of NSCLC based on MGG stained smear and IHC on CS, was very good among experienced pathologists. With only sparse material available, CS should be used to achieve reproducible diagnoses, including subtyping of NSCLC.

Cochlear ossification in patients with profound hearing loss following bacterial meningitis.

CONCLUSION: Cochlear ossification following bacterial meningitis is related to causative pathogen, but not age at disease or time point of evaluation. However, progression may occur over time, especially in case of primary signs of ossification. OBJECTIVE: To investigate the occurrence and degree of cochlear ossification on CT and MRI in patients with bilateral profound hearing loss following bacterial meningitis, in relation to causative pathogen, age at disease, and time point of evaluation. Progression of ossification in cases that underwent more than one scan was evaluated. METHODS: In the period 1982-2008, 47 cochlear implantations were performed in 34 consecutive candidates suffering from bilateral profound hearing loss following bacterial meningitis. A retrospective review of patient files and preoperative CT and MR images was performed. RESULTS: Cochlear ossification was observed in 35% of patients and 26% of ears on CT. The corresponding values for MRI were 44 and 30% (difference not significant). Streptococcus pneumoniae infection caused ossification more frequently than Neisseria meningitidis. No difference was found between pediatric and adult cases, and the occurrence of ossification was not related to the time point of evaluation. Signs of progressive ossification were found in cases with two CT scans, especially if ossification was present at the first scan.