Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Cortical lesions in multiple sclerosis

none3Abstract Multiple sclerosis (MS) is typically considered to be a chronic inflammatory-demyelinating disease of CNS white matter. In the past decade, however, pathological and MRI studies have shown that lesions are often located in the gray matter, especially in the cerebral cortex. The histopathological characteristics of these cortical lesions differ substantially from lesions located in the white matter, which suggests location-dependent expression of the MS immunopathological process. Double inversion recovery imaging--an MRI technique that selectively images gray matter and lesions--has enabled researchers to image cortical lesions in vivo. Double inversion recovery studies have shown that cortical lesions can be detected at the earliest clinical stages of MS, and cortical lesion burden positively correlates with the severity of physical and cognitive impairments. These gray matter lesions are also independent predictors of subsequent disease evolution. This Review provides a summary of the main histopathological and MRI findings with regard to cortical lesions in MS, and indicates that increasing our understanding of cortical lesions has increased our knowledge of MS pathobiology.noneM. Calabrese;M. Filippi;P. GalloM., Calabrese; M., Filippi; Gallo, Paol

As classificações das fraturas do rádio distal são reprodutíveis? Concordância intra e interobservadores

CONTEXT AND OBJECTIVE: Various classification systems have been proposed for fractures of the distal radius, but the reliability of these classifications is seldom addressed. For a fracture classification to be useful, it must provide prognostic significance, interobserver reliability and intraobserver reproducibility. The aim here was to evaluate the intraobserver and interobserver agreement of distal radius fracture classifications. DESIGN AND SETTING: This was a validation study on interobserver and intraobserver reliability. It was developed in the Department of Orthopedics and Traumatology, Universidade Federal de São Paulo (UNIFESP) - Escola Paulista de Medicina. METHOD: X-rays from 98 cases of displaced distal radius fracture were evaluated by five observers: one third-year orthopedic resident (R3), one sixth-year undergraduate medical student (UG6), one radiologist physician (XRP), one orthopedic trauma specialist (OT) and one orthopedic hand surgery specialist (OHS). The radiographs were classified on three different occasions (times T1, T2 and T3) using the Universal (Cooney), Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation (AO/ASIF), Frykman and Fernández classifications. The kappa coefficient (κ) was applied to assess the degree of agreement. RESULTS: Among the three occasions, the highest mean intraobserver k was observed in the Universal classification (0.61), followed by Fernández (0.59), Frykman (0.55) and AO/ASIF (0.49). The interobserver agreement was unsatisfactory in all classifications. The Fernández classification showed the best agreement (0.44) and the worst was the Frykman classification (0.26). CONCLUSION: The low agreement levels observed in this study suggest that there is still no classification method with high reproducibility.CONTEXTO E OBJETIVO: Para que as classificações das fraturas possam ser úteis, elas devem prover o prognóstico, apresentar concordância interobservador e reprodutibilidade intraobservador. O objetivo foi avaliar a concordância intra e interobservadores das classificações das fraturas do rádio distal. TIPO DE ESTUDO E LOCAL: Estudo de validação (concordância intra e interobservadores), desenvolvido no Departamento de Ortopedia e Traumatologia da Universidade Federal de São Paulo (UNIFESP) - Escola Paulista de Medicina (UNIFESP-EPM), São Paulo, Brasil. MÉTODO: Foram avaliadas 90 fraturas do rádio distal com desvio por meio de radiografias por cinco observadores (um médico residente de Ortopedia do terceiro ano, um graduando do sexto ano de medicina, um médico radiologista, um ortopedista especializado em trauma e um ortopedista especializado em cirurgia da mão) em três momentos diferentes, empregando as classificações Universal (Cooney), AO/ASIF (Osteosynthesfragen/Association for the Study of Internal Fixation), Frykman e Fernández. Aplicou-se o coeficiente de concordância kappa (κ) para avaliação das classificações. RESULTADOS: O maior κ intraobservador médio, se considerarmos os três momentos, foi da classificação Universal (κ = 0,61), seguida da Fernández (κ = 0,59), Frykman (κ = 0,55) e AO/ASIF (κ = 0,49). A concordância interobservador foi insatisfatória em todas as classificações. A classificação de Fernández mostrou a melhor concordância (κ = 0,44) e a pior foi a de Frykman (κ = 0,26). CONCLUSÃO: Os baixos níveis de concordância observados neste estudo sugerem que atualmente ainda não há um método de classificação plenamente reprodutível