Background: Solid organ-transplant recipients (SOTR) have an increased risk of cutaneous squamous-cell carcinoma (cSCC), metastasis and death from cSCC. In immunocompetent patients with mucosal SCC... Show moreBackground: Solid organ-transplant recipients (SOTR) have an increased risk of cutaneous squamous-cell carcinoma (cSCC), metastasis and death from cSCC. In immunocompetent patients with mucosal SCC, downregulation of HLA class I is associated with poor prognosis. Since the degree of HLA expression on tumor cells could play a role in immunogenicity and pathophysiology of cSCC metastasis, we hypothesized that decreased HLA expression is associated with an increased risk of metastasis.Methods: We compared HLA expression between primary metastasized cSCCs, their metastases, and nonmetastasized cSCCs from the same patients. Samples were stained for HLA-A, HLA-B/-C and quantified by calculating the difference in immunoreactivity score (IRS) of the primary cSCC compared with all nonmetastasized cSCCs. Results: The mean IRS score for HLA-B/C expression was 2.07 point higher in metastasized compared to nonmetastasized cSCCs (p = 0.065, 95 % CI -0.18-4.32). 83.3 % of the primary metastasized cSCCs had an IRS score of 4 or higher, compared to 42.9 % in non-metastasized cSCCs. Moderately to poorly differentiated cSCCs had more HLA class I expression compared to well-differentiated cSCCs. Conclusion: Contrary to immunocompetent patients, HLA-B/C expression tends to be upregulated in metastasized cSCC compared to non-metastasized cSCC in SOTR, suggesting that different tumor escape mechanisms play a role in SOTR compared to immunocompetent patients. Show less
Huisman, B.W.; Nené, L.E.H.; Linders, F.L.L.; Gambrah, T.K.; Kolk, T.N. van der; Kam, M.L. de; ... ; Rissmann, R. 2022
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.... Show moreBackground 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. Show less
Jong, E. de; Lammerts, M.U.P.A.; Genders, R.E.; Bavinck, J.N.B. 2022
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... Show moreThe 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. Show less
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... Show moreBackground 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. Show less
Background: Peripheral arterial occlusive disease (PAOD) and chronic venous insufficiency (CVI) in organ transplant recipients (OTR) can lead to harmful outcomes. We made an inventory of cutaneous... Show moreBackground: Peripheral arterial occlusive disease (PAOD) and chronic venous insufficiency (CVI) in organ transplant recipients (OTR) can lead to harmful outcomes. We made an inventory of cutaneous manifestations of PAOD and CVI in OTR in relation with diabetes and other potential risk factors.Methods: A prospective study in a single center was performed. OTR (n = 112) were included at the outpatient clinic to investigate clinical signs of PAOD and CVI. The most commonly associated risk factors were determined.Results: PAOD had been diagnosed in 15.6% and CVI in 30.0% of the patients. Diabetes was the cause of organ failure in 9.8% of the patients. Type 1 diabetes had been diagnosed in 8.9% and type 2 diabetes in 21.4% (59.1% newonset diabetes alter transplantation). Type 1 diabetes showed an increased risk for PAOD and limb amputation with hazard ratios of 11.0 (95%CI 3.0-40.2) and 9.1 (95%CI 1.4-58.6). Type 2 diabetes showed no increased risk.Conclusions: Patients with a history of type 1 diabetes were at high risk for PAOD even years after a simultaneous pancreas kidney transplantation and they should remain under dose observation for PAOD even though they are supposedly "cured" from their diabetes to prevent a harmful outcome. (C) 2020 Elsevier Inc. All rights reserved. Show less
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... Show moreThe 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. Show less
Rijsbergen, M.; Niemeyer-van der Kolk, T.; Rijneveld, R.; Pinckaers, J.H.F.M.; Meshcheriakov, I.; Bavinck, J.N.B.; ... ; Rissmann, R. 2020
BackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have... Show moreBackgroundAssessment 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.ObjectivesTo investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials.MethodsAn 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.ResultsTreatment 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.ConclusionsThe 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. Show less
Rijsbergen, M.; Niemeyer-van der Kolk, T.; Rijneveld, R.; Pinckaers, J.H.F.M.; Meshcheriakov, I.; Bavinck, J.N.B.; ... ; Rissmann, R. 2020
BackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have... Show moreBackgroundAssessment 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.ObjectivesTo investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials.MethodsAn 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.ResultsTreatment 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.ConclusionsThe 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. Show less
Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects,... Show morePatients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty-two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p < .01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p = .7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10-point scale, median patient satisfaction score was 9.0 (interquartile range 7.8-10.0) and 8.0 (interquartile range 5.1-9.7) for children and adults respectively (p < .01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children. Show less
Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects,... Show morePatients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty-two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p<.01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p=.7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10-point scale, median patient satisfaction score was 9.0 (interquartile range 7.8-10.0) and 8.0 (interquartile range 5.1-9.7) for children and adults respectively (p<.01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children. Show less
