Cutaneous infections from viral sources in solid organ transplant recipients.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are susceptible to various dermatological complications caused by long-term immunosuppressive therapy. Of these complications, viral infections are noteworthy because of their high prevalence and the potential morbidity associated with viral carcinogenesis. OBJECTIVES: To evaluate the occurrence of cutaneous viral infections in SOTRs and their correlation with clinical features, transplant type, and the length and intensity of immunosuppressive therapy. METHODS: This retrospective cohort study included SOTRs followed up at the Department of Dermatology in a tertiary hospital. The outcomes analyzed were the occurrence of cutaneous viral infections, including human papillomavirus (HPV) infection, herpes simplex, herpes zoster, molluscum contagiosum, Merkel cell carcinoma, Kaposi's sarcoma, and cytomegalovirus, and the occurrence of HPV-related neoplasms. Clinical variables, such as length and intensity of immunosuppression, type of transplanted organ, and comorbidities, were analyzed as possible risk factors for cutaneous viral infections in SOTRs. RESULTS: A total of 528 SOTRs were included in this study, among which 53.8% had one or more viral infections. Of these, 10% developed a virus-associated malignancy (HPV-associated carcinoma, Merkel cell carcinoma, or Kaposi's sarcoma). The higher risk of viral infections among SOTRs was associated with cyclosporine intake (1.40-fold higher risk) and younger age at transplantation. The use of an immunosuppressive regimen, including additional drugs, was associated with a higher risk of genital HPV infection (1.50-fold higher risk for each incremental drug). CONCLUSIONS: The occurrence of cutaneous viral infections in SOTRs is directly associated with the duration and intensity of immunosuppressive therapy. Patients at higher risk were those taking drugs with a stronger impact on cellular immunity and/or those on an immunosuppressive regimen comprising various drugs.

A 12-month follow-up split-scalp study comparing calcipotriol-assisted MAL-PDT with conventional MAL-PDT for the treatment of actinic keratosis: a randomized controlled trial.

To enhance the efficacy of photodynamic therapy (PDT) for actinic keratosis (AKs), physical and chemical pre-treatments, such as calcipotriol (CAL) have been suggested. To compare the long-term 12-month efficacy and safety between methylaminolevulinate (MAL)-PDT and prior application of topical CAL versus conventional MAL-PDT for AKs of the scalp. Twenty patients with multiple AKs on the scalp were randomized to receive conventional PDT on one side of the scalp and CAL-assisted PDT, in which CAL was applied daily for 15 days beforehand, on the other side. Patients were evaluated for AK clearance at three, six and 12 months thereafter. All 20 patients completed the study. At three months, overall AK clearance was 92.07% and 82.04% for CAL-PDT and conventional PDT, respectively (p < 0.001). Similar results were found at six and 12 months: 92.07% and 81.69% (p < 0.001), and 90.69% and 77.46% (p < 0.001) for CAL-PDT and conventional PDT, respectively. Grade I AKs showed a similar response rate for both sides (p = 0.055) at three months and significant differences were obtained at six (p = 0.001) and 12 months (p < 0.001) for CAL-PDT and conventional PDT. Grade II AKs showed greater improvement on the CAL-PDT side (89.55% vs 62.90%) (p < 0.001) at three months. No difference was found at six and 12 months. CAL-PDT proved to be safe and more effective than conventional PDT for the treatment of AKs on the scalp after 12 months. CAL pre-treatment may have enhanced the efficacy of PDT for AK treatment, however, larger trials are needed to corroborate our findings.

Identification of Polyomaviruses in Skin Cancers.

BACKGROUND: Polyomaviruses (PyVs) were initially described in animals. They have also been detected in humans with some evidence that could play a role in skin carcinogenesis. OBJECTIVES: This study aimed to verify the presence of PyVs in different skin tumour samples and to make clinical correlations with patients' epidemiological data from Clinics Hospital of Medical School of University of São Paulo, Brazil. METHODS: This is a cross-sectional study. A random selection was performed of 120 patients with histopathological exams of different cutaneous neoplasms equally divided into 6 groups and 20 patients with normal skin. The available skin specimens were analysed with 2 different techniques of PCR (conventional and real time) for detection of PyV DNA. Concomitantly, retrospective analysis of the respective medical records for the collection of epidemiological data was done. Analyses suitable for categorical data were used to compare the proportion of patients in each group. RESULTS: PyV DNA was found in 25.69% of the samples: 15% in basal cell carcinoma group, 15% in squamous cell carcinoma, 28.57% in melanoma, 15% in dermatofibrosarcoma protuberans, 13.33% in Kaposi sarcoma, 65% in Merkel cell carcinoma (MCC), and none in normal skin. Merkel cell PyV detection was statistically significant in MCC patients (p value <0.01), but no correlations were found between PyVs and others skin tumours. CONCLUSION: This study demonstrated the presence of PyVs in different skin tumours; however, no association of any PyVs found in any skin tumour with epidemiological data could be shown. Further studies are still needed to elucidate the mechanisms of PyVs in skin carcinogenesis.

Nodular primary cutaneous melanoma is associated with PD-L1 expression.

BACKGROUND: In previous studies, patients with Stage III melanomas expressing PD-L1 in more than 5% of their neoplastic cells had improved recurrence-free survival with anti-PD1 adjuvant therapy. OBJECTIVES: We examined PD-L1 expression as a possible biomarker of primary cutaneous melanomas in the vertical growth phase. MATERIALS AND METHODS: This was a retrospective study including 66 patients with invasive primary cutaneous melanomas. We assessed patient clinical and histopathological data and performed immunohistochemical assays with melanoma specimens from the patients to evaluate PD-L1, PD-1, CD3, CD8 and FoxP3 expression. RESULTS: We observed PD-L1 expression in 21% (14/66) of our samples, and this expression correlated with increased melanoma thickness (p = 0.002) and nodular-type melanoma (p = 0.001). After adjusting for tumor thickness using a logistic regression test, the association of PD-L1 with nodular-type melanoma persisted. Nodular-type melanoma was 6.48 times more likely to be positive for PD-L1 than other histological types (p = 0.014; 95% CI: 1.46-28.82). As expected, PD-L1 expression correlated with the number of PD-1-expressing cells in the tumor-infiltrating lymphocyte population (p = 0.04). No correlation with PD-L1 was observed for age, sex, tumor site, skin phototype, ulceration status, sentinel lymph node status, metastasis development or survival. Regarding the immune profile of the tumor-infiltrating lymphocytes of PD-L1-positive and -negative groups, no significant differences were observed in the numbers of CD3 + , CD8 + FoxP3-, CD8-FoxP3+ and CD8 + FoxP3+ cells by immunohistochemistry. CONCLUSION: Nodular-type melanoma is associated with PD-L1 expression and may be a suitable candidate for adjuvant therapy of primary melanomas treated with immunotherapy.

Worse survival of invasive melanoma patients in men and "de novo" lesions.

BACKGROUND: The incidence and mortality of melanoma is increasing in many countries, including Brazil. Survival studies are still scarce in our country, but much needed to know and address this problem better. OBJECTIVE: To analyze the disease-specific survival of patients with invasive melanoma and to correlate it with clinical and histopathological variables. METHODS: Retrospective cohort analysis of 565 cases of invasive melanoma in a tertiary hospital with the objective of testing variables that could be associated with a worse prognosis, such as gender, phototype, thickness, histological type and presence of pre-existing clinical lesion at the site of the tumor. RESULTS: The worst survival rates were significantly associated with thicker tumors (p<0.001), male sex (p=0.014), high phototype (p=0.047), nodular melanoma (p=0.024) and "de novo" lesions (p=0.005). When all variables were adjusted for melanoma thickness, male patients (p=0.011) and "de novo" melanomas (p=0.025) remained associated with worse survival. STUDY LIMITATIONS: Retrospective study of a single tertiary hospital. CONCLUSIONS: Although the causes are still unknown, melanoma-specific survival was statistically worse for males and for "de novo" melanomas even after adjustment of tumor thickness.

In vivo confocal microscopy of dermoscopic suspicious lesions in patients with xeroderma pigmentosum: A cross-sectional study.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare genetic disease characterized by extreme photosensitivity, resulting in a higher incidence of cutaneous tumors. Reflectance confocal microscopy (RCM) is a noninvasive imaging method for diagnosing cutaneous lesions. OBJECTIVE: To explore the application of RCM in the follow-up of patients with XP. METHODS: Patients with XP underwent RCM for suspicious lesions from January 2010 through April 2019. Lesions with malignant RCM features were excised, and the results were compared with their histopathologic features. Benign lesions on RCM were monitored every 3 months. We recorded the confocal features that were related to malignancy and specifically to melanoma. RESULTS: A total of 61 suspicious lesions from 13 patients with XP were included. Thirty-three lesions (54%) were malignant (14 melanomas, 15 basal cell carcinomas, and 4 squamous cell carcinomas). Nonvisible papillae (OR, 11.8; 95% CI, 2.6-53.1; P = .001) and atypical cells at the dermoepidermal junction (OR, 11.7; 95% CI, 2.7-50.3; P = .001) were independent predictors of malignancy. LIMITATIONS: There were limited numbers of patients and lesions. Most cases were retrospectively included, and some did not have a histologic analysis. CONCLUSIONS: RCM is a valuable tool in the follow-up of patients with XP, reducing the need for excisions by 35%.

Antitumor effect of cell therapy with mesenchymal stem cells on murine melanoma B16-F10

In this study, the antitumor and immunomodulatory effects of mesenchymal stem cells (MSC) obtained from bone marrow in the treatment of dorsal melanoma B16-F10. The MSC cells were obtained from the bone marrow of isogenic C57BL/6J mice, characterized and inoculated by two routes, intratumor (it) and intravenous (iv). The hematological profile, expression markers and receptors, phases of the cell cycle and mitochondrial electrical potential were evaluated by flow cytometry. The dorsal tumor mass showed a significant reduction after treatment by the two routes of administration with a significant effect by the intravenous route. MSC showed immunomodulatory potential and did not induce an increase in the markers involved in tumor control and progression. The number of cells in the sub-G1 phase increased significantly after treatments compared to the control group. The percentage of cells in phases G0/G1, S and G2/M decreased, with only the group (it) showing a significant reduction. The intratumor group showed a significant decrease in the G2/M phase. Treatment with MSC provided a significant decrease in the percentage of metabolically active tumor cells, demonstrating its intrinsic effect in the control of cell proliferation. Regarding the mechanism of cell death, MSCs modulated the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors and pro-apoptotic proteins by intrinsic and extrinsic routes. Therefore, the use of undifferentiated MSC, administered intratumor and intravenous is possibly a promising treatment for melanoma.

Antitumor effect of cell therapy with mesenchymal stem cells on murine melanoma B16-F10

In this study, the antitumor and immunomodulatory effects of mesenchymal stem cells (MSC) obtained from bone marrow in the treatment of dorsal melanoma B16-F10. The MSC cells were obtained from the bone marrow of isogenic C57BL/6J mice, characterized and inoculated by two routes, intratumor (it) and intravenous (iv). The hematological profile, expression markers and receptors, phases of the cell cycle and mitochondrial electrical potential were evaluated by flow cytometry. The dorsal tumor mass showed a significant reduction after treatment by the two routes of administration with a significant effect by the intravenous route. MSC showed immunomodulatory potential and did not induce an increase in the markers involved in tumor control and progression. The number of cells in the sub-G1 phase increased significantly after treatments compared to the control group. The percentage of cells in phases G0/G1, S and G2/M decreased, with only the group (it) showing a significant reduction. The intratumor group showed a significant decrease in the G2/M phase. Treatment with MSC provided a significant decrease in the percentage of metabolically active tumor cells, demonstrating its intrinsic effect in the control of cell proliferation. Regarding the mechanism of cell death, MSCs modulated the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors and pro-apoptotic proteins by intrinsic and extrinsic routes. Therefore, the use of undifferentiated MSC, administered intratumor and intravenous is possibly a promising treatment for melanoma.

Skin lesions in organ transplant recipients: a study of 177 consecutive Brazilian patients.

BACKGROUND: Skin lesions are very common among organ transplant recipients (OTR), particularly infections and tumors, because of the immunosuppressive state these patients are put in. METHODS: 177 OTR were examined. Skin lesions were categorized into neoplastic, infectious, and inflammatory diseases. RESULTS: The mean age of OTR was 52 years, the mean age at transplantation was 42.7 years, and kidney was the most common organ transplanted (72%). Skin lesions were found in 147 patients (83%). Cutaneous infections were seen in 106 patients (60%). Warts (30%) had the larger incidence and were associated with azathioprine (P = 0.026), cyclosporine (P = 0.006), and tacrolimus (P = 0.009). Superficial mycoses occurred in 16% of OTR, mostly onychomycosis, which was associated with tacrolimus (P = 0.040). Actinic keratosis (AK) occurred in 31% of patients and cutaneous tumors in 56%. Squamous cell carcinoma (SCC) was the most common tumor type affecting 36% of OTR (n = 64), with invasive SCC predominating over in situ SCC, whereas basal cell carcinoma (BCC) accounted for 17%. Both SCC and BCC were more numerous in patients' skin type I (P < 0.05). SCC was more frequent (36%) in combined kidney and liver recipients (P = 0.004), and BCC was associated with cyclosporine (P = 0.047). Inflammatory complications (acne, alopecia, hypertrichosis, and gingival overgrowth) were observed in 17.5% of patients. CONCLUSIONS: Organ transplant recipients must be regularly evaluated by dermatologists, who should be alert to the onset of infections and skin (pre)malignant diseases in these patients.

High-risk mucosal HPV types associated with squamous cell carcinoma on the nose tip in an immunocompetent young man

Abstract: The oncogenic role of high-risk HPV in anogenital, head and neck, and cervical cancer is well recognized, but not in skin cancer in the general population. Some authors have demonstrated their appearance mainly on the hands and feet, particularly in the area of the nail bed, which could be due to contamination with HPV types from anogenital regions. Here, we describe a case of genital HPV associated with SCC on the nose tip in an immunocompetent young man, which was confirmed by histopathological findings and in situ hybridization. The importance of this report is to highlight the potential role of HPV in the etiology of skin cancer in an immunocompetent individual.

High-risk mucosal HPV types associated with squamous cell carcinoma on the nose tip in an immunocompetent young man.

The oncogenic role of high-risk HPV in anogenital, head and neck, and cervical cancer is well recognized, but not in skin cancer in the general population. Some authors have demonstrated their appearance mainly on the hands and feet, particularly in the area of the nail bed, which could be due to contamination with HPV types from anogenital regions. Here, we describe a case of genital HPV associated with SCC on the nose tip in an immunocompetent young man, which was confirmed by histopathological findings and in situ hybridization. The importance of this report is to highlight the potential role of HPV in the etiology of skin cancer in an immunocompetent individual.

Sweet Syndrome: Clinical Features, Histopathology, and Associations of 83 Cases.

BACKGROUND: Sweet syndrome (SS) is an infrequent skin disease characterised by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous plaques infiltrated by neutrophils. Multiple conditions have been associated with this syndrome. OBJECTIVES: The aim of this study was to evaluate the clinical, epidemiological, laboratory, and histopathological findings and associations of patients with SS. METHODS: We conducted a retrospective study of 83 patients with SS followed between January 1, 2006, and January 31, 2015. RESULTS: Of the patients, 82% were female; the mean age at onset was 48 years. Clinical presentation was mainly characterised by erythematous and edematous plaques, mostly on upper extremities and trunk. Fever was observed in 32%; 60% presented leukocytosis and 39% neutrophilia. On histopathological examination, neutrophilic and lymphohistiocytic infiltrate and edema were the most frequent findings. Fourteen percent of patients had malignancy or hematologic disorders, 26% were classified as having drug-induced SS, and 24% noted recent infection. Only 2 cases occurred during pregnancy. Systemic corticosteroid was the most common choice of treatment, with excellent response. In malignancy-associated SS, the mean hemoglobin level was lower ( P = .01) and the erythrocyte sedimentation rate (ESR) was higher ( P = .04) in comparison to classic and drug-induced SS. Leukocytoclasia was associated with higher risk of recurrence ( P = .01). CONCLUSION: All patients with SS deserve careful investigation of possible underlying conditions. Higher ESR and lower hemoglobin levels might reinforce the need of malignancy screening. Also, leukocytoclasia appears to be a potential marker of higher recurrence rate, demanding closer and longer follow-up.

Melanoma: tumor microenvironment and new treatments

Abstract: In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy. In this article, we will review the molecular bases for these new metastatic melanoma therapeutic agents cited above and also analyze new molecular discoveries in melanoma study, as Cancer-Testis antigens (CT). They are capable of induce humoral and cellular immune responses in cancer patients and because of this immunogenicity and their restrict expression in normal tissues, they are considered an ideal candidate for vaccine development against cancer. Among CT antigens, NY-ESO-1 is the best characterized in terms of expression patterns and immunogenicity. It is expressed in 20-40% of all melanomas, more in metastatic lesions than in primary ones, and it is very heterogeneous inter and intratumoral. Breslow index is associate with NY-ESO-1 expression in primary cutaneous melanomas, but its relation to patient survival remains controversial.