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Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m2 every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended. [ABSTRACT FROM AUTHOR]

The t(4;14)(p16;q32) translocation, found in 15% of multiple myeloma (MM) cases, indicates a poor prognosis. Plasma cells (PC) with t(4;14) ectopically express the fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase receptor, which has potential transforming activity and may represent a therapeutic target. To detect FGFR3 protein expression, bone marrow (BM) aspirate from 200 consecutive newly diagnosed ( n = 116) or relapsing ( n = 74) MM patients was studied by flow cytometry (FC) using anti-CD138 and anti-FGFR3 antibodies. FC data was compared to real time quantitative-polymerase chain reaction (RQ-PCR) of the IGH-MMSET and FGFR3 transcripts. An IGH-MMSET transcript was found in 24/200 patients (12%). In 20 of these, FC detected CD138+/FGFR3+ cells. No expression of FGFR3 was detected in the 4 FGFR3− cases by RQ-PCR. FGFR3 was never expressed on PC without t(4;14). Circulating PC (CPC) were detected in patients with (11/11) and patients without (13/41) t(4;14). In 2/8 t(4;14) cases studied longitudinally, coexisting FGFR3+ and FGFR3− CPC were observed. Fluorescent in situ hybridisation (FISH) analysis of the FGFR3− subclones showed deletion of the der(14) in one patient. In conclusion, as a supplemental method to RQ-PCR or FISH, FC analysis of FGFR3 expression is a reliable and routinely available method for the detection and management of new therapeutic approaches of t(4;14) MM. [ABSTRACT FROM AUTHOR]

Many epidemiological and clinical studies in Europe, especially in Eastern Europe and countries in transition, are of poor methodological quality because of lack of background knowledge in clinical epidemiology methods and study designs. The only way to improve the quality of epidemiological studies is to provide adequate undergraduate and/or postgraduate education for the health professionals and allied health professions. To facilitate this process, the European Federation of Neurological Societies (EFNS) Task Force on teaching of clinical epidemiology in Europe was set up in October 2000. Based on analyses of the current teaching and research activities in neuroepidemiology in Europe, this paper describes the Task Force recommendations aimed to improve these activities. [ABSTRACT FROM AUTHOR]

Retrospective and cross-sectional studies have suggested that both bacterial and viral infections may be risk factors for atherosclerosis, ischemic stroke and acute coronary events. The correlation between Chlamydia pneumoniae and atherosclerosis remains a source of controversy. Our case–control study is aimed at evaluating the frequency of C. pneumoniae infection in a cohort of young adults with recent cerebrovascular disease and in particular etiologic stroke subtypes. Chlamydia pneumoniae IgG, IgM and IgA antibodies were evaluated by microimmunofluorescence method and antibody titers to both recombinant antigens chlamydial outer protein 2 and 60-kDa chlamydial heat shock protein (HSP60) by ELISA. The two groups differed with regard to the prevalence of C. pneumoniae IgA ( P < 0.001) and IgG ( P < 0.0001), as well as the titer of anti-R-HSP60 IgG ( P < 0.001). We found an increase in IgA titers, suggestive of persistent, chronic active infection, in 16 patients in whom the etiology of the cerebral ischemic event was large-vessel atherothrombosis. Persistent, active C. pneumoniae infection may be an additional risk factor for ischemic stroke mainly of atherotrombotic origin in young subjects. However, a large-scale prospective confirmation of our findings is required. [ABSTRACT FROM AUTHOR]

Idiopathic multicentric Castleman disease (iMCD) is a non-clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD-not otherwise specified (iMCD-NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD-NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD-NOS, respectively. The two-year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm 3 ), high lymphocyte count (>3000/mm 3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

We report the off-label use of bortezomib combined with dexamethasone in eight adults with severe and multi-refractory warm auto-immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1-4) cycles. After a median follow-up of 14 (6-36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

We retrospectively analysed 71 cases of Unicentric Castleman disease, a rare, usually asymptomatic, benign lymphoproliferative disorder presenting as a unique nodal mass. Although surgery is considered as the gold standard therapy, only 38 patients (54%) underwent initial surgical resection and 95% were cured. An additional 9 patients had surgery after an attempt at medical reduction. Reduction therapy was used in 21 patients with a 55% response rate, but without evidence for an optimal regimen. Radiotherapy was limited to 8 patients because of associated toxicity. Watch and wait was considered in 13 asymptomatic patients and 11 of these remained stable for up to 17 years., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman-like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV-8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV-8 negative/idiopathic multicentric CD (iMCD). 2-( 18 F)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline-vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV-8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV-8+ MCD, particularly in HIV-infected patients., (© 2017 John Wiley & Sons Ltd.)

Objective: To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor alpha (TNFalpha) receptor (TNFR1) in the pathogenesis of the disease., Methods: The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFalpha promoter by DNA sequencing., Results: Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFalpha promoter., Conclusion: TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.

Fifty-three patients with relapsing-remitting multiple sclerosis who had monthly Gd (gadolinium) enhanced MRI (Magnetic Resonance Imaging) and clinical evaluation, were divided into two subgroups: 1) patients with a clinical relapse, treated with IVMP (intravenous methylprednisolone) and at least one enhancing lesion on MRI. 2) patients who did not have a clinical relapse but with at least one enhancing lesion on MRI. In group 1, we evaluated the number and volume of enhancing lesions on the scan before and three scans after IVMP therapy; in group 2, we considered the first scan with enhancing lesions and the subsequent three scans. The mean number and volume of enhancing lesions on the first scan was significantly higher in patients with clinical relapse compared to patients without clinical relapse. In group 1, we found a consistent reduction in the first scan following steroid treatment which returned to initial levels at the following scan. Both volumetric and numerical evaluation are appropriate MRI outcome measures in monitoring therapeutic trials.

We studied polysomnographic recordings using an Oxford Medilog 9000 System in 18 patients with ischemic stroke in the middle cerebral artery territory. All patients underwent neurologic examination and brain CT scan within 5 h after the onset of symptoms. Polysomnographic recordings were started immediately thereafter and went on for three nights. Clinical and polysomnographic follow-up were performed 3 weeks after admission. The number and duration of REM phases were significantly reduced in the acute phase. This reduction correlated with the severity of neurological deficit at outcome and with the anatomical site of the lesion on CT scan. Our data provide evidence that polysomnographic recording is useful to detect symptoms of patients with different clinical outcomes during the acute phase of ischemic stroke.

This study investigated the relationship between depression, physical disability, cognitive deficit and brain abnormalities on magnetic resonance imaging (MRI) in patients with early MS. Eighteen relapsing-remitting MS patients were evaluated: depression was diagnosed according to DSM-III R and measured by the MMPI depression subscale, physical disability was assessed by using the Kurtzke Expanded Disability Status Scale (EDSS) and cognitive functions by means of an extensive neuropsychological test battery. A neuroradiologist blinded to clinical findings quantified cerebral lesion on MRI. Weighted brain area lesion score were developed according to number and size of cerebral lesions. On the basis of DSM-III criteria, six patients were classified as having major depression, seven patients had minor depression and five patients were without depressive symptoms. No significant differences were found among the three groups on both neuropsychological performances and weighted MRI lesion scores. However patients with major depression exhibit greater physical disability than the other MS subgroups. A significant correlation was found between MMPI depression subscale and physical disability. This study suggests that at least in the early phase of MS, depression appears more related to the physical disability than to the severity of pathological brain involvement.

The influence of pregnancy on the relapse rate (number of relapses per person per year) in MS was analysed for 52 women who had a pregnancy during the disease. The relapse rate was lower during the pregnancy-year (9 months of pregnancy and 6 months immediately post partum) than the non-pregnancy time. There was a heterogeneous pattern during the pregnancy-year with a sharp decrease in the relapse rate observed during pregnancy and a slight non-significant increase in the puerperium: both these relapse rates were compared with figures observed in the same group of women during the non-pregnancy time. Pregnancy does not appear to be a period at greater risk for exacerbations but, on the contrary it seems to act, on the whole, as a protective event. These data allow physicians to provide reassuring counselling to women.

Blood levels of triglycerides, total cholesterol, isolated lipoprotein fractions (VLDL-LDL- and HDL-cholesterol) and apoproteins (Apo-A1 and Apo-B) were examined in multi-infarct dementia, senile dementia of the Alzheimer type, ischemic stroke associated with carotid atherosclerosis and in control subjects. Forty patients divided into 10 consecutive patients for each group were studied. Alzheimer patients showed mean total cholesterol and Apo-B values significantly higher than control subjects. Apo-B was significantly higher in stroke patients than in controls. The mean lowest HDL-cholesterol (HDL-c) value was observed in stroke patients. No significant differences in mean HDL-c levels were found between patients with multi-infarct and Alzheimer dementia.

Amantadine, administered at a dose of 200 mg/day, antagonized the extapyramidal symptomatology induced by neuroleptic drugs in fifteen psychiatric patients. Steady-state levels were reached within 4-7 days of treatment. Individual plasma levels ranged from 200-900 ng/ml. Apparent plasma half-lives varied from 10-28.5 h with an apparent VD of 200-400 litres. A significant relationship was found between the plasma levels of amantadine and the effects on the extrapyramidal symptomatology. The data suggest a direct effect of amantadine on dopaminergic receptors.

Peripheral white blood cell (WBC) count was determined in 95 patients with ischemic cerebral infarction 3 days after the onset of the stroke. At this time, higher WBC counts were found in patients with more severe neurological impairment and larger infarct size. A relationship between increase of WBC count and poor clinical outcome was also demonstrated. The elevation of peripheral WBC count observed soon after cerebral infarction reflects the degree of the inflammatory response in the acute hase and seems to have a direct relationship with the extent of the local cerebral damage.

Cerebral blood flow (CBF) was studied in 4 patients with acute reversible ischemia (RIND). To test the ischemic areas' vasoreactivity, CBF was measured by the Xenon-133 inhalation method, before and after acetazolamide injected intravenously. At the baseline CBF study, 3 patients presented hypoperfused areas while one patient had increased CBF over the affected hemisphere. The acetazolamide test, showed in this latter case a "steal phenomenon" while in the other 3 an increase of perfusion was evidenced, in areas of normal flow, as well as in areas with reduced flow. These results suggest that in the acute phase of patients with RIND, when brain regions of hypoperfusion and neurological signs are still present, the vasomotor response may be preserved.