Sural nerve involvement in Guillain-Barré syndrome: Clinical and prognostic implications. A prospective cohort.

BACKGROUND: Sural sparing is common in Guillain-Barré syndrome (GBS). However, one third of patients have sural nerve compromise. Its clinical implications associated factors and short-term prognosis are still unknown. The objective of this study is to identify if sural nerve compromise is associated with a worse prognosis and to describe clinical and electrophysiological characteristics in Guillain-Barré syndrome. MATERIALS AND METHODS: We prospectively analyzed patients with Guillain-Barré diagnosis with vs without sural nerve compromise. All patients underwent nerve conduction studies within the first 3 days of hospital admission. Clinical and electrophysiological characteristics were compared between groups. RESULTS: 174 patients were included in this study. Acute inflammatory demyelinating polyneuropathy was the predominant variant (43.7 %). Thirty percent of patients had sural nerve involvement. In the comparative analysis between affected vs unaffected sural groups, age ≥50 years and Guillain-Barré disability score ≥3 demonstrated a statistically significant difference. Regarding short-term recovery period for independent walking, there was no significant difference. In the multivariate analysis, age ≥50 years was identified as independent factors for sural nerve compromise on admission. CONCLUSION: sural nerve compromise occurs in 30 % of patients with GBS and is not associated with a worse functional prognosis. Age ≥50 years was identified as an independent factor for sural nerve compromise.

Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.

PURPOSE: One of the hallmarks of cancer immunotherapy is the long duration of responses, evident with cytokines like interleukin-2 or a variety of cancer vaccines. However, there is limited information available on very long term outcomes of patients treated with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies. Tremelimumab is an anti-CTLA-4 antibody of immunoglobulin G2 (IgG2) isotype initially tested in patients with advanced melanoma over 12 years ago. METHODS: We reviewed the outcomes of patients with advanced melanoma enrolled in four phase 1 and 2 tremelimumab trials at two sites to determine response rates and long-term survival. RESULTS: A total of 143 patients were enrolled at two institutions from 2002 to 2008. Tremelimumab administration varied between a single dose of 0.01 mg/kg and 15 mg/kg every 3 months. Median overall survival was 13 months (95% confidence interval (CI), 10-16.6), ranging from less than a month to 12+ years. An objective response rate of 15.6% was observed, with median duration of response of 6.5 years, range of 3-136+ months. The Kaplan-Meier estimated 5 year survival rate was 20% (95% CI, 13-26%), with 10 and 12.5 year survival rates of 16% (95% CI, 9-23%). CONCLUSIONS: CTLA-4 blockade with tremelimumab can lead to very long duration of objective anti-tumour responses beyond 12 years.

Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma.

PURPOSE: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. EXPERIMENTAL DESIGN: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. RESULTS: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. CONCLUSION: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

Las actividades docentes de los profesores clínicos del PUEM desde la perspectiva de sus residentes / PUEM's clinical professors' teaching activities from their residents' perspective

Introducción: Se busca describir las actividades docentes en el ámbito clínico desde la perspectiva de los residentes del PUEM. Objetivos: 1) Identificar la frecuencia con que los profesores clínicos realizan actividades educativas en 4 áreas: docencia, supervisión, organización y relaciones interpersonales, 2) distinguir por especialidad el desempeño de los instructores, 3) indagar diferencias en la evaluación del docente según el grado académico de los residentes. Material y métodos: La "Encuesta de Alumnos del PUEM 2010" incluyó en la sección del desempeño docente 13 preguntas de frecuencia y 2 de valoración. Se consideraron actividades educativas de las 4 áreas mencionadas en 10 especialidades. La muestra fue de 1816 casos y se buscaron asociaciones significativas (p < 0.05) entre las variables. Resultados: En las opciones de respuesta "siempre" y "casi siempre", las relaciones interpersonales fueron las mejor valoradas (> 80%), la organización continua de actividades académicas y asistenciales fue mencionada en más de 2 terceras partes de las respuestas. La frecuencia de actividades docentes vinculadas a la estructura curricular, y la supervisión se ubicaron en promedio por debajo de la media. Las mejores calificaciones fueron para los profesores de Medicina Familiar y las más bajas para Ortopedia. Por grado académico, R1 y R5 consideraron que la labor docente fue más constante y los R2 menos. Discusión: La relación personal entre profesores y residentes es adecuada y los estudiantes se perciben integrados a sus servicios; no obstante, el apego a los programas académicos y la supervisión no sucede con suficiente frecuencia.

Introduction: The aim is to describe the teaching activities in the clinical context from the residents' perspective. Objectives: 1) To determine how frequently clinical professors perform teaching activities in the four areas: teaching, supervision, organization and interpersonal relationships, 2) to distinguish professors' performance by specialty 3) To inquire differences in the evaluation of professors according the residents' academic year. Materials and methods: The "Survey among PUEM's Students 2010" included 13 frequency questions and 2 of valuation in the section of teaching performance. Teaching activities from the four previously mentioned areas in ten specialties were considered. The sample was 1816 cases; significant associations (p <0.05) among variables were assessed. Results: In the answer choices: "always" and "almost always", interpersonal relationships obtained the highest score (>80%), the regular organization of academic and healthcare activities was mentioned in more than 2/3 of the answers. The frequency of teaching activities related to the curricular structure, and supervision were situated below average. The highest scores were for family medicine professors and the lowest for orthopedia. By academic grade, first and fifth year residents considered that teaching activities were more constant; while second year students considered them the least constant. Discussion: Personal relationships between clinical professors and residents are adequate. Students perceive themselves integrated to their wards; however the fulfillment of academic programs and supervision are not frequent enough.

Lupus neuropsiquiátrico: Reporte de Caso y revisión de la literatura / Neuropsychiatric systemic lupus erythematosus: Case report and review of literature

Se presenta el caso de una mujer de 42 años de edad que inicia manifestaciones neurológicas caracterizadas por parestesias y hemiparesia corporal derecha. Con importante duda diagnóstica en su debut, pero la características de las lesiones (localización en corteza, ausencia en sustancia -lanca, falta de distribución arterial), serología positiva para LES y proteinuria, determino el diagnóstico de Lupus eritematoso Sistémico Neuropsiquiátrico (LENSP). El propósito de este manuscrito es informar la baja prevalencia (menor al 4%)¹ de esta manifestación y como representa un reto diagnóstico.

The case of a 42-year-old woman who presented neurologic symptoms characterized by paresthesias and right hemiparesis is presented here. Although the diagnosis was difficult at the beginning; yet, the features of the lesions (located in the cerebral cortex but not in the white matter; no arterial distribution), positive serology for SLE and proteinuria, determined the diagnosis of Neuropsychiatric systemic lupus erythematosus. The purpose of this work is to inform about the low prevalence (<4%) of the disease and how it is a diagnostic challenge.

CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans.

BACKGROUND: CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses. METHODS: Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3. RESULTS: There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3. CONCLUSION: CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.

Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma.

BACKGROUND: Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. METHODS: The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity. RESULTS: Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays. CONCLUSIONS: The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma. CLINICAL TRIAL REGISTRATION: NCT00107159.

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.

PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma.

BACKGROUND: CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated. METHODS: Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis. RESULTS: Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup. CONCLUSION: Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood. CLINICAL TRIAL REGISTRATION NUMBER: NCT00086489.

Bases moleculares de la esclerosis múltiple / Multiple sclerosis: molecular findings

La esclerosis múltiple EM es una enfermedad inflamatoria, caracterizada por destrucción primaria de la mielina, en mayor frecuencia se presenta con una evolución de brote-remisión en ocasiones progresiva. En la actualidad se acepta que en los países latinoamericanos la prevalencia se encuentra entre 12-15 casos por 100 000 habitantes. La etiología de la enfermedad y los factores que determinan su curso permanecen desconocidos. El diagnóstico de la EM depende de la historia clínica y la exploración neurológica, así como de imagen por resonancia magnética, potenciales evocados y examen de líquido cefalorraquídeo. El tratamiento depende de la evolución de la enfermedad y de las secuelas que haya deidado. La esclerosis múltiple es una enfermedad que debe ser reconocida como una entidad que se observa con relativa frecuencia en México.

La adrenopausia femenina a nivel del mar y en la altura (4200 m) implicación en envejecimiento / The feminine adrenopausia at level of the sea and in the height (4200 m) implication in aging

El presente estudio ha sido diseñado para determinar si el envejecimiento, determinado a través de la adrenopausia o disminución de los andrógenos adrenales, ocurre más temprano en la altura que a nivel del mar en Perú se determinará igualmente la relación de la adrenopausia con la menopausia en mujeres de nivel del mar y de la altura. A si mismo se determina la relación de los andrógenos adrenales plasmáticos con la saturación arteria de oxigeno, el hematocrito y los niveles de testosterona y estradiol. El estudio se ha realizado en 210 mujeres mestizas, nativas de altura y residentes en Cerro de Pasco. Perú (4340 m) de edades entre 20 y 70 años y en 123 mujeres es de entre 24 y 69 años, que viven en Lima a 150 m sobre el nivel del mar. Los resultados demuestran que la menopausia se presenta a una edad más temprana en la altura. Con la edad se observa una disminución en los niveles de la dehidroepiandrosterona (DHEA) y su sulfato (DHEAS) en la altura y al nivel del mar, siendo más temprana y de mayor magnitud en la altura. La disminución de los andrógenos adrenales precede a la elevación de la FSH sérica propia de la perimenopausia: igualmente se observa con la edad una disminución de la saturación arterial de oxigeno con aumento del hematocrito y de la relación testosterona / estradiol en las mujeres de la altura. En conclusión la adrenopausia es más temprana y de mayor magnitud en mujeres mestizas en la altura que a nivel del mar.