Carmen Vergara

Clinical and neuropathological study of six patients with spastic paraparesis associated with HTLV-I : An axomyelinic degeneration of the central nervous system

Between 1990 to 1994, 6 TSP/HAM patients, 3 women and 3 men with an average age of 57.1 years (39 to 76 years old), who died in the Salvador Hospital were submitted to postmortem examination. The mean time of paraparesis was 7 years (3 to 17 years), and 2 patients had pseudobulbar signs. Three cases had macroscopic atrophy of the spinal cord. Histologically, all cases had lesions in the pyramidal tracts and 4 cases showed somatotopic lesions of the Golls tracts which followed a “dying back” ascendant and descendant distribution, respectively. In 2 cases, both of which had intellectual impairment, demyelination of the subcortical and parathalamic areas was observed without U fiber involvement. Abnormal vessels with gross thickening of the adventitia, many of them with lymphocytic cuffs, were seen everywhere, especially in the spinal cord, brain stem, midbrain and meninges, but no relation between these findings and the parenchymal lesions was observed. Also, in the cases with posterior column involvement, neuronal changes and proliferation of satellite cells in the dorsal ganglia were found. All cases showed histological sialoadenitis and none had inflammatory muscle changes. We conclude that the lesions affected the neuraxis in a systemic axial fashion as in degenerative diseases, and did not seem to be secondary to vascular or inflammatory abnormalities.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein

Background: ERp57 is a disulfide isomerase up-regulated in prion related-disorders, but its impact on PrP biology is unknown. Results: ERp57 gain- and loss-of-function can increase or reduce, respectively, PrP levels in neurons, both in cell culture and animal models. Conclusion: ERp57 regulates steady-state prion protein levels. Significance: ERp57 is a cellular factor involved in the synthesis and folding of PrP, representing a novel therapeutic target in prion-related diseases. Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.

Leucemia linfoblástica aguda estirpe B philadelphia negativa en adolescentes y adultos jóvenes. Resultados del Protocolo Terapéutico LLA 15-30, Programa Nacional de Cáncer del Adulto (PANDA), Ministerio de Salud, Chile.

BACKGROUND Intensified treatment of Philadelphia chromosome negative acute lymphoblastic leukemia (Ph(-)ALL) in adolescents by pediatric teams, with fve years disease free survival (DFS) rate of 65%, encouraged the use of intensified protocols in patients between 15 and 30 years, improving the DFS from 45% to 60-80%. The protocol LLA 15-30 for patients between 15 and 30 years with Ph(-)ALL, based on the Childrens Oncology Group (COG) protocol AALL0232 resulting in a five years DFS of 78%, was started in 2007 by the PANDA national program. AIM To report the results of the prospective cohort study evaluating the results of this protocol four years after its implementation. PATIENTS AND METHODS Between January 2007 and December 2010, 68 Ph(-) ALL patients, aged between 15-30 years (75% males) were incorporated. Survival was evaluated using Kaplan-Meier and log-rank tests. RESULTS Fifty percent of patients were of high risk. A complete response was achieved in 91%, early death occurred in 6% and induction failure in 3%. Median follow-up was 23 months. Overall survival, disease free survival and relapse rates at 35 months were 61.8, 67.5% and 31% respectively. CONCLUSIONS LLA 15-30 protocol significantly improved three-year overall survival from 31 to 62%. The 20% difference observed with AALL0232 protocol is explained by the high rate of relapse. Improving provider and patient compliance with protocols may eliminate this gap.

Expresión de O6-metilguanina-ADN-metiltransferasa (MGMT) en pacientes chilenos con glioblastoma multiforme

BACKGROUND Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. AIM To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. MATERIAL AND METHODS Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. RESULTS The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. CONCLUSIONS Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.

O 6 -methylguanine-DNA-methyltransferase immunostaining intensity in glioblastoma

Immunohistochemistry (IHC) for O6-methylguanine-DNA-methyltransferase (MGMT) has shown heterogeneous results. Cell staining intensity has not been included as a quantifiable variable in IHC analyses. We performed MGMT IHC in 29 patients diagnosed as glioblastoma classifying cells into three categories based on nuclear staining intensity compared with adjacent endothelium. The median proportions of strong-moderate, weak and no staining cells were 10%, 16% and 71%, respectively. The proportion of positive cases for MGMT expression varies from 38% to 52% depending on the classification of weakly stained cells. This letter challenges previous studies that have not included intensity as a variable for IHC analysis.

Leucemia promielocítica aguda: Resultados del protocolo terapéutico LPA2000, Programa Nacional de Cáncer del Adulto (PANDA), Ministerio de Salud, Chile

Antecedentes: Las recomendaciones actuales de tratamiento de la leucemia promielocitica aguda (LPA) incluyen acido transretinoico (ATRA) y quimioterapia basada en antraciclinas. Objetivo: Evaluar los resultados del protocolo chileno, basado en el LPA99 del grupo espanol PETHEMA, con remplazo de idarrubicina por daunorrubina. Pacientes y metodo: La induccion consistio en Daunorrubicina 45 mg/m2 dias 2, 4, 6, y 8 mas ATRA 45 mg/m2 diario hasta la remision completa (RC). Los pacientes en CR recibieron cursos de quimioterapia cada tres meses: Daunorrubicina 45 mg/m2/d/4dias i.v. y ATRA 45 mg/m2/d/15 dias p.o (1°curso); mitoxantrona 10 mg/m2/d/5 dias i.v. y ATRA 45 mg/m2/d/15 dias p.o. (2°curso); Daunorrubicina 60 mg/m2/d/dia 1 i.v., en el grupo de bajo riesgo, y 1 y 2 en el grupo intermedio y alto ATRA 45 mg/m2/d/15 dias p.o. (3° curso). El tratamiento de mantencion consistio en mercaptopurina 90 mg/m2/d p.o., metotrexato 15 mg/m2/semanal p.o., y ATRA intermitente 45 mg/m2/d p.o. por 15 dias cada tres meses. Resultados: Entre Enero 2000 y Diciembre 2005, 56 pacientes con LPA recien diagnosticada fueron enrolados en 10 centros. Cuarenta y seis pacientes lograron RC (85%), 8 (15%) fallecieron por complicaciones tempranas, 7 pacientes recayeron, con riesgo de recaida a 3 anos de 16%. La sobrevida global y la sobrevida libre de recaida a 5 anos fue 64% y 84%, respectivamente. Conclusion: Los datos presentados muestran que el protocolo LPA2000 tiene buen efecto antileucemico pero se requiere reducir la mortalidad precoz para alcanzar mejores resultados.BACKGROUND The current recommendations for treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) include all-trans-retinoic acid (ATRA) and anthracycline based chemotherapy. AIM To evaluate the results of the Chilean protocol following the LPA99 regimen of the Spanish PETHEMA group, except for the replacement of Idarubicin by Daunorubicin. PATIENTS AND METHODS Induction consisted of Daunorubicin 45 mg/m² on days 2, 4, 6 and 8 plus ATRA 45 mg/m² daily until complete remission. Patients in complete remission (CR) received three monthly chemotherapy courses: Daunorubicin 45 mg/m²/d/4days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 1); Mitoxantrone 10 mg/m²/d/5 days i.v. and ATRA 45 mg/m²/d/15 days p.o. (course no. 2); Daunorubicin 60 mg/m²/d/ day 1 i.v. in the low risk group, and 1 and 2 in the intermediate-high risk groups and ATRA 45 mg/m²/d/15 days p.o. (course no. 3). Maintenance therapy consisted of mercaptopurine 90 mg/m²/d p.o., methotrexate 15 mg/m²/wk p.o. and, ATRA intermittently, 45 mg/m²/d p.o. for 15 days every three months. RESULTS Between January 2000 and December 2005, 56 patients with newly diagnosed APL from 10 centers were enrolled. A total of 46 patients achieved CR (85%), 8 (15%) died of early complications, seven patients relapsed, with a 16% relapse risk at three years. The 5-year Kaplan-Meier estimates of overall survival and relapse-free survival were 64% and 84% respectively. CONCLUSIONS These data indicate that this protocol has a good antileukemic effect but further reduction of early death and relapse, especially in the high risk group is needed.

Neuropathological Study of Acute Myelopathy and Encephalopathy Associated to HTLV-I

Background a chronic and progressive parapares is without remission silent on MRI is the ordinary neurological presentation of HTLV-I, expression of a central axonopathy product of axoplasmic transport alterations. Infrequently acute forms like “T2 hyperintense acute myelopathy on MRI” have been reported. The Purpose of this presentation will be to describe the histopathological expression of this acute form and look for their pathogenesis. Patient and method: A 60 years old woman carrier of refractory anaemia and subjected to multiple transfusions, positive for HTLV-I. She developed a severe cognitive impairment and paraplegia set up in four weeks. MRI showed T2 hyper intense lesions in white matter of brain hemispheres and in cervico-thoraxic segments of the spinal cord. She died suddenly by myocardial infarction. The neuropathological studies showed white matter necrosis insymmetricfrontal areas, conservation of cortical structures and U fibbers; necrosis in bothlateral tracts of the spinal cord (T2T4) without gray substance damage; the microvascular walls of these areas immuno-stained with anti-Tax, expressed Taxprotein suggesting HTLV-I infection. Conclusions: This necrotizing leukopathy in absence of a primary inflammation would be the expression of HTLV-I endothelial cells infection in specific white matter areas, changing of the blood-brain barrier permeability.