Low rCBV values in glioblastoma tumor progression under chemoradiotherapy.

PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.

Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.

AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

Cerebral amyloid angiopathy-related inflammation: clinical features and treatment response in a case series.

INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an entity characterised by an inflammatory response to ß-amyloid deposition in the walls of cerebral microvessels. METHODS: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. RESULTS: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. CONCLUSIONS: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy.

Cerebral amyloid angiopathy-related inflammation: clinical features and treatment response in a case series. / Inflamación relacionada con angiopatía amiloide: características clínicas y respuesta al tratamiento en una serie de casos.

INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an entity characterised by an inflammatory response to ß-amyloid deposition in the walls of cerebral microvessels. METHODS: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. RESULTS: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. CONCLUSIONS: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy.

Classification of oligodendroglial tumors based on histopathology criteria is a significant predictor of survival--clinical, radiological and pathologic long-term follow-up analysis.

BACKGROUND: The clinical course of oligodendroglial tumors is variable and there is a lack of consensus with regard to precisely diagnose which minimal criteria are required to make a diagnosis of a high-grade oligodendrial tumor. The aims of the present study are to assess pathologic factors with prognostic significance, in addiction to clinical and neuroradiologic variables, in an attempt to identify reproducible histological parameters that are useful for classification of oligodendroglial tumors. METHODS: 80 oligodendroglial tumors diagnosed between 1977 and 2004 were analyzed. To make a diagnosis of anaplastic tumor we used reproducible parameters: endothelial proliferation, high cellularity, increased mitotic activity and necrosis. Oligoastrocytomas (mixed gliomas) were diagnosed when the astrocytic component was clearly identified as part of the neoplastic cell population. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log-rank probability test. A Cox regression model was made for multivariable analysis. RESULTS: The histologic diagnosis was low-grade oligodendroglioma in 35 patients (43.75%), anaplastic oligodendroglioma in 23 patients (28.75%), low-grade oligoastrocytoma in 11 patients (13.75%) and anaplastic oligoastrocytoma in 11 patients (13.75%). Median overall survival of the whole series was 80 months. The median overall survival of oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma and anaplastic oligoastrocytoma was 148, 105, 47 and 7 months, respectively (p < 0.0001). Multivariate analysis revealed that age, Karnofsky performance status, histological grade and histological diagnosis (oligodendroglioma vs. oligoastrocytoma) were independently associated with survival. CONCLUSIONS: Clear cut histopathological criteria (endothelial proliferation, high cellularity, mitotic activity and necrosis) allow to establish different oligodendroglial tumor entities with distinct survival outcome.

Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.

Morphologic Features on MR Imaging Classify Multifocal Glioblastomas in Different Prognostic Groups.

BACKGROUND AND PURPOSE: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously. MATERIALS AND METHODS: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006-2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis. RESULTS: Age (P < .001, hazard ratio = 2.11, c-index = 0.705), surgery (P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width (P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity (P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width (P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity (P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes (P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival (P < .001, hazard ratio = 18.67, c-index = 0.967). CONCLUSIONS: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups.

SEOM clinical guidelines for anaplastic gliomas (2017).

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

Correction to: SEOM clinical guidelines for anaplastic gliomas (2017).

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

SEOM clinical guideline of diagnosis and management of low-grade glioma (2017).

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk-benefit ratio of adjuvant treatment must be weighed for each individual.

Correction to: SEOM clinical guideline of diagnosis and management of low-grade glioma (2017).

The original version of this article unfortunately contained a mistake. Figure 3 was incorrect.

[Sensory ganglionopathy as a manifestation of celiac disease]. / Ganglionopatia sensitiva como manifestacion de enfermedad celiaca.

INTRODUCTION: The neurological manifestations of celiac disease (CD) may be caused by the disease itself, by associated autoimmune diseases or by complications from the tumours that may develop in the long term. We report a case of sensory ganglionopathy associated to CD. CASE REPORT: A 59-year-old female with chronic diarrhoea and loss of weight, who visited because of a clinical picture of gait disorders that progressed to the point where she was barely able to walk. Having been diagnosed with CD, finding a sensory ganglionopathy with dysautonomia (an atypical manifestation of this disease) led to a diagnosis of associated Sjogren's syndrome (SS). CONCLUSIONS: The neurological manifestations of CD are very varied, but in the presence of a sensory ganglionopathy, a neurological picture that is atypical in this disease, it becomes necessary to suspect SS, which is an infrequent but well established association. Likewise, all patients with SS must be screened for CD, which (albeit subclinically) can be complicated in the long term by the development of tumours. The differential diagnosis of the neurological manifestations of CD and of sensory ganglionopathy, as well as the association between celiac disease and SS, is also discussed.

Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab.

BACKGROUND AND PURPOSE: In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome. MATERIALS AND METHODS: We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log rank probability test. RESULTS: Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5. CONCLUSIONS: Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.

Early complete recanalization in internal carotid artery embolism treated with high-dose t-PA: a sequential angiographic study in a novel model of embolism in rats.

Complete early recanalization rate of human internal carotid artery embolic occlusion treated with thrombolytic drugs is low. To study factors related with this difficulty to recanalize we have developed a novel model of rat ica embolism using a fragment of human embolus. In 50 male Wistar rats the ica was embolized through the external carotid artery with a fragment of an embolus obtained from a human embolectomy passed through a catheter of 0.8 mm diameter. Recanalization was assessed by sequential angiograms from 15 to 120 min after embolization. Reperfusion was classified according to TIMI grades. Emboli of either 1 (group 1) or 2 mm (group 2) in length were cut. In group 1, four groups of nine animals each were treated, 15 min after embolization, with i.v. t-PA at doses of 1 mg/kg, 10 mg/kg and 20 mg/kg or saline. In group 2 there was one control group of seven animals treated with saline and another of seven animals treated with 10 mg/kg t-PA. Complete recanalization (TIMI grade 3) within the first 30 min was present in two animals treated with 10 and 20 mg/kg. Complete recanalization within the first 60 min was present in 0% of controls and animals treated with 1 mg/kg and in 44% of the 10 and 20 mg/kg groups (P<0.05 in chi-square test). Incomplete recanalization (TIMI grades 0, 1 and 2) occurred in 33%. In group 2 total recanalization occurred in 1/7 controls and in 3/7 animals receiving 10 mg/kg of t-PA. Early (60 min) complete i.v. t-PA induced internal carotid artery embolic recanalization is low with standard doses and increases moderately when high doses are used. Further increases in the dose do not improve recanalization rate, which is not clearly influenced by embolus size. Complete recanalization within 30 min, the period after which infarction develops in the rat, is uncommon in our model.

Time window for clinical effectiveness of mass evacuation in a rat balloon model mimicking an intraparenchymatous hematoma.

The purpose of this study is to evaluate in a rat model if the early removal of an experimental intracerebral mass mimicking an extensive subcortical hematoma improves neurological outcome. Fifty six male Wistar rats were studied. A balloon was placed sterotactically at the level of the striatum. The balloon was inflated to 100 microl for periods of 10, 60 or 120 min (with 10 animals in each group). In 10 animals the balloon was not deflated and there were four sham operated cases. Neurological deficit was evaluated by a blinded observer by means of a clinical scale from 0 to 8 points at 24 and 72 h after inflation. Three additional animals at each inflation period were sacrificed after 6 h for pathological study with hematoxylin-eosin staining. Death rate was 9/10 animals who had permanent inflation, 4/10 in those with 2 h inflation, 2/10 for 1 h inflation and 0/10 for 10 min inflation (P<0.01 in chi square test). Many animals developed a particular clinical syndrome not previously described. Mean 72 h clinical scores (0-8 points) were 7.6 (S.D.: 1. 2) for the permanent inflation group, 4.4 (S.D.: 3.2) for 2 h of inflation, 2.3 (S.D.: 3.2) for 1 h and 0.4 (0.9) for 10 min of inflation (P<0.01 in Kruskal Wallis test). In the pathological study the rate of damaged neurons was significantly higher in the permanent than in transient inflation groups. In conclusion, in this balloon model evacuation of an extensive acute expanding subcortical (hematoma-like) mass must be performed within a limited time window to prevent the development of irreversible neurological deficits or death.

[Acalculia. Neurological bases, evaluation and disorders]. / Acalculia. Bases neurológicas, evaluación y trastornos.

OBJECTIVE: To make a review of the literature on alterations in mathematical ability secondary to structural cerebral lesions. DEVELOPMENT AND CONCLUSIONS: We refer to the initial classification of acalculia of Berger (secondary acalculia when this is due to broader neuropsychological deficits and primary acalculia when it occurs alone) to the classical division of Hecaen (alexia and numerical agraphia with or without alterations in reading and writing of letters and words, visuo-spatial acalculia due to alterations in the spatial organization of multi-digit figures and the partial results of arithmetical operations, anarithmetia or primary failure in mathematical ability) and the most recent classifications based on neurocognitive models, which subdivide the acalculias into those secondary to changes in the system for processing numbers and those due to changes in the cognitive system for mathematics (McCloskey and Caramazza). Similarly, we review the correlations between the clinical changes in mathematics and the cerebral localization of the causative lesions (left parieto-temporal, right and including frontal and subcortical associative areas) together with the association of acalculia and other neuropsychological deficits. Finally we review the neuropsychological instruments available for the evaluation of acalculias, with particular reference to the tools validated and scaled for our language and sociocultural setting.