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.

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 The early classical immunosuppressive drugs, azathioprine and cyclosporine, have largely been replaced by modern immunosuppressants, namely mycophenolate mofetil and tacrolimus, as well as sirolimus and everolimus.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.

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.

Pain identifies squamous cell carcinoma in organ transplant recipients: the SCOPE-ITSCC PAIN study.

Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient-reported warning signals predicting the presence of invasive SCC.Patient-reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy-proven diagnoses. Receiver-operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient-reported warning signals and the occurrence of SCC. Pain was an independent predictive patient-reported warning signal for a biopsy-proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4(95% confidence interval: 2.4­8.2). Higher scores on the visual analog scale (VAS) for pain were associated witha greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1to 3, 4 to 6 and 7 to 10 were 4.9 (2.2­10.5), 2.3 (0.96­5.5)and 16.5 (3.6­75.8), respectively. Pain is the most powerful patient-reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.

Psychosis in neurosyphilis -- clinical aspects and implications.

BACKGROUND: The World Health Organization estimates that 10-12 million new syphilis infections occur each year. Without treatment, years to decades after initial infection, 30% of affected individuals may develop tertiary syphilis, which can manifest as neurosyphilis. The aim of this review is to evaluate the research literature examining the psychopathological manifestations of psychosis in association with neurosyphilis. METHOD: The authors performed a systematic electronic search for published studies (1995-2012). The following databases were used: Medline, Embase and the Cochrane Library as well as the search engines Scopus and Google Scholar. RESULTS: 61 articles were used for detailed analysis. Psychotic symptoms due to neurosyphilis are numerous and can inform differential diagnosis for many psychotic manifestations according to ICD-10 or DSM-IV. CONCLUSION: Due to our results, current epidemiological data, and the difficulties in differential diagnosis of neurosyphilis, routine screening tests are still recommended in the psychiatric field. Long-term psychiatric input, with periodic syphilis titre controls, seems indicated in individuals affected by neurosyphilis with psychiatric symptoms. Furthermore, individuals with mental health problems may be at higher risk of acquiring syphilis.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

Psoriasin (S100A7) is a major Escherichia coli-cidal factor of the female genital tract.

The female urogenital tract requires an efficient defense against bacteria, potentially derived from the adjacent intestinal tract. We have thus sought to identify the factors that protect against Escherichia coli (E. coli) in the female genital tract. Vaginal fluid from healthy human donors consistently killed E. coli in vitro and vaginal epithelium strongly expressed and secreted psoriasin. Psoriasin was constitutively produced in an organotypic vaginal epithelium model, and exposure of these cells to supernatants of E. coli cultures led to an enhanced psoriasin expression. Secreted psoriasin in vaginal fluids accounted for approximately 2.5-3% of total protein. Fractionation of vaginal fluids by high performance liquid chromatography (HPLC) showed that psoriasin co-eluted with a peak of E. coli killing activity. Our data show that normal vaginal fluid contains a powerful intrinsic antimicrobial defense against E. coli and that psoriasin contributes to the innate immune response of the female genital tract.

Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric' histological morphology.

A patient with a 25-year history of rheumatoid arthritis and a 3-year history of methotrexate treatment developed a generalized papular rash. The papules rapidly became necrotic and then resolved, leaving a depressed scar. The rapid course of lesion development and regression was reminiscent of pityriasis lichenoides. Histology revealed a nodular infiltrate composed of a mixture of pleomorphic large B cells positive for CD20, CD30 and CD79a, and of small T cells positive for CD3 and CD4. The T cells had a striking angiocentric distribution, with some of the vessels exhibiting fibrinoid necrosis of the vessel wall reminiscent of lymphomatoid granulomatosis. However, B cells were consistently negative for Epstein-Barr virus (EBV) antigen expression. A thorough examination excluded involvement of organs other than the skin. Thus, this patient was classified as having a rare form of an EBV-negative primary cutaneous T-cell-rich B-cell lymphoma in association with methotrexate treatment.

Mucosal Candida infection and colonisation as well as associated risk factors in solid organ transplant recipients.

More detailed information on Candida colonisation and infection of the mucous membranes in organ transplant recipients (OTR) is of particular interest. Therefore, this issue was prospectively evaluated in 400 different OTR in different posttransplantation periods as well as in 405 healthy age- and sex-matched controls. In addition, possible risk factors and the clinical condition in the OTR were evaluated. Independent of the transplanted organ there is a statistically significant decrease in the number of positive culture results, of symptomatic candidiasis and an increase of isolated non-albicans Candida species corresponding to length of the posttransplantation period. No significant differences could be observed in the OTR in association with different immunosuppressive regimen; however, higher dosages of corticosteroids and tacrolimus correlated with symptomatic candidiasis. As Candida spp. may also cause systemic infection and dissemination, additional knowledge about cofactors and associated strains may have an impact on therapeutic decisions.

Melanoma in organ transplant recipients: clinicopathological features and outcome in 100 cases.

Organ transplant recipients have a higher incidence of melanoma compared to the general population but the prognosis of this potentially fatal skin cancer in this group of patients has not yet been established. To address this, we undertook a multicenter retrospective analysis to assess outcome for 100 melanomas (91 posttransplant and 9 pretransplant) in 95 individuals. Data were collected in 14 specialist transplant dermatology clinics across Europe belonging to the Skin Care in Organ Transplant Patients, Europe (SCOPE) Network, and compared with age, sex, tumor thickness and ulceration status-matched controls from the American Joint Committee on Cancer (AJCC) melanoma database. Outcome for posttransplant melanoma was similar to that of the general population for T1 and T2 tumors (< or = 2 mm thickness); but was significantly worse for T3 and T4 tumors (> 2 mm thickness); all nine individuals with a pretransplant melanoma survived without disease recurrence following organ transplantation. These data have implications for both cutaneous surveillance in organ transplant recipients and management of transplant-associated melanoma.

Successful treatment of an aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS patient.

Management of the increasing frequency of aciclovir-resistant herpes simplex virus (HSV) infections among immunocompromised human immunodeficiency virus-infected people demands additional treatment options. We report the case of a 38-year-old patient with acquired immune deficiency syndrome who suffered from a perianal butterfly ulcer, which was HSV-2 positive by polymerase chain reaction (PCR) analysis. The ulcer appeared during treatment of a cytomegalovirus (CMV) pneumonitis with ganciclovir. Despite additional valaciclovir therapy the lesion gradually progressed in size. Investigations including histology, PCR analysis and in situ hybridization of a biopsy from the growing ulcer margin confirmed the presence of HSV-2 infection. Importantly, HSV isolates from this specimen were resistant to aciclovir. Based on a report about the successful treatment of aciclovir-resistant HSV infection with cidofovir, our patient received this drug intravenously at a dose of 5 mg kg-1 body weight once weekly for a total of 3 weeks. Concomitant oral probenecid and prehydration were administered to minimize nephrotoxicity. Within 30 days of treatment the ulcer had almost (> 95%) completely healed. We conclude that cidofovir is a potent antiviral drug with a potential usefulness in the treatment of aciclovir-resistant HSV-2 infection. It deserves further investigation in clinical trials.

Risk factors for nasal carriage of Staphylococcus aureus in infectious disease patients, including patients infected with HIV, and molecular typing of colonizing strains.

Nasal carriage is an important risk factor for Staphylococcus aureus infection, particularly in HIV-infected individuals. In this analytical cross-sectional study, a variety of probable risk factors associated with nasal carriage of Staphylococcus aureus were investigated. HIV-infected patients were examined within a larger cohort of infectious diseases patients. Staphylococcus aureus strains from HIV-infected and non-HIV-infected carriers were identified by molecular biological analysis. One hundred seventy infectious disease patients, 47 of them infected with HIV, were included. All patients were admitted to the University Hospital of Vienna, Austria, between January and July 1999. Independent significant effects on Staphylococcus aureus nasal carriage were found to be HIV status (OR 2.5, 95% CI 1.1-5.6; P=0.0303), history of operation or severe wound within 3 months prior to admission (OR 4.0, 95% CI 1.3-13.0; P=0.0208), presence of an intravenous device within 2 weeks prior to admission (OR 10.8, 95% CI 2.0-59.4; P=0.0065), and intake of antibiotics within 2 weeks prior to hospitalisation (OR 0.2, 95% CI 0.09-0.6; P=0.0016). Molecular analysis of the Staphylococcus aureus strains revealed that the strains in both groups resembled those of healthy nonhospitalized carriers in the community.

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects.

A variety of health effects have been attributed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but little information is available on the course of a verified high-level TCDD intoxication. In this paper we describe two cases of heavy intoxication with TCDD and present a 2-year follow-up including clinical, biochemical, hematologic, endocrine, and immunologic parameters monitored in two women, 30 and 27 years of age, who suffered from chloracne due to TCDD intoxication of unknown origin. Patient 1, who had the highest TCDD level ever recorded in an individual (144,000 pg/g blood fat), developed severe generalized chloracne, whereas in the second patient, despite heavy intoxication (26,000 pg/g blood fat), only mild facial acne lesions occurred. Both patients initially experienced nonspecific gastrointestinal symptoms. In Patient 1 we observed a moderate elevation of blood lipids, leukocytosis, anemia, and secondary amenorrhoea. The laboratory parameters in Patient 2 were all normal. Despite the high TCDD levels, apart from chloracne, only few clinical and biochemical health effects were observed within the first 2 years after TCDD intoxication.

Cutaneous elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

BACKGROUND: After exposure, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is excreted via the faeces, breast milk and epidermal lipids. OBJECTIVES: To determine to what extent TCDD is eliminated via the skin and to evaluate whethe cutaneous elimination can be accelerated by the application of petrolatum. METHODS: In two patients severely intoxicated with TCDD, material obtained from the skin surface and, in one patient, cerumen and the content of epithelial cysts, was analysed for TCDD. RESULTS: The TCDD concentration in the initial blood sample taken was 144 000 pg g(-1) blood fa in patient 1, and 26 000 pg g(-1) blood fat in patient 2. Six months later, when the skin tests were performed, the blood TCDD levels had decreased to 80 900 and 16 100 pg g(-1) blood fat, respectively. In the two samples of pooled cyst contents from patient 1, TCDD levels of 34 400 an 18 600 pg g(-1) fat were found. A cerumen sample contained TCDD at 20 500 pg g(-1) fat. In the material collected from the skin surface we observed a linear increase of the amount of TCD measured per test field with time, indicating a continuous elimination of TCDD via the skin. Th daily amount of TCDD eliminated via the skin was 1.51 pg cm(-2) in patient 1 and 0.57 pg cm(-2) in patient 2. Application of petrolatum led to a twofold increase in the amount of TCDD measured in patient 1, but had no significant effect in patient 2. CONCLUSIONS: In our patients, elimination of TCDD via the skin, most probably through desquamating scales, represented 1-2% of the overall daily TCDD elimination rate, with regard to the body surface and when calculated on the basis of the half-life of TCDD at the time of the skin test. If a more typical overall elimination half-life of 7 years is used as the basis for the calculatio the skin would account for 9% (patient 1) and 15% (patient 2) of the overall elimination. Although we observed an increase in TCDD in material derived from the skin surface of up to 100% after application of petrolatum in patient 1, such an approach appears not to be a feasible means to increase elimination. Owing to the small amount of TCDD measured in skin-surface material, as well as in the cyst contents and cerumen obtained from one patient, contamination of the environment and other persons appears highly unlikely.

Cutaneous dendritic cells are main targets in acute HIV-1-infection.

Acute human immunodeficiency virus (HIV) infection is a transient illness that typically presents with mucocutaneous and constitutional symptoms. It is soon followed by seroconversion with the detection of anti-HIV antibodies in the peripheral blood. To better understand the pathogenetic events leading to this clinical picture, we sought to investigate the (immuno)histologic features of the skin rash occurring in an acutely infected person. A skin biopsy of an acutely infected person was investigated histologically and immunohistologically using paraffin-embedded tissue sections. Interface dermatitis with pronounced vacuolization of the basal keratinocytes was a prominent histological finding. The inflammatory infiltrate was composed of CD3+/CD8+ T cells with coexpression of Granzyme B7 and TIA-1, and CD68+ histiocytes/dendritic cells. CD1a+ intraepidermal Langerhans cells (LC) were significantly decreased and individual LC coexpressed HIV-p24 antigens as evidenced in double labeling experiments. HIV-infected LC were demonstrated in close apposition to cytotoxic T cells. This study provides the first definitive evidence for infection of LC at extramucosal sites in this very early stage of disease. Our findings emphasize the critical role of dendritic cells as a virus reservoir and the skin as a major site of HIV replication during the course of the disease.

Punctate keratoderma-like lesions on the palms and soles in a patient with chloracne: a new clinical manifestation of dioxin intoxication?

We report what we believe to be a novel skin manifestation of dioxin intoxication. A 30-year-old woman with 2,3,7, 8-tetrachlorodibenzo-p-dioxin levels of 144,000 pg g-1 blood fat presented with severe chloracne that affected the entire integument. She also exhibited acral granuloma annulare-like lesions and distal onycholysis and, at a later time point, showed signs of hypertrichosis, as well as brownish-grey hyperpigmentation of the face. In addition, she developed punctate keratoderma-like lesions on the palms and soles. These lesions were negative for human papillomavirus and histologically characterized by cone-shaped hyperkeratoses invaginating, but not penetrating, into the dermis. Squamous syringometaplasia of the eccrine glands was observed in the immediate vicinity of these lesions. Both clinically and histologically these alterations are essentially indistinguishable from what is described as keratosis punctata palmaris et plantaris (KPPP). Although a fortuitous coincidence of chloracne and KPPP cannot be formally excluded, the possibility exists that in our patient toxic levels of dioxin were causally involved in this disorder of keratinization.

Keratinocytes express the CD146 (Muc18/S-endo) antigen in tissue culture and during inflammatory skin diseases.

The CD146 (or MUC18/MEL-CAM) antigen is a cell adhesion molecule of the immunoglobulin superfamily. Besides in melanoma, expression of CD146 antigen has been demonstrated in breast epithelia and hair follicles. We studied its expression by human keratinocytes in culture as well as in neoplastic and inflammatory skin diseases. Staining of primary cultured keratinocytes revealed expression of CD146 on the cell membrane, preferentially on cell-cell contact sites. Western blot analysis of keratinocytes detected a band of approximately 113 kDa, corresponding to the CD146 protein. In contrast to primary keratinocytes, neither CD146 protein nor mRNA expression was found in the keratinocyte-derived cell lines A431 and HaCaT. Treatment of keratinocytes with the proinflammatory cytokines interleukin-1 and interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, resulted in no change of CD146 expression and incubation with phorbol 12-myristate 13-acetate led to a reduction of CD146 on keratinocytes. By contrast, when culturing keratinocytes in medium devoid of growth supplements, a distinct upregulation was observed as compared with culture in fully supplemented medium. In normal human epidermis expression of the CD146 antigen was not detectable. It was strongly upregulated, however, on suprabasal keratinocytes in psoriasis, in lichen planus, in the epidermis overlying skin neoplasms, and in viral warts. In squamous cell carcinomas and basal cell carcinomas only a minority of tumor cells expressed CD146. Our findings suggest that the CD146 antigen represents an activation marker of keratinocytes and may be involved in cutaneous inflammatory tissue reaction.