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Background: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint‐ (ICIs) and MAPKinase inhibitors (MAPKis). Objective: Our aim was to describe therapy response and survival in a real‐world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first‐line ICIs or MAPKis. Methods: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow‐up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression‐free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. Results: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M‐stage (OR 0.65; 95% CI 0.45–0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19–0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83–0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12–0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M‐stage (HR 1.34; 95% CI 1.07–1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19–2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01–1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08–1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02–1.09; P = 0.005) for PFS. Conclusion: ICIs and MAPKis were effective in this real‐world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation. [ABSTRACT FROM AUTHOR]

Background: Although considered as a first‐group carcinogen, indoor tanning is a common practice in Europe. Euromelanoma is a pan‐European skin cancer prevention campaign. Objectives: To compare several European countries in terms of the prevalence and determinants of sunbed use. Methods: Participants in the Euromelanoma campaigns filled in questionnaires containing demographics and risk factors, including type/duration of sunbed use. Multivariate analyses adjusted for age, gender, education, skin type and year of survey were employed to assess factors independently associated with sunbed use in each country. Results: In total, 227 888 individuals (67.4% females, median age 44, 63.4% highly educated, 71.9% skin types III–VI) from 30 countries participated. Overall, the prevalence of sunbed ever use was 10.6% (≤19‐year‐olds: 5.9%; 20 to 35‐year‐olds: 17.0%; >35‐year‐olds: 8.3%). Females displayed a higher prevalence than males in all countries. Balkan countries displayed the highest female/male ratios (≥4). Sunbed use was significantly more prevalent among skin type III–VI (14/30 countries) and highly educated participants (11/30 countries). Significant correlations were found between sunbed use prevalence and countries' latitude (P < 0.001) and sunshine (P = 0.002); Italy and Spain represented exceptions towards excessive exposure. Very different prevalence rates were found for Spain (19.3%) and Portugal (2.0%). Scandinavian countries ranked highest in sunbed use among ≤19‐year‐olds, Baltic countries among 20 to 35‐year‐olds. Conclusions: Sunbed use prevalence was higher in northern, sun‐deprived countries, with the exception of Italy and Spain. The main determinants of sunbed use were age (young adults) and gender (females), whereas education and skin type had a less relevant effect. Geographic particularities were found in four regions: Iberian (prevalence ten times higher in Spain than Portugal), Balkan (prevalence disproportionately higher among women), Baltic (highest prevalence among young adults) and Scandinavian (highest prevalence among adolescents). These data have public health relevance for future interventions aimed at reducing sunbed use in Europe. [ABSTRACT FROM AUTHOR]

Introduction: Sunbed use has been significantly associated with increased risk of melanoma and non‐melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once‐a‐year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires. Objectives: To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer. Methods: To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use. Results: Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I–II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01–1.10)], atypical nevi [SOR = 1.04 (1.00–1.09)], lentigines [SOR = 1.16 (1.04–1.29)] and suspicion of melanoma [SOR = 1.13 (1.00–1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91–1.10)]. Conclusions: Indoor tanning is significantly associated with well‐recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high‐risk phenotypes. [ABSTRACT FROM AUTHOR]

Statins are notorious for causing myalgia and sometimes mild elevation of CPK (creatine phosphokinase). Herein, we present a case of necrotizing autoimmune myopathy induced by statins. The patient was on therapy with atorvastatin for about six years before she started developing myalgia and mild elevation in CPK that resolved after discontinuation of therapy. Since her cardiovascular risk was high and she had hypercholesterolemia, three months after CPK levels normalization, she was re-challenged with pravastatin. Few months later, she again presented severe myalgia, weakness, and elevated CPK levels. Hence, medication was discontinued, and she undergone an extensive workup for possible causes of inflammatory myopathies that revealed necrotizing autoimmune myopathy. Our case report offers an excellent source of “identification patterns” of muscular autoimmune disease which can be easily mistaken as common side effect of a drug. [ABSTRACT FROM AUTHOR]

Anti‐HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single‐center retrospective chart review of pediatric KT recipients with anti‐HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty‐six patients (mean age 15.4y) with DSAs initially detected 1 month‐14.3 years post‐transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty‐two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3‐ patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97‐55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA‐positive pediatric KT recipients. [ABSTRACT FROM AUTHOR]

Purpose: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%) which preferentially occurs in the liver. Conventional chemotherapy being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. Experimental Design: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. Result: We showed that PPP efficiently block growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanism involved in metastasis, including tumor cells adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layer. Furthermore, PPP significantly delayed established of uveal melanoma tumor and drastically reduced the indence of liver metastasis in mice. Conclusions: Our data suggest that IGR-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease. [ABSTRACT FROM AUTHOR]

Purpose: The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulin-like growth factor-1 receptor (IGF-1R) and inhibits growth of uveal melanoma cells in vitro and in vivo. In this study, we aimed to investigate the efficiency of orally administered PPP on growth of uveal melanoma xenografts. Further, we focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established anti-tumor agents in vitro. Methods: Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-FU and doxorubicin. Cell viability was determined by XTT assay. SCID mice xenografted with uveal melanoma cells were used to determine anti-tumor efficacy of oral PPP in vivo. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by western blotting. Results: PPP was found to be superior to the other anti-tumor agents in killing uveal melanoma cells. Oral PPP inhibited uveal melanoma growth in vivo and was well tolerated by the animals. PPP decreased VEGF expression in the tumors. Conclusions: Oral PPP is well tolerated in vivo and caused total growth inhibition of uveal melanoma xenografts as well as it decreased the levels of VEGF in the tumors. [ABSTRACT FROM AUTHOR]

Systemic sclerosis is a rare autoimmune disorder with a wide spectrum of clinical manifestations and a multitude of autoantibodies that are associated with it. In the past several years, advances in serologic testing have led to research indicating important prognostic and phenotypic associations with certain subsets of autoantibodies. In particular, anti-RNA polymerase III (anti-RNAP III) has been associated with diffuse cutaneous disease, scleroderma renal crisis, a temporal relationship with malignancy, myositis, synovitis, joint contractures, and gastric antral vascular ectasia. However, anti-RNAP III has not been associated with systemic sclerosis sine scleroderma. We describe a patient with an atypical presentation of anti-RNAP III positive systemic sclerosis sine scleroderma who presented without the typical features of anti-RNAP III disease. Instead, she presented with critical digital ischemia, pulmonary arterial hypertension, gastroesophageal reflux disease, interstitial lung disease, and no clinically detectable sclerodactyly. [ABSTRACT FROM AUTHOR]

Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor therapy for antibody-mediated rejection. Pediatr Transplantation 2011: 15: 548-556. © 2011 John Wiley & Sons A/S. Abstract: AMR is being recognized with increasing efficiency, but continues to present a significant threat to renal allograft survival. Traditional therapies for AMR (IVIG, plasmapheresis, rituximab, and antilymphocyte preparations) in general have provided inconsistent results and do not deplete the source of antibody production, viz., the mature plasma cell. Recently, the first plasma cell-targeted therapy in humans has been developed using bortezomib (a first in class PI) for AMR treatment in kidney transplant recipients. Initial experience with bortezomib involved treatment of refractory AMR. Subsequently, the efficacy of bortezomib in primary therapy for AMR was demonstrated. In a multicenter collaborative effort, the initial results with bortezomib in AMR have been confirmed and expanded to pediatric and adult heart transplant recipients. More recently, results from a prospective, staged desensitization trial has shown that bortezomib alone can substantially reduce anti-HLA antibody levels. These results demonstrate the significant potential of proteasome inhibition in addressing humoral barriers. However, the major advantage of proteasome inhibition lies in the numerous potential strategies for achieving synergy. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to report a case of orbital solitary fibrous tumour (SFT) in a child and to review the relevant literature. Methods: We describe an SFT in a 13-year-old boy with a 1-month history of painless proptosis in the left eye. Results: Magnetic resonance imaging revealed a well circumscribed mass filling most of the left intraconal orbit. The lesion was excised and histopathological examination revealed a malignant SFT. Postoperative follow-up for 18 months was uneventful. Conclusions: Malignant SFT of the orbit should be included in the differential diagnosis of paediatric orbital tumours. Complete surgical excision remains the preferred method of management and the longterm prognosis is guarded. [ABSTRACT FROM AUTHOR]

Purpose: Uveal melanoma disseminates preferentially to the liver. The mechanism for this homing is largely unknown, but growth factors synthesized in the liver may be involved. The present study was undertaken to investigate the possible relationship between cell surface receptors for two such growth factors: the c-Met proto-oncogene, which constitutes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), and the insulin-like growth factor 1 receptor (IGF-1R). Their role as a prognostic factor was also clarified. Methods: Paraffin-embedded tumor specimens from 132 patients with primary uveal melanoma were analyzed by using well-established specific antibodies against c-Met and IGF-1R. The intercorrelation of receptor expression and association with melanoma-related survival of patients were determined by univariate and multivariate analyses. Results: Whereas the expression of both IGF-1R and c-Met was significantly associated with melanoma-specific mortality by univariate analysis (p = 0.004 and p = 0.007, respectively) only IGF-1R showed independent prognostic value by multivariate analysis, p = 0.004. The prognostic value of IGF-1R was stronger than such currently used prognostic parameters as tumor cell type and tumor diameter (p = 0.021 and p = 0.026, respectively). The expression patterns of the two growth factors receptors were weakly intercorrelated. Conclusions: In conclusion, the data suggest that the receptors for IGF-1 and HGF/SF may play a role in the spread of uveal melanoma and its affinity to the liver. The strong correlation between IGF-1R expression and melanoma-specific mortality points to the use of IGF-1R as a prognostic tool [Economou MA, All-Ericsson C, Bykov V, Girnita L, Bartolazzi A, Larsson O & Seregard S (2005): Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications. Invest Ophthalmol Vis Sci 46: 4372–4375]. [ABSTRACT FROM AUTHOR]

Introduction: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. Purpose: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. Materials and Methods: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. Results: Mice treated with PPP, administered intraperitoneally or orally, showed 22–32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. Conclusions: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD. [ABSTRACT FROM AUTHOR]

Inosine 5′-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the rate-limiting step of the de novo pathway for purine synthesis and is a major target of the immunosuppressive drug mycophenolic acid (MPA). Few variants of the IMPDH1 gene have been reported. The objective of this study was to identify and characterize IMPDH1 variants to determine whether genetic variation contributes to differences in MPA response and toxicity in transplant patients. Seventeen genetic variants were identified in the IMPDH1 gene with allele frequencies ranging from 0.2 to 42.7%. In this study, 191 kidney transplant patients who received mycophenolate mofetil were genotyped for IMPDH1. Two single-nucleotide polymorphisms, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post-transplantation. Future studies of the multifactorial nature of acute rejection must consider IMPDH1 polymorphisms in MPA-treated patients.Clinical Pharmacology & Therapeutics (2008); 83, 5, 711–717. doi:10.1038/sj.clpt.6100347 [ABSTRACT FROM AUTHOR]

An increasing number of studies demonstrate the clinical impact of preformed and de novo anti-human leucocyte antigen alloantibody (HLA-Ab) in solid organ transplantation (Tx). The screening of HLA-Ab in candidates and transplant recipients has evolved over time, with continuous improvement in the sensitivity and specificity of assays for HLA-Ab detection. Furthermore, histologic markers of complement activation pathways are currently implemented in the diagnosis of antibody-mediated rejection (AMR). Therapeutic strategies, including depletion of HLA-Ab and B cells, have allowed Tx across antibody barriers, or have rescued patients with AMR. The purpose of the present review is to summarize the state-of-the-art of HLA-Ab detection, clinical significance and therapeutic strategies in pediatric solid organ Tx. [ABSTRACT FROM AUTHOR]

Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting. In Table 3, the confidence interval for the age group >=50 <70 for immune checkpoint inhibitors (ICIs) was 0.17-1.18, rather than 0.17-1.78, and the third category for Performance status (PS) was 3-4 but was automatically converted to 03-Apr. Finally, in the univariable analyses of BMI for ICIs in Table 4, the p-value for BMI as a continuous variable should be 0.736, while that for BMI >=30 was in fact 0.298 rather than 0.2980.736, as the two values ended up in the same cell. Corrigendum: Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting. [Extracted from the article]