NRAS mutation status is an independent prognostic factor in metastatic melanoma.

BACKGROUND: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease. RESULTS: The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT"). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05). CONCLUSIONS: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma.

Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome.

PURPOSE: To compare the efficacy and safety of voriconazole with itraconazole as prophylaxis in leukemia patients. METHODS: Open-label, randomized study. Patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy or first salvage were eligible. Patients received voriconazole (400 mg intravenous (i.v.) every 12 h for two doses, followed by 300 mg BID) or itraconazole (200 mg i.v. twice daily for 2 days, followed by 200 mg i.v. daily). RESULTS: A total of 127 patients were enrolled. Four were excluded because they did not receive study drug (n=3) or received two antifungal agents during the first week on study (n =1), leaving 123 patients for analysis. None of the 71 patients receiving voriconazole developed proven or probable invasive fungal infection, compared to two (4%) of the 52 patients receiving itraconazole (P=0.17). Drug discontinuation because of adverse events occurred in 15 patients (21%) receiving voriconazole and six (11%) receiving itraconazole (P=0.23). CONCLUSIONS: Voriconazole is a good alternative for prophylaxis in patients with leukemia. Elevated baseline bilirubin levels were associated with a higher risk of side effects in patients receiving i.v. voriconazole or i.v. itraconazole. Monitoring of liver function and drug levels should be considered for some patients.

Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features.

Brain metastases (BM) are among the most devastating and debilitating complications of melanoma. This retrospective study was conducted to gain a better understanding of patient and disease characteristics that have the greatest impact on overall survival in melanoma patients with BM; therapeutic interventions were also assessed. The records of all patients diagnosed with cutaneous melanoma and BM who were seen at Memorial Sloan-Kettering Cancer Center between 1991 and 2001 were retrospectively reviewed. A variety of factors, including age at diagnosis of stage IV disease, gender, race, disease stage at diagnosis, presence of BM at diagnosis of stage IV disease, neurologic symptoms, radiographic findings, number of BM, status and site(s) of extracranial metastasis, and treatment modalities, were analyzed for correlation with overall survival using univariate and multivariate Cox regression models. The records of 355 patients with BM were included in the analysis. On univariate analysis, seven patient and disease characteristics were significantly associated with poorer survival: age > 65 years, extracranial metastases, BM at stage IV diagnosis, neurologic symptoms, four or more BM, hydrocephalus, and leptomeningeal metastases. Of these, age, extracranial metastasis, neurologic symptoms, and number of BM were significantly associated with poorer survival in a multivariate analysis. Multivariate analysis of treatment modalities suggested that patients who had surgery, radiosurgery, or chemotherapy with temozolomide had improved survival outcomes, although this analysis has limitations. The prognostic factors identified in this retrospective study should be considered when making treatment decisions for patients with BM and used as stratification factors in future clinical trials.

Prácticas corporales e innovación en educación infantil (0-6 años): análisis crítico desde la mirada de expertos

Resumen Este estudio de tipo cualitativo, fenomenológico, tiene por objetivo identificar las concepciones, características y lineamientos orientadores de las prácticas corporales con un carácter innovador. Para la recogida de información se aplican entrevistas en profundidad a un grupo de expertos en la temática, y su análisis, se realiza desde una lógica inductiva interpretativa, siguiendo las directrices de la "Grounded Theory"; categorías emergentes y codificación abierta, axial y selectiva. Todo ello, apoyado por el software Nvivo. Los hallazgos relevan como ejes centrales de la innovación en dichas prácticas: su renovación o transformación, contextualización social, pensamiento renovador y creativo del educador, libertad de exploración, y posibilidades de creación de nuevas relaciones por parte de los niños y las niñas. Aspectos en crisis identificados son: pérdida del sentido pedagógico, del carácter lúdico, y los procesos de escolarización.

Abstract The aim of this qualitative and phenomenological study is to identify conceptions, characteristics and guidelines of innovative corporal practices. Data collection was performed through in-depth interviews to experts. The analysis is performed from an interpretative inductive logic, following guidelines from "Grounded Theory": emergent categories, and open, axial and selective coding by means of Nvivo software. Findings reveal the following central axes of innovation: renewal or transformation, social contextualization, renovating and creative knowledge of the educator, freedom of exploration, and possibilities to create new relationships by the children. Also, the study identifies the loss of both the pedagogical sense, the playful character and the schooling processes.

Resumo Este estudo qualitativo, fenomenológico, tem como objetivo identificar os conceitos, as características e as diretrizes que orientam as práticas corporais com um carácter inovador. A produção de informações foi por meio de entrevistas com um grupo de especialistas na área e a sua análise foi feita a partir de uma lógica indutiva interpretativa, seguiu as diretrizes da Grounded Theory; categorias emergentes e codificação aberta, axial e seletiva, com uso do software NVivo. Os resultados revelam alinhamento central para a inovação em tais práticas: renovação ou transformação, contextualização social, o renovador e educador pensamento criativo, a liberdade de exploração e as possibilidades de criação de relacionamentos por crianças. Além disso, o estudo identifica a perda do sentido pedagógico, do caráter lúdico e dos processos de escolarização.

Estudio Descriptivo: Detección del Dolor Músculo - Esquelético y Enfermedades Reumáticas Aplicando el COPCORD en la Población Indígena de Saraguro - Ecuador / Descriptive Research: Pain Muscle ­ Esquelectic Detecction and Copcord Aplication Reumatics Copcord Reumatics Illness in Indigena Population of the Saraguro - Ecuador

INTRODUCCIÓN: El instrumento COPCORD permite identificar el dolor músculoesquelético y enfermedades reumáticas como artrosis, artritis reumatoide, lumbalgia. El objetivo de esta investigación es validar y adaptar transculturalmente el instrumento COPCORD en la población indígena como prueba de tamizaje para la detección de estas enfermedades. MÉTODOS: Se trata de un estudio descriptivo, el universo fue de 210 indígenas mayores de 18 años que residen en Saraguro ­ Loja, Ecuador. Durante el periodo del 1 diciembre de 2016 al 30 de enero de 2017. El COPCORD se ajustó al lenguaje español, se realizó adecuación y validación transcultural al contexto del grupo indígena. La información fue ingresada en el programa estadístico Stata Versión 11, se analizó: alfa de Cronbach, matrices de correlación con la prueba de Spearman. Se correlacionó las variables con el diagnóstico establecido por el reumatólogo. RESULTADOS: La edad promedio fue 46.1 años, 64.7 % del género femenino, la prueba de tamizaje para detectar una enfermedad reumática tiene sensibilidad del 92.3 % y especificidad de 57.9 %. La consistencia interna del cuestionario presentó unidimensionalidad en los apartados de carga biomecánica y capacidad funcional; y multidimensionalidad en la trayectoria del dolor músculo - esquelético y comorbilidades. Se observaron correlaciones significativas del COPCORD comparado con la evaluación del reumatólogo. CONCLUSIONES: Al realizar la validación y adaptación transcultural del cuestionario COPCORD se demostró su utilidad como prueba de tamizaje para la detección del dolor músculo - esquelético y enfermedades reumáticas en la población aplicada

BACKGROUND: The COPCORD instrument allows the identification of musculoskeletal painand rheumatic diseases such as osteoarthritis, rheumatoid arthritis, low back pain. The aim of this research is to validate and cross-culturally adapt the COPCORD instrument in the indigenous population as a screening test for the detection of these diseases. METHODS: It is a descriptive study, the universe of 210 indigenous people over 18 years residing in Saraguro - Loja, Ecuador. During the period from December 1, 2016 to January 30, 2017. The COPCORD was adjusted to the Spanish language, a transcultural adaptation and validation was made to the context of the indigenous group. The information was entered into the statistical program of Stata Version 11, analyzed: Cronbach's alpha, correlation matrixes with the Spearman test. The variables were correlated with the diagnosis established by the rheumatologist. RESULTS: The average age was 46.1 years, 64.7 % of the female gender, the screening test to detect a rheumatic disease has sensitivity of 92.3 % and specificity of 57.9 %. The internal consistency of the questionnaire presented a dimensionality in the biomechanical load and functional capacity sections; and multidimensionality in the path of musculoskeletal pain and comorbidities. Significant correlations of the COPCORD were observed compared with the rheumatologist's evaluation. CONCLUSIONS: By carrying out the cross-cultural validation and adaptation of the COPCORD questionnaire, its usefulness could be demonstrated as a screening test for the detection of musculoskeletal pain and rheumatic diseases in the population of Saraguro.of approach including the laparoscopic approach.

Chemical castration of melanoma patients does not increase the frequency of tumor-specific CD4 and CD8 T cells after peptide vaccination.

Peptide vaccination against tumor-associated antigens remains one of the most common methods of immunization in cancer vaccine clinical trials. Although peptide vaccination has been reported to increase circulating antigen-specific T-cells, they have had limited clinical efficacy and there is a necessity to increase their capacity to generate strong antitumor responses. We sought to improve the clinical efficacy of peptide-based vaccines in cancer immunotherapy of metastatic melanoma using a LHRH agonist (leuprolide) as adjuvant. Seventy HLA-A*0201 stage IIb-IV melanoma patients were vaccinated with class I HLA-A*0201-restricted gp100209-2M peptide and stratified for HLA-DP4 restriction. HLA-DP4 patients were also vaccinated with class II HLA-DP4-restricted MAGE-3243-258 peptide. Patients from both groups were randomized to receive 2 doses of leuprolide or not. Here we report the increase in PBMC TREC levels at week 24 after peptide vaccination, which was independent of the leuprolide treatment. This change was mirrored by a small increase in the TREC-enriched CD8CD45RAROCD27CD103, but not the TREC-enriched CD4CD45RAROCD31 T-cell population. Serum concentration of 2 important factors for thymopoiesis was measured: insulin growth factor 1 (IGF-1) levels were not changed, whereas a moderate increase in IL-7 levels was noted in the sera of all patients 6 weeks after vaccination. Increased expression of CD127 (IL-7 receptor-α) at week 24, compared with baseline, was only seen in the CD8CD45RAROCD27CD103 T-cell population. Our results suggest that leuprolide has no effect on thymic output when used as peptide vaccine adjuvant, but IFA-based peptide vaccination may unexpectedly affect the thymus by increasing thymic output of new T cells.

Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases.

Venous thromboembolism (VTE) is a frequent complication in melanoma patients with brain metastases (BM). The management of these patients is challenging because of the high risk of intracranial hemorrhage (ICH) and the limited data available on the safety of anticoagulation in this scenario. We reviewed the treatments and outcomes among melanoma patients with BM and VTE at our institution to determine the safety of anticoagulation in these patients. A retrospective chart review was performed to identify melanoma patients with BM who were diagnosed with VTE. The clinical characteristics of the BM and the VTE, the treatments given for VTE, subsequent ICH, and overall survival (OS) were determined. The characteristics and outcomes were compared between patients who received systemic anticoagulation and those who did not. A total of 74 evaluable melanoma patients with BM and VTE were identified. Fifty-seven (77%) patients received systemic anticoagulation. There was no significant difference in the number (P=0.40) or the maximum diameter (P=0.55) of brain metastasis between the patients who received anticoagulation and those who did not. Two (4%) patients who received anticoagulation developed ICH, which was not statistically different from the patients who did not receive anticoagulation (0%, P=1.00). There was a trend toward longer OS from VTE among patients who received systemic anticoagulation (median OS: 4.2 vs. 1.2 months, P=0.06). Anticoagulation for VTE did not significantly increase the risk of ICH or decrease OS in patients with melanoma BM. These data support the safety of systemic anticoagulation for VTE in these patients.

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.

PURPOSE: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. EXPERIMENTAL DESIGN: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. RESULTS: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. CONCLUSION: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.

Uso de Terapias Complementarias en el Tratamiento de Pacientes con Lumbalgia Crónica del Seguro Social de Salud. La Libertad, 2009 / Use of complementary therapies in the treatment of chronic low back pain in patients from Peruvian Health Insurance (EsSalud). La Libertad, 2009

Objetivo: Describir las variaciones en el consumo de analgésicos en pacientes con lumbalgia crónica que recibieron terapias con medicina complementaria. Materiales y métodos: Estudio descriptivo. Se realizó en el Centro de Atención de Medicina Complementaria (CAMEC) ­ La Libertad en el periodo marzo-mayo de 2009, de seis semanas de seguimiento en 45 pacientes que recibieron terapias con medicina complementaria. Se incluyeron pacientes con diagnóstico de lumbalgia mayor de 12 semanas y tratamiento farmacológico activo. Se evaluaron características clínico-epidemiológicas, factores de riesgo asociados (obesidad, estrés, sedentarismo, polifarmacia), tiempo de enfermedad, terapia utilizada, disminución del consumo de analgésicos y el grado de satisfacción. Resultados: Un 77,8% presentó el diagnóstico de lumbalgia crónica inespecífica. Las terapias complementarias más indicadas fueron acupuntura, masoterapia y fitoterapia; en su mayoría de modo combinado. En seis semanas de seguimiento el 93,3% de la población redujo, en alguna medida, la dosis habitual de analgésicos; mientras que el 40% suspendió totalmente su consumo. El 86,7% de los pacientes manifestaron haber obtenido resultados excelentes o buenos después de la aplicación de terapias alternativas. Conclusiones: El uso de terapias complementarias en el tratamiento de la lumbalgia crónica disminuye el uso de analgésicos y brinda una percepción de satisfacción en los pacientes.

Pelvic computed tomography scans for surveillance in patients with primary melanoma in the head and neck.

Although pelvic computed tomography (CT) scans are frequently performed as a part of routine surveillance, the evidence for or against the routine use of these scans in patients with primary melanoma in the head and neck is weak. We conducted a retrospective study to evaluate the value of pelvic CT scans as routine surveillance in patients with primary melanoma in the head and neck. We identified 146 patients with either primary or mucosal primary melanoma who had adequate follow-up evaluation for at least 5 years at our institution. Among them, 33 patients (23%) had stage III melanoma, and four (3%) had stage IV melanoma at the time of diagnosis. At a median follow-up duration of 49 months, 110 patients (75%) had developed recurrences, and the median time to the first recurrence was 13 months. A total of 82 (56%) patients had eventually developed distant metastases, but only 10 (7%) had developed metastases in the pelvis, and none had developed pelvic metastases as the first and the only site of recurrence. If the true rate of finding the pelvic metastasis as the first and the only recurrence was at least 3%, the probability of seeing 0 events of the 146 patients was 1.17%. This study, which is the largest series to evaluate the value of pelvic CT scans in this patient population to date, suggests that the routine use of a pelvic CT scan as a surveillance method does not have any impact on the management in patients with primary melanoma in the head and neck.

Multielemental fractionation in human peripheral blood mononuclear cells by size exclusion liquid chromatography coupled to UV and ICP-MS detection.

An analytical methodology is presented in this work to determine metal-biomolecule complexes size distribution patterns of several elements, among different compounds present in human peripheral blood mononuclear cells (PBMC). A hyphenated technique based on size exclusion chromatography (SEC) coupled online to UV and inductively coupled plasma mass spectrometry (ICP-MS) detection is used. Two different SEC columns with separation ranges between 1,500-1,000,000 relative molecular mass (M(r)) (Nanofilm SEC-250) and 5,000 and 100,000 relative molecular mass (M(r)) (TSK-Gel G2000 SW) are used with 10 mmol/L tris-HCl at pH 7.3 as mobile phase. Retention behavior (retention time and peak-area ratios) remained unchanged for several successive separations. Metal-containing compounds are found to a wide range of M(r). Copper-zinc superoxide dismutase, copper and zinc metallothionein, and copper and zinc transferrin are identified in PBMC samples. A high M(r) (147,000) metal-binding protein containing copper and zinc and a high M(r) (107,000) manganese-binding protein were also found; however, these remained unknown.

The clinical efficacy of combination of docetaxel and temozolomide in previously treated patients with stage IV melanoma.

No standard therapy exists for patients with metastatic melanoma whose disease failed to respond to first-line systemic treatment. We conducted a retrospective study to evaluate the clinical efficacy of the combination of docetaxel and temozolomide in previously treated patients. We searched our institution's patient and pharmacy databases for patients with metastatic melanoma who received docetaxel-tamozolomide and reviewed their medical records. We identified 38 patients who received docetaxel-temozolomide between February 2002 and January 2007 for resistant or refractory melanoma to a first-line therapy. The median age was 50 years, and all patients had stage IV melanoma (M1c, 87%) including 16 (42%) with brain metastases. All patients had received the same combination regimen: 80 mg/m docetaxel intravenously on day 1 and 150 mg/m temozolomide orally on days 1-5 every 28 days. Five patients (13%) had a partial response, and five (13%) had stable disease. The median time to disease progression was 8 weeks, and the overall survival duration was 26 weeks. Among the 10 patients who had a clinical benefit, the median time to disease progression was 51 weeks. Among 16 patients with brain metastases, none had confirmed clinical response in the brain. The regimen was generally well tolerated, with less than or equal to 8% of patients experiencing grade III or IV neutropenia or thrombocytopenia. Within the limitation of being a retrospective study with a potential patient selection bias, the docetaxel-temozolomide combination has modest activity, and is a reasonable option for previously treated patients with metastatic melanoma.

A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence.

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-alpha-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled - 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies.

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.