Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study.

BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.

Risk factors for incomplete excision of cutaneous squamous cell carcinoma: a large cohort study.

BACKGROUND: The standard treatment for cutaneous squamous cell carcinoma (cSCC) is surgical excision. Failure to radically remove a cSCC is a risk for recurrence, progression and metastasis. OBJECTIVES: This study investigates several risk factors for incomplete excision of cSCC. METHODS: All consecutive patients in a single institution treated with wide local excision for primary cSCC over a 10-year period were included in this study. Risk factors such as: gender, age, immunosuppression, tumour size, location, differentiation grade, tumour depth, perineural and lymphovascular invasion (PNI and LVI) were extracted from the database. Univariable and (if applicable) multivariable logistic regression analysis were used to identify risk factors (P < 0.05). Generalized estimating equations (GEEs) were used for multiple tumours within the same patients. RESULTS: A total of 566 patients with 1159 cSCC were identified. Univariable and multivariable logistic regression analysis showed that depth beyond the dermis (OR: 5.7 95% CI: 3.1-10.5) was the only risk factor for incomplete excision of cSCC. Immunosuppression was only a risk factor in the deep plane (OR: 2.5, 95% CI: 1.3-4.6). CONCLUSION: Tumour depth beyond the dermis is the most important risk factor for incomplete excision of cSCC. Immunosuppression is a risk factor in the deep plane but its relevance is uncertain. Immunosuppression is not consistently included in the current cSCC staging systems, but care should be taken when treating these patients.

Update of advanced cutaneous squamous cell carcinoma.

The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing. A growing part of this patient group is formed by immunocompromised patients, for example organ-transplant recipients (OTR). Although over 90% of the cSCC show a relatively harmless clinical behaviour, there is also a chance of developing advanced cSCC and metastases. Locally advanced cSCC are defined as cSCC that have locally advanced progression and are no longer amenable to surgery or radiation therapy. Better understanding of the clinical behaviour of cSCC is essential to discriminate between low- and high-risk cSCC. Staging systems are important and have recently been improved. Genetic characterisation of SCC will likely become an important tool to help distinguish low and high-risk cSCC with an increased potential to metastasise in the near future. Available treatments for high-risk and advanced cSCC include surgery, radiotherapy, chemotherapy and targeted therapy with epidermal growth factor receptors inhibitors. Anti-PD-1 antibodies show promising results with response rates of up to 50% in both locally advanced and metastatic cSCC but, in its present form, is not suitable for OTR.

HPV type-specific distribution among family members and linen in households of cutaneous wart patients.

BACKGROUND: Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. OBJECTIVE: To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. METHODS: In a cross-sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart-associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. RESULTS: HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. CONCLUSION: Dissemination of skin wart-causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN).

The severe cutaneous adverse reaction epidermal necrolysis (EN) which includes toxic epidermal necrolysis and the milder Stevens-Johnson syndrome is characterized by epidermal loss due to massive keratinocyte apoptosis and/or necroptosis. EN is often caused by a drug mediating a specific TCR-HLA interaction via the (pro)hapten, pharmacological interaction or altered peptide loading mechanism involving a self-peptide presented by keratinocytes. (Memory) CD8 + T cells are activated and exhibit cytotoxicity against keratinocytes via the perforin/granzyme B and granulysin pathway and Fas/FasL interaction. Alternatively drug-induced annexin release by CD14 + monocytes can induce formyl peptide receptor 1 death of keratinocytes by necroptosis. Subsequent keratinocyte death stimulates local inflammation, activating other immune cells producing pro-inflammatory molecules and downregulating regulatory T cells. Widespread epidermal necrolysis and inflammation can induce life-threatening systemic effects, leading to high mortality rates. Research into genetic susceptibility aims to identify risk factors for eventual prevention of EN. Specific HLA class I alleles show the strongest association with EN, but risk variants have also been identified in genes involved in drug metabolism, cellular drug uptake, peptide presentation and function of CD8 + T cells and other immune cells involved in cytotoxic responses. After the acute phase of EN, long-term symptoms can remain or arise mainly affecting the skin and eyes. Mucosal sequelae are characterized by occlusions and strictures due to adherence of denuded surfaces and fibrosis following mucosal inflammation. In addition, systemic pathology can cause acute and chronic hepatic and renal symptoms. EN has a large psychological impact and strongly affects health-related quality of life among EN survivors.

Mobile e-diary application facilitates the monitoring of patient-reported outcomes and a high treatment adherence for clinical trials in dermatology.

BACKGROUND: Assessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have limited reliability, particularly for outpatient trials. OBJECTIVES: To investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials. METHODS: An e-diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient-reported outcomes, i.e. pain and itch, were evaluated by the e-diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e-diary adherence, and patients' perception of usefulness and acceptability of the e-diary were evaluated. RESULTS: Treatment adherence rates of the included 256 patients were high (median 98%, range 97-99%). E-diary adherence was also high with a median of 93% (range 87-97%) for capturing the applied drug by camera, and 89% (range 87-96%) and 94% (range 87-96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e-diary as good to excellent with respect to user acceptability. CONCLUSIONS: The results suggest that the e-diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e-diary may also be valuable for frequent and reliable monitoring of patient-reported outcomes in daily clinical practice.

Cutaneous squamous cell carcinoma (cSCC) and immunosurveillance - the impact of immunosuppression on frequency of cSCC.

Solid organ transplant recipients (OTR) are at extreme risk of developing cutaneous squamous cell carcinomas (cSCC) post-transplantation due to the immunosuppressive medication needed to retain the transplanted organ. The early classical immunosuppressive drugs, azathioprine and cyclosporine, have largely been replaced by modern immunosuppressants, namely mycophenolate mofetil and tacrolimus, as well as sirolimus and everolimus. Although still very high, the risk of cSCC in OTR seems to be decreasing which suggests that cSCC risk may be lower in OTR treated with these modern immunosuppressive drugs and that cSCC preventive measures may be effective. OTR should be closely monitored so that cSCC can be treated at an early stage. (Chemo)prevention of cSCC as well as changing immunosuppression to more favourable regimens will be important in future to reduce skin cancer incidence.

A randomized controlled proof-of-concept trial of digoxin and furosemide in adults with cutaneous warts.

BACKGROUND: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts. OBJECTIVES: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT. METHODS: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643. RESULTS: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts. CONCLUSIONS: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts.

BACKGROUND: Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (Cutaneous WARTS diagnostic tool, CWARTS) based on phenotypical characteristics. OBJECTIVES: To assess whether patient and morphological wart characteristics predict the human papillomavirus (HPV) type in a specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response. METHODS: Photographs were used to score nine morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart-associated HPV types was performed using the hyperkeratotic skin lesion-polymerase chain reaction/multiplex genotyping assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a generalized estimating equations model. RESULTS: Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or a combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective in the presence of callus and when the wart was located deeper in the skin. CONCLUSIONS: Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts.

Developing and validating the Cutaneous WARTS (CWARTS) diagnostic tool: a novel clinical assessment and classification system for cutaneous warts.

BACKGROUND: The clinical appearance of cutaneous warts is highly variable and not standardized. OBJECTIVES: To develop and validate a reproducible clinical tool for the standardized assessment of cutaneous warts to distinguish these lesions accurately. METHODS: Nine morphological characteristics were defined and validated regarding intra- and interobserver agreement. Based on literature and semistructured interviews, a systematic dichotomous assessment tool, the Cutaneous WARTS (CWARTS) diagnostic tool was developed. The validation consisted of two independent parts performed with photographs from the recent WARTS-2 trial. In part A, the CWARTS diagnostic tool was tested by 28 experienced physicians who assessed photographs of 10 different warts to investigate interobserver concordance. In part B, morphological characteristics were validated by masked and independent scoring of 299 photographs by six different observers. Part B also entailed reassessment of the photographs after at least 1 week. The primary outcome measurement was the intraclass correlation coefficient (ICC). RESULTS: Presence of black dots (capillary thrombosis) had the greatest ICC (0·85) for interobserver agreement in part A, followed by arrangement (0·65), presence of border erythema (0·64) and sharpness of the border (0·60). In part B, results were similar for interobserver agreement with presence of black dots having the highest ICC (0·68), followed by border erythema (0·64), arrangement (0·58) and colour (0·55). For intraobserver agreement, presence of black dots had the highest agreement (0·70), followed by presence of border erythema (0·694) and colour (0·59). CONCLUSIONS: Wart phenotype can be reliably assessed using the CWARTS diagnostic tool.

The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients.

The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.

Epidemiology of keratinocyte carcinomas after organ transplantation.

Keratinocyte carcinoma (KC) is the most common type of cancer among white populations, but it is even more common among solid organ transplant recipients (OTRs). The most frequent histological type of KC among OTRs is cutaneous squamous cell carcinoma (cSCC), followed by basal cell carcinoma, although the reverse is seen in the general population. Metastatic cSCCs are more frequent, and mortality is increased compared with immunocompetent populations. There is strong evidence that the risk of KC among OTRs rises with increasing time after transplantation and older age at transplantation, and that KC is enhanced in those with sun-damaged skin. This evidence suggests that accelerated accumulation of genetic damage from several sources leads to excess KC in OTRs. We describe international variation in KC and focus on trends in immunosuppressive regimens, the role of ultraviolet susceptibility and exposure, and the contribution of genetics to tumour development. Further epidemiological studies are needed to address gaps in our understanding of the mediation of excess KC by immunosuppressive drugs, viral infection, genetic susceptibility, timing of relevant ultraviolet exposure or some combination of these factors.

Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts.

BACKGROUND: DNA viruses such as HPV rely on K+ influx for replication. Both digoxin and furosemide inhibit the K+ influx by interacting with cell membrane ion co-transporters (Na+ /K+ -ATPase and Na+ -K+ -2Cl- co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT). OBJECTIVE: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT. METHODS: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect. RESULTS: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14. CONCLUSION: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity.

Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study.

BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1·6 [95% confidence interval (CI) 0·97-2·7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1·7 (95% CI 1·0-2·8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.

High prevalence of cutaneous warts in elementary school children and the ubiquitous presence of wart-associated human papillomavirus on clinically normal skin.

BACKGROUND: One-third of Dutch primary school children have cutaneous warts; each year around 20% of them seek medical treatment. However, little is known about the epidemiology of the types of human papillomavirus (HPV) causing these warts. OBJECTIVES: To investigate the distribution of cutaneous wart-associated HPV types in three primary school classes by analysing skin swabs taken from warts, and the forehead, hand dorsum and sole of the foot of included children. METHODS: Using the hyperkeratotic skin lesion polymerase chain reaction/multiplex genotyping assay, each swab sample was used to genotype for 23 cutaneous wart-associated HPV types. RESULTS: Thirty-one (44%) of the 71 children had a total of 69 warts, with a maximum of six warts per child. In the wart swabs, HPV2, HPV27 and HPV57, members of Alphapapillomavirus species 4, were most frequently detected (27%, 32% and 14%, respectively), whereas HPV1 was only found in two plantar warts. The prevalence of HPV carriage, detected in swabs of clinically normal skin of the forehead, left hand and left sole was 80%, with the most prevalent types being HPV1 (59%), HPV2 (42%), HPV63 (25%) and HPV27 (21%). CONCLUSIONS: Cutaneous wart-associated HPV types were highly prevalent in primary school children, but did not correlate with the HPV types in warts. In contrast to the existing literature, HPV1 was frequently detected on clinically normal skin but was much less frequent in warts.