Pityriasis rubra pilaris heralding diagnosis of urothelial carcinoma: a case report.

Pityriasis rubra pilaris is a papulosquamous inflammatory dermatosis that can be associated with HIV, autoimmunity, infections, certain medications, and neoplasms. Paraneoplastic pityriasis rubra pilaris has previously been reported in association with solid organ malignancies and once with leukemia. Herein, we present an elderly man with paraneoplastic pityriasis rubra pilaris, heralding the diagnosis of low-grade papillary urothelial carcinoma. Our patient's pityriasis rubra pilaris resolved after surgical resection of the tumor.

Degenerative collagenous plaques of the hands in an elderly woman.

Degenerative collagenous plaques of the hands is an underrecognized acquired dermatosis characterized by slowly progressive linear depressed bands appearing symmetrically at the margins of palmar and dorsal skin of the hands. It is more common in the elderly and is believed to result from chronic pressure and ultraviolet radiation. We present an elderly woman with degenerative collagenous plaques of the hands to highlight an underrecognized rare dermatosis.

"Involved in something (involucrado en algo)": Denial and stigmatization in Mexico's "war on drugs".

This article responds empirically to the question posed by Stan Cohen about "why, when faced by knowledge of others' suffering and pain-particularly the suffering and pain resulting from what are called 'human rights violations'-does 'reaction' so often take the form of denial, avoidance, passivity, indifference, rationalisation or collusion?". Our context is Mexico's "war on drugs." Since 2006 this "war" has claimed the lives of around 240,000 Mexican citizens and disappeared around 60,000 others. Perpetrators include organized criminal gangs and state security services. Violence is pervasive and widely reported. Most people are at risk. Our study is based on qualitative interviews and focus groups involving 68 "ordinary Mexicans" living in five different Mexican cities which have varying levels of violence. It investigates participant proximity to the victims and the psychological defense mechanisms they deploy to cope with proximity to the violence. We found that 62 of our participants knew, directly or indirectly, one or more people who had been affected. We also found one dominant rationalization (defense mechanism) for the violence: that the victims were "involved in something" (drugs or organized crime) and therefore "deserved their fate." This echoes prevailing state discourses about the violence. We argue that the discourse of "involved" is a discourse of denial that plays three prominent roles in a highly violent society in which almost no-one is immune: it masks state violence, stigmatizes the victims, and sanctions bystander passivity. As such, we show how official and individual denial converge, live, and reproduce, and play a powerful role in the perpetuation of violence.

Pregnancy-Associated "Cutaneous Type" Pemphigus Vulgaris.

The development of pemphigus, including pemphigus vulgaris (PV) and pemphigus foliaceus, during pregnancy is rare. PV manifests with mucosal and/or cutaneous erosions with flaccid bullae that are histologically characterized by suprabasilar acantholysis. In contrast, pemphigus foliaceus manifests with cutaneous-only involvement and superficial epidermal acantholysis. Enzyme-linked immunosorbent assay specific for autoantibodies against desmoglein 1 and desmoglein 3 aids in the diagnosis and differentiation between pemphigus subtypes. High-dose systemic corticosteroids are first-line agents in management of PV, yet their potential long-term use raises complex management issues associated with pregnancy and fetal risk. Here we report a rare case of cutaneous-limited PV in association with pregnancy.

Expression of Notch signaling components in cutaneous foreign body and sarcoidal granulomas and fusing macrophages.

The evolutionarily conserved Notch signaling pathway affects tissue-specific cell differentiation, proliferation, and apoptosis. In the immune system, Notch has been implicated in the development and function of both adoptive and innate immune cells. Notch signaling is initiated by Notch receptor binding to cognate ligands, which results in the enzymatic cleavage and intranuclear translocation of the intracellular domain of Notch receptor (ICN). Recent murine models of chronic inflammation highlighted a critical role for a Notch ligand, Delta-like ligand (Dll)-4, in granuloma formation. In this study, we aimed to assess Notch-1 receptor activation and Dll4 expression in human cutaneous granulomas and in cultured human macrophages and multinucleated giant cells. ICN1 and Dll4 expression was evaluated by immunohistochemistry of cutaneous foreign body (n = 15) and sarcoidal (n = 19) granulomas. The results showed consistent intranuclear staining for ICN1 in foreign body but not in sarcoidal granulomas and strong cytoplasmic staining for Dll4 in mononuclear histiocytes and multinucleate giant cells in both types of granulomas. Additionally, immunofluorescence confocal microscopy showed ICN1 and Dll4 expression by cultured human macrophages undergoing fusion in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. These findings indicate a potential role for the Notch-1-Dll4 signaling pathway in foreign body-induced granulomatous reactions and possibly distinct Notch pathway utilization in sarcoidal granulomas.

Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.

Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.

A multimarker prognostic assay for primary cutaneous melanoma.

PURPOSE: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers in primary cutaneous melanoma. EXPERIMENTAL DESIGN: We assessed expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of 395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival (DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections. RESULTS: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN status (P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS (P < 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic factors, including SLN status (P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort (P = 0.01). CONCLUSIONS: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with melanoma in two distinct cohorts.

A multi-marker assay to distinguish malignant melanomas from benign nevi.

The histopathological diagnosis of melanoma can be challenging. No currently used molecular markers accurately distinguish between nevus and melanoma. Recent transcriptome analyses have shown the differential expression of several genes in melanoma progression. Here, we describe a multi-marker diagnostic assay using 5 markers (ARPC2, FN1, RGS1, SPP1, and WNT2) overexpressed in melanomas. Immunohistochemical marker expression was analyzed in 693 melanocytic neoplasms comprising a training set (tissue microarray of 534 melanomas and nevi), and 4 independent validation sets: tissue sections of melanoma arising in a nevus; dysplastic nevi; Spitz nevi; and misdiagnosed melanocytic neoplasms. Both intensity and pattern of expression were scored for each marker. Based on the differential expression of these 5 markers between nevi and melanomas in the training set, a diagnostic algorithm was obtained. Using this algorithm, the lesions in the validation sets were diagnosed as nevus or melanoma, and the results were compared with the known histological diagnoses. Both the intensity and pattern of expression of each marker were significantly different in melanomas compared to nevi. The diagnostic algorithm exploiting these differences achieved a specificity of 95% and a sensitivity of 91% in the training set. In the validation sets, the multi-marker assay correctly diagnosed a high percentage of melanomas arising in a nevus, Spitz nevi, dysplastic nevi, and misdiagnosed lesions. The multi-marker assay described here can aid in the diagnosis of melanoma.

Novel role for RGS1 in melanoma progression.

RGS1 (regulator of G protein signaling 1) encodes a member of the regulator of G protein family. Recently, RGS1 was found to be overexpressed in gene expression-profiling studies of melanoma. However, no analyses have been reported of its expression at the protein level in melanoma. In this study, the potential impact of RGS1 as a molecular prognostic marker for melanoma was assessed using immunohistochemical analysis of a melanoma tissue microarray containing primary cutaneous melanomas from 301 patients. High RGS1 expression was significantly correlated with increased tumor thickness (P=0.0083), mitotic rate (P=0.04), and presence of vascular involvement (P<0.02). Kaplan-Meier analysis demonstrated a significant association between increasing RGS1 expression and reduced relapse-free survival (P=0.0032) as well as disease-specific survival (DSS) (P=0.018) survival. Logistic regression analysis showed RGS1 overexpression to be significantly correlated to sentinel lymph node metastasis (P=0.04). Multivariate Cox regression analysis showed that increasing RGS1 immunostaining had an independent impact on the relapse-free survival (P=0.0069) and DSS (P=0.0077) of this melanoma cohort. In the analysis of DSS, RGS1 expression level was the most powerful factor predicting DSS. RGS1 immunostaining retained independent prognostic impact even when sentinel lymph node status was included in the prognostic model (P=0.0039). These results validate the role of RGS1 as a novel prognostic marker for melanoma given its impact on the survival associated with melanoma.

Osteopontin as a molecular prognostic marker for melanoma.

BACKGROUND: Osteopontin has been suggested as a marker of disease progression in patients with melanoma because of its overexpression in recent microarray analyses. However, its prognostic role in melanoma has not been fully defined. METHODS: Osteopontin expression status was examined using immunohistochemical analysis of a tissue microarray that contained primary cutaneous melanomas from 345 patients. The correlation between osteopontin expression and several histologic markers for melanoma was assessed by using the Chi-square test and the Le directional test. The impact of osteopontin expression on recurrence-free survival (RFS) and disease-specific survival (DSS) of patients with melanoma was examined using Cox regression and Kaplan-Meier analyses. The impact of increasing osteopontin expression on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: High osteopontin expression was associated with increased tumor thickness (P = .037), Clark level (P = .035), and mitotic index (P = .046). Kaplan-Meier analysis demonstrated an association between osteopontin expression and reduced RFS (P < .03) and DSS (P = .05). Multivariate Cox regression analysis demonstrated that high osteopontin immunostaining had an independent impact on the DSS of this melanoma cohort (P = .049). In addition, osteopontin expression was significantly predictive of SLN metastasis (P = .009) and SLN burden, as assessed by the mean number of SLN metastases (P = .0025). Multivariate logistic regression analysis demonstrated an independent role for osteopontin expression in predicting SLN status (P = .0062). CONCLUSIONS: The current results validated the role of osteopontin as an independent prognostic marker for melanoma and provided new evidence for its predictive role in melanoma lymph node metastasis.

Prognostic significance of nuclear receptor coactivator-3 overexpression in primary cutaneous melanoma.

PURPOSE: To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. PATIENTS AND METHODS: NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. RESULTS: Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration. CONCLUSION: These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.

Genes and pathways downstream of telomerase in melanoma metastasis.

Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.

Fertilización IN VITRO; experiencia de tres años del grupo SER, en la Clínica Carlos Ardila Lülle / IN VITRO Fertilization: Three years of experience in SERïS group

Se presenta el estudio y análisis retrospectivo de 3 años de trabajo en Fertilización in vitro (IVF), del grupo SER, de la Clínica Carlos Ardila Lülle de Bucaramanga; durante los cuales realizaron 68 ciclos. Se establecen correlaciones entre la edad de la paciente, etiología de la infertilidad, número de ciclos realizados por paciente con el éxito reproductivo, encontrándose que las tasas de embarazo corresponden a un 24,56 por ciento, teniendo mayor probabilidad de éxitos aquellas parejas donde la infertilidad es inexplicada y en segundo término aquellas donde la causa de ésta es debida a factor anatómico diferente a endometriosis