Michela Magistrello

TDP-43 Redistribution is an Early Event in Sporadic Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP‐43 has been identified as a component of ubiquitin‐immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP‐43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP‐43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP‐43 immunoreactivity was higher than that of ubiquitin‐immunoreactive ones. The percentage of TDP‐43‐positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP‐43, the immunoblot analysis of spinal cord and frontal cortex showed that full‐length TDP‐43, the 45 kDa form and ubiquitinated TDP‐43 are found in the soluble inclusion‐free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP‐43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.

Risk of cancer in patients with Guillain-Barré syndrome (GBS). A population-based study.

Abstract.The possible relationship between Guillain-Barré syndrome (GBS) and cancer is still controversial and the existence of a paraneoplastic GBS remains unconfirmed. To better define whether there is a relationship between GBS and malignancy, we compared the observed and the expected number of patients with tumours in a population-based cohort of subjects with GBS. Clinical differences between GBS patients with or without malignancies were analysed. Data were obtained from the Piemonte and Valle d’Aosta Register for GBS (PARGBS) (years 1990–1998). GBS was diagnosed according to NINCDS criteria. The number of expected cases of malignancy in the PARGBS population was calculated using the incidence rate of all types of cancer (ICD codes 140–208) in Piemonte [1985–1987], and in the most important town of this region, that is Turin (years 1993–1997). In the nine-year period, 435 incident patients with GBS were found. Nine of them developed cancer in the six months preceding or following GBS; in seven of them, the diagnosis of cancer and GBS was concomitant. The expected number of malignant tumours was 3.7 (using the incidence in Piemonte) and 3.8 (using the incidence in Turin); therefore, the odds ratios were 2.43 (95 % CI, 1.11–4.62) and 2.37 (95% CI, 1.09–4.50), respectively (p < 0.01). Although the cases with malignancies were clinically similar to the other cases of GBS observed through the Register, the mortality in GBS patients with cancer was higher and was the final cause of death in two patients affected by severe cancer. These results suggest a possible correlation between some cases of GBS and cancer. However, GBS in cancer patients does not meet all the criteria for paraneoplastic diseases.

Neuropathology of Olfactory Ensheathing Cell Transplantation into the Brain of Two Amyotrophic Lateral Sclerosis (ALS) Patients

Although a large number of amyotrophic lateral sclerosis (ALS) patients have undergone transplantation procedures with olfactory ensheathing cells (OECs) in the Bejing Hospital, to our knowledge, no post‐mortem neuropathologic analyses have been performed. We examined the post‐mortem brain of two Italian patients affected by ALS who underwent cellular transplantation in Beijing with their consent. Our aim was to assess the events following the graft procedure to possibly support the rationale of the treatment strategy. The neuropathologic findings were analyzed on the basis of the limited awareness of the experimental conditions and discussed in relation to the safety, efficacy and long‐term outcome of the transplanted cells. Islands of quiescent, undifferentiated cells within the delivery track persisting for up to 12 months–24 months were found. Prominent glial and inflammatory reaction around the delivery track strongly supports the encasement of the graft. Evidence of axonal regeneration, neuronal differentiation and myelination was not seen. The surgical procedure of implantation was not compatible with a neurotrophic effect. The OEC transplantation did not modify the neuropathology of ALS in the two patients. In conclusion, the present neuropathologic analysis does not support a beneficial effect of fetal OEC implantation into the frontal lobes of ALS patients.

Antiangiogenic therapy of brain tumors: the role of bevacizumab

Abstract Angiogenesis is one of the hallmarks of cancer, including brain tumors. Malignant gliomas have the highest degree of vascular proliferation among solid tumors; thus, angiogenic pathways represent an attractive target to interfere with tumor growth. Up to date VEGF pathway targeting with specific drugs has yielded interesting therapeutics results. In particular bevacizumab, a monoclonal antibody against VEGF-A, has shown clinical activity in malignant gliomas, especially glioblastomas, in terms of a high response rate on MRI and a significant increase in progression-free survival.

Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study

BACKGROUND Few data are available on temozolomide (TMZ) in ependymomas.We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy. PATIENTS AND METHODS We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria. RESULTS Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1-24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22-30.98) and 30.55 months (95% CI, 12.85-52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome. CONCLUSION TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.

Central neuropathic itch as the presenting symptom of an intramedullary cavernous hemangioma: Case report and review of literature

Itch, or pruritus, is an unpleasant cutaneous sensation associted with a pressing urge to scratch. It is one of the most frequent ymptoms in dermatology (e.g., in inflammatory skin disorders) nd general medicine (where it can be related to cholestasis, diaetes, uremia and lymphoma). Itch may also be observed in both peripheral and central nerous system (CNS) lesions, but it is rarely the isolated or the main ymptom of neurological disorders, especially in cases of spinal ord diseases. We report a case of localized itch as an isolated symptom of spinal cavernous hemangioma. Surgical excision allowed relief rom symptom. We reviewed different theories on the generation f itching and discussed its association with cervical lesions.

Molecularly based management of gliomas in clinical practice

Histological subtyping and grading of malignancy are the cornerstone of the present World Health Organization (WHO) Classification of CNS tumors. However, among diffuse gliomas of the adult, patients with histologically identical tumors may have different outcomes. As the genomic analysis of these tumors has progressed, it has become clear that specific molecular features transcend histologically defined variants, and may become markers of prognostic and/or predictive value. At the present time, the number of molecular biomarkers with confirmed clinical relevance (MGMT promoter methylation, 1p/19q codeletion, IDH1/2 mutations) remains limited, but new technologies will hopefully provide new candidates requiring rigorous validation in well-designed clinical trials.

Perspectives of Personalized Chemotherapy of Gliomas Based on Molecular Tumor Profiling

Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations. These markers may have either a prognostic or a predictive value, differentiation of which is often difficult as both can coexist. At present, MGMT promoter methylation is considered as a predictive marker for response of glioblastoma to chemotherapy with temozolomide, particularly in elderly patients, 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and predictive marker for response of anaplastic gliomas to PCV chemotherapy, and IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades.

Bevacizumab and temozolomide in secondary gliomatosis from gemistocytic astrocytoma: a case report

Gliomatosis cerebri is a rare diffuse glioma with a growth pattern consisting of exceptionally extensive infiltration of the CNS with involvement of at least three lobes. It may appear de novo (primary gliomatosis) or result from the spreading of a focal glioma (secondary gliomatosis). Bevacizumab is a monoclonal antibody anti-VEGF active against recurrent high grade gliomas after standard therapy. We report the case of a 41-year-old man with a secondary gliomatosis treated with bevacizumab and temozolomide who responded and the response lasted 17 months. Moreover, we focus on the side effects (hypertension, deep vein thrombosis) induced by bevacizumab and their effective treatments.