Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10-5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10-6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the "cellular response to UV" to be significantly associated with multiple keratinocyte cancers.

Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation-A Case Control Study.

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

The spectrum of skin diseases in four different types of organ-transplant recipients: a comparative single-centre cohort study.

BACKGROUND: Organ transplant recipients (OTR) are at marked increased risk of skin cancer and skin infections compared to the general population. OBJECTIVES: The purpose of this study was to acquire long-term incidence data on commonly occurring skin diseases in four different transplant groups. MATERIALS & METHODS: This retrospective single-centre cohort study included 621 OTR. By counting defined malignant, inflammatory, infectious or drug-related skin conditions per patient and visit, incidence rates (IR) for the different groups of OTR were calculated as cases per 1000-patient years and cumulative incidences of non-melanoma skin cancer (NMSC), respectively. RESULTS: Overall, 2,309 non-malignant skin conditions and 340 NMSC were registered. Skin infections were most common (51.4%), followed by inflammatory skin conditions (35.6%) and sun-induced skin damage (32.9%). Kidney transplant recipients (KTR) had a 4.7-fold (95% CI: 2.7-8.0; p < 0.0001), 2.6-fold (95% CI: 1.2-5.3; p = 0.0098) and 5.4-fold (95% CI: 2.8-10.3; - < 0.0001) higher IR for oral candidiasis, oral aphthosis and herpes simplex virus infections, respectively, compared to the other OTR. Pruritus was most commonly reported in liver transplant recipients (95% CI: 1.3-5.3; p = 0.0047). KTR and lung transplant recipients (LuTR) had a 10.7-fold (95% CI:3.6-43.2; p < 0.0001) higher IR of steroid induced acne. KTR had a 1.6-fold (95% CI: 1.1-2.3; p = 0.0096) higher IR of squamous cell carcinoma compared to the other groups. The incidence of basal cell carcinoma was 2.5-fold higher (95% CI: 1.7-3.6; p < 0.0001) in LuTR, compared to the other OTR. CONCLUSION: This study provides additional organ-specific incidence data on non-malignant skin diseases and skin cancer in OTR.

Dysregulation of tissue and serum microRNAs in organ transplant recipients with cutaneous squamous cell carcinomas.

Micro RNAs (miRNAs) are considered as promising biomarkers for skin cancer. By next generation sequencing (NGS), we measured and compared miRNA expression profiles of tumor, peri-lesional, and control tissue of immunosuppressed organ transplant recipients (OTR), suffering from localized cutaneous squamous cell carcinoma (cSCC). Out of 490 miRNAs detected in cSCC tissue, 23 significantly regulated miRNAs were selected for quantitative targeted analysis in serum samples of our patients and control sera from OTR without cSCC. Two onco-miRNAs (mir-1290, mir-1246), previously identified as crucial drivers for tumor initiation and cancer progression, were significantly and exclusively upregulated in both tumor tissue and serum. This finding suggests that miRNA dysregulation in cSCC tissue is reflected in serum even in patients without advanced disease and highly differentiated cSCCs.

Peptidase inhibitor 3 and chemokine ligand 27 may serve as biomarkers for actinic keratoses in organ transplant recipients.

Molecular profiling of tissue samples in organ transplant recipients (OTRs) may allow early and minimally invasive identification of actinic keratosis (AK). The aim of this study was to compare mRNA expression profiles of 13 genes, as putative genetic biomarkers of AK, before and after treatment using two different field therapies, and to correlate the results with histological and clinical parameters. For this single-centre prospective randomized intra-patient-controlled study, 10 OTRs with AKs were recruited for field therapy with two cycles of methyl-5-aminolevulinate 16% cream-photodynamic therapy (PDT) at one site and imiquimod 5% cream for four weeks at another site. AKs in the PDT area were reduced significantly at one, two, and six months after completion of the treatment (p < 0.001). The effect of imiquimod was weaker but still significant when evaluated during the same intervals (p < 0.001). By comparing the mRNA expression profiles of various genetic markers before, during, and three months after therapy, we observed specific patterns of expression for skin-derived peptidase inhibitor 3 (PI3) and chemokine ligand 27 (CCL27) in all groups, regardless of the treatment modality. Compared to healthy skin, the expression of PI3 was strongly decreased and that of CCL27 increased in AK lesions before therapy. The expression level of both genes showed a significant convergence to values observed in healthy skin in both groups after therapy. The pattern and level of specific gene expression in actinic keratoses could serve as a biomarker.

Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I).

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice.

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

[The chameleon of psychiatry - psychiatric manifestations of neurosyphilis]. / Das Chamäleon der Psychiatrie - Psychiatrische Manifestationsformen der Neurosyphilis.

OBJECTIVE: Recent epidemiological data have shown a significant increase in the prevalence of syphilis. If left untreated, up to 30 % of patients may develop tertiary syphilis, which can manifest as neurosyphilis. The aim of our review is to evaluate psychiatric manifestations of neurosyphilis according to ICD-10. METHODS: A systematic electronic search for published studies (1995-2010) was performed using the databases Medline, Embase, Cochrane as well as the search engines Scopus and Google Scholar. RESULTS: 113 studies were used for detailed analysis. Clinical manifestations of various forms of neurosyphilis are protean, numerous and non-specific and could be on the differential diagnosis for many psychiatric presentations according to ICD-10. CONCLUSION: Due to our results, the difficulties in diagnosing syphilis and current epidemiological data, routine screening tests are still mandatory in the psychiatric field. Further, neurosyphilis still has to be considered in the differential diagnosis within the context of psychiatric conditions and diseases.

Sirolimus in renal transplant recipients with tuberous sclerosis complex: clinical effectiveness and implications for innate immunity.

Tuberous sclerosis complex (TSC) is caused by constitutively activated mammalian target of rapamycin (mTOR) resulting in nonmalignant tumours of several organs and consequently renal failure. Recent reports suggest a possible beneficial role of the mTOR-inhibitor (mTOR-I) sirolimus for TSC; however, safety and efficiency of sirolimus in TSC patients after renal transplantation, both as primary immunosuppressant as well as anti-proliferative agent, are still undefined. Moreover, it is currently unknown whether the TSC mutation affects the primary immune response in these patients. In this article, we report on three TSC patients after renal transplantation who have been converted from a calcineurin-inhibitor (CNI)-based immunosuppression to sirolimus. During 2 years of follow-up, renal allograft function was stable or even improved, and no significant sirolimus-associated side-effects were noted. Beneficial effects of sirolimus against TSC were detected in the skin, along with improved spirometric measurements and an arrest of astrocytoma progression. We show that the inflammatory immune response was significantly altered in TSC patients as compared with controls and sirolimus potently affected both inflammatory cytokine production and vascular endothelial growth factor levels in these patients. Larger studies are warranted to further examine the relationship between clinical parameters and the molecular response to mTOR-inhibition in TSC patients after renal transplantation.

Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease.

PURPOSE: To evaluate the prevalence of nephrogenic systemic fibrosis (NSF) in a patient population being at highest risk for developing this disease and to evaluate possible risk factors. MATERIALS AND METHODS: The radiological records of 552 patients with ESRD being on hemodialysis (HD) or peritoneal dialysis (PD) were retrospectively reviewed to identify whether the patients underwent MR-examinations with or without intravenous administration of GBCA. In case of exposure to GBCA, the number of contrast injections, the benchmark and the cumulative doses of GBCA, and possible cofactors regarding pathogenesis of NSF were recorded. Diagnosis of NSF was confirmed either by deep skin biopsy or by review of medical and histopathological records. Data of NSF patients were compared with data of dialysis patients who did not develop NSF after MR-examinations. RESULTS: 146 dialysis patients underwent MRI without i.v.-administration of GBCA. No case of NSF was observed in this patient population. 195/552 patients proved to have a total number of 325 well-documented exposures to GBCA. Seven different types of GBCA were used during these MR-examinations. NSF prevalence rate was 1.6%. One patient died of NSF. Three different types of GBCA were involved in 6 NSF cases. 4/6 proved to be confounded cases. The cumulative dose of GBCA, history of thrombosis, recent surgery, and the combination of HD and PD proved to be significant cofactors for the development of NSF (p<.05). No significant difference regarding residual renal clearance (p=.898) and residual urine volume (p=.083) was found between NSF and non-NSF patients. CONCLUSION: The prevalence of NSF proved to be much lower in this high risk patient group being exposed to GBCA compared to the literature. NSF was not observed in ESRD patients undergoing MRI without administration of GBCA. Our data support a positive association between cumulative dose of GBCA and development of NSF. No positive association was found between residual renal clearance and residual urine volume and NSF.

Manifest psychosis in neurosyphilis.

INTRODUCTION: Recent surveys have assessed a remarkable increase in the prevalence of infectious syphilis. If left untreated, 30% of patients may develop tertiary syphilis, which can manifest as neurosyphilis. CASE REPORT: The authors present a case of an acute psychosis during and after pregnancy in a 37-year-old woman, which was identified as a manifestation of neurosyphilis after admission to a psychiatric ward. The positive screening test for syphilis provided the first hint of syphilis and gave direction for further diagnosis and specific treatment. Subsequently, the patient was treated with psychotropic medication concurrent with an adequate antibiotic treatment for neurosyphilis and was simultaneously psychologically monitored. An improvement of psychotic symptoms during antibiotic therapy was observed. CONCLUSION: This case emphasises that neurosyphilis still has to be considered in the differential diagnosis within the context of psychiatric conditions and diseases. Owing to current epidemiological data and difficulties in diagnosing syphilis, routine screening tests in the psychiatric field are necessary.

Non-melanoma skin cancer and its risk factors in an Austrian population of heart transplant recipients receiving induction therapy.

BACKGROUND: Solid organ transplant recipients have a high risk of developing nonmelanoma skin cancers (NMSC). We describe the characteristics and incidence of skin tumors in an Austrian population of heart transplant recipients (HTR). METHODS: Three hundred and twenty-two HTR out of 970 who had received their organ between December 1984 and July 2003 were analyzed for NMSC. Factors associated with tumor development including the different immunosuppressive (IS) modalities were evaluated. Besides triple combination immunosuppressive therapy, all allograft recipients had received induction therapy either with antithymocyte globulin, OKT3 or monoclonal anti-IL-2 receptor antibodies. RESULTS: Median post-transplant follow-up for all patients was 74.18 months (minimum: 2.6, maximum: 224.8). The median time from transplantation until the excision of the first NMSC was 79.57 months (minimum: 2.69, maximum: 192.8). A total of 263 NMSC were excised in 73 patients. The cumulative incidence of developing a skin tumor increased from 7.3% after 5 years to 26.9% after 10 years and to 56.5% after 15 years. Older age at transplantation (P < 0.0001) and the presence of pre-cancerous skin conditions (P < 0.0001) were associated with an increased occurrence of NMSC. No significant difference in NMSC incidence was found when the different IS therapies were compared. CONCLUSIONS: The cumulative incidence of NMSC in our cohort of HTR is comparable to published data on HTR adjusted according to the geographic location. Transplant patients with clinical evidence of pre-cancerous skin conditions have a higher degree of susceptibility for the development of NMSC and require particular dermatologic care.

Cutaneous human papillomavirus 88: remarkable differences in viral load.

A human papillomavirus (HPV) was cloned from a patient with multiple squamous cell carcinomas (SCCs) and identified as HPV88, recently categorized into a new species within the genus Gamma. The HPV88 viral load in an SCC of the index patient exceeded 1 million copies/cell. By contrast, a survey of 447 skin lesions (79 actinic keratoses, 73 seborrhoeic keratoses, 169 basal cell carcinomas and 126 SCCs) and 362 healthy skin biopsies found detectable HPV88 DNA in only 7 specimens. All these had very low viral loads (<1 copy/10(3) cells) implying extreme biological variability in viral load.