Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

MIF functional polymorphisms (-794 CATT5-8 and -173 G>C) are associated with MIF serum levels, severity and progression in male multiple sclerosis from western Mexican population.

Macrophage migration inhibitory factor (MIF) is a cytokine associated with tissue damage in multiple autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis. The role of MIF in multiple sclerosis (MS) and the contribution of its polymorphisms are unknown in our population. Therefore, we decided to investigate the genetic association of -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms with MS, clinical variables and MIF serum levels in the population of western Mexico. 230 MS patients diagnosed according to McDonald criteria and 248 control subjects (CS) were recruited for this study, both polymorphisms were genotyped by PCR and PCR-RFLP and MIF serum levels were measured by ELISA kit. Severity and progression of MS were evaluated by EDSS and MSSS scores, respectively. Genotypes carrying the 5 repeats alleles of -794 CATT5-8MIF polymorphism present higher MIF serum levels in comparison with no carriers, and the presence of 5,7 heterozygous genotype contribute to the increase of disease severity and damage progression in MS patients. Notably when we stratified by sex, an effect of risk alleles (7 repeats and -173*C) of both MIF polymorphisms on EDSS and MSSS scores on males was found (p < 0.01). This study suggests that polymorphic alleles of MIF polymorphisms could act as sex-specific disease modifiers that increase the severity and progression of MS in male Mexican-Mestizo western population.

Hospital arrival time and functional outcome after acute ischaemic stroke: results from the PREMIER study.

INTRODUCTION: Information regarding hospital arrival times after acute ischaemic stroke (AIS) has mainly been gathered from countries with specialised stroke units. Little data from emerging nations is available. We aim to identify factors associated with achieving hospital arrival times of less than 1, 3, and 6 hours, and analyse how arrival times are related to functional outcomes after AIS. METHODS: We analysed data from patients with AIS included in the PREMIER study (Primer Registro Mexicano de Isquemia Cerebral) which defined time from symptom onset to hospital arrival. The functional prognosis at 30 days and at 3, 6, and 12 months was evaluated using the modified Rankin Scale. RESULTS: Among 1096 patients with AIS, 61 (6%) arrived in <1 hour, 250 (23%) in <3 hours, and 464 (42%) in <6 hours. The factors associated with very early (<1 hour) arrival were family history of ischemic heart disease and personal history of migraines; in <3 hours: age 40-69 years, family history of hypertension, personal history of dyslipidaemia and ischaemic heart disease, and care in a private hospital; in <6 hours: migraine, previous stroke, ischaemic heart disease, care in a private hospital, and family history of hypertension. Delayed hospital arrival was associated with lacunar stroke and alcoholism. Only 2.4% of patients underwent thrombolysis. Regardless of whether or not thrombolysis was performed, arrival time in <3 hours was associated with lower mortality at 3 and 6 months, and with fewer in-hospital complications. CONCLUSIONS: A high percentage of patients had short hospital arrival times; however, less than 3% underwent thrombolysis. Although many factors were associated with early hospital arrival, it is a priority to identify in-hospital barriers to performing thrombolysis.

Aspirin versus anticoagulation in intra- and extracranial vertebral artery dissection.

BACKGROUND AND PURPOSE: To evaluate the incidence and predictors of ischaemic recurrent stroke and the adverse events of antithrombotic therapy in patients with first intra- or extracranial vertebral artery dissection (VAD) who were treated with aspirin or oral anticoagulation (OA). METHODS: A 21-year database of consecutive patients with confirmed diagnoses of VAD (n = 110, 63% men; mean age 37.9 ± 8.5 years) without intracerebral hemorrhage and who were treated with aspirin or OA were analyzed retrospectively. In all cases, the admission diagnosis was ischaemic stroke. Three groups were defined according to the site of the dissection: (i) extracranial, (ii) intracranial, and (iii) intra-/extracranial. Clinical follow-up was obtained by neurologic examination. Outcome measures were (i) recurrent ischaemic events (ischaemic stroke or transient ischaemic attack) and (ii) intra- and extracranial major bleeding. RESULTS: No difference in age, smoking, or hypertension was found between patients treated with OA (n = 49) and those treated with aspirin (n = 50). Extracranial artery dissection (49%) had preponderance over intracranial (27%) or intra-/extracranial (23%) location. During the follow-up, recurrent ischaemic events were rare (one case). There were no bleeding complications. The treatment that was used did not influence the functional outcome or recanalization. A good functional outcome (modified Rankin score ≤ 2) was observed in 82 patients. CONCLUSIONS: Although this was a non-randomized study, our data suggest that the frequency of recurrent ischaemic stroke in patients with intra- or extracranial VAD is low and most likely independent of the type of antithrombotic treatment.

Cerebrovascular complications during pregnancy and postpartum: clinical and prognosis observations in 240 Hispanic women.

BACKGROUND AND PURPOSE: Although pregnancy and postpartum have long been associated with stroke, there is a dearth of information in Latino-American populations. The aim of this study was to describe the cerebrovascular complications occurring during pregnancy/postpartum and compare the characteristics amongst stroke types occurring in this period in Hispanic women. PATIENTS AND METHODS: We studied 240 women with cerebrovascular complications during pregnancy and the first 5 weeks postpartum, from our stroke registry. Patients were classified into three groups: cerebral venous thrombosis (CVT), ischaemic stroke (IS), and intracerebral hemorrhage (ICH). For each group, clinical data, timing of the event, and outcome were analyzed. RESULTS: Of the 240 women, 136 had CVT (56.7%), 64 IS (26.7%), and 40 ICH (16.6%). In 72 women (30%), the event occurred during pregnancy, in 153 (64%) during postpartum, and in 15 (6%) closely related to labor. CVT was more common in the first trimester of pregnancy and in the second and third weeks following delivery; whilst IS and ICH were seen mainly during pregnancy and the first 2 weeks following delivery. Pre-eclampsia/eclampsia was more common in patients with ICH (57.5%) and IS (36%) than in those with CVT (9.6%) (P < 0.001). An excellent recovery (modified Rankin Scale: 0-1) was observed amongst women with CVT (64%) and IS (50%) compared to ICH (32%), (P = 0.004). CONCLUSIONS: Pre-eclampsia/eclampsia is a frequent risk factor in patients with ICH and IS, but not in CVT. Stroke types clustered different within the pregnancy-postpartum period. A good prognosis is observed in patients with CVT.

[Neuromyelitis optica: a clinical update]. / Neuromielitis optica: actualizacion clinica.

INTRODUCTION: Neuromyelitis optica (NMO) or Devic's disease is an autoimmune, inflammatory and demyelinating central nervous system disorder that affects mainly to optic nerve and spinal cord. Recent advances have substantially permitted to expand the knowledge about this entity. AIM: To present a clinical update on the current understanding of the nature, progression, diagnosis and treatment of NMO. DEVELOPMENT: Due to its demyelinating nature and its recurrent behavior in most cases, NMO was first considered a form of multiple sclerosis (MS). However, recent findings have led to the conclusion that NMO is a distinct disorder, presenting important immunopathological, clinical, prognostic and therapeutic differences from MS. Fundamental in the under-standing of the disease was the recent discovery of antibodies directed against aquaporin-4 (anti-AQP4, also known as NMO-IgG), which are present in the majority of NMO cases clinically defined, and in a minority of patients with MS. Despite the knowledge on its immunopathogenesis and advances in diagnosis, the treatment of NMO is still challenging. CONCLUSION: NMO is a demyelinating disease different from MS. Current diagnostic criteria have been enriched with the recent description of the humoral disorder underlying NMO. However, current treatment options for NMO are far from being ideal.

Citicoline for acute ischemic stroke in Mexican hospitals: a retrospective postmarketing analysis.

Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline within the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age (+/- 5 years), gender and NIHSS (+/- 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analyses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this observational study, citicoline use was associated with a better functional status and lower rates of short-term mortality, possibly due to fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a randomized, controlled clinical trial.

Apolipoprotein E genotypes in Mexican patients with Parkinson's disease.

BACKGROUND: The association of the apolipoprotein (Apo E) -epsilon4 allele to neurodegenerative diseases such as Parkinson's disease (PD) has been analyzed in several studies. This association has been identified by amyloid deposits and neurofibrillary tangles in the brains of patients with neurodegenerative diseases. METHOD: In this study the possible relationship between Apo E alleles and PD patients was analyzed in 105 patients with PD and 107 healthy controls from a Mexican population. RESULTS: Allele analysis in PD vs. controls was: epsilon2 in 6% and 2.3%, respectively; epsilon3 in 73% and 88.3%; and epsilon4} in 21% and 9.4%. The epsilon3 allele showed a protective risk effect with an Odds ratio (OR) of 0.36 (95%CI 0.20-0.61) and p < 0.05; contrary results were observed for the epsilon4 allele, which showed an increased risk for PD, with an OR of 2.57(95% CI 1.42-4.79) and p < 0.05. Upon multivariate analysis showed PD risk was evident in patients who were carriers of the genotype epsilon3/epsilon4; age group (fifty or more years) and had exposure to pesticides and solvents (p < 0.05). CONCLUSIONS: The epsilon3/epsilon3}; epsilon3/epsilon4 genotypes of the Apo E, were positively associated with sporadic PD.

Controlled operation of a membrane SBR for inhibitory wastewater treatment.

This work presents the design and practical implementation of a control strategy for the operation of a sequencing batch reactor with a submerged membrane. The bioreactor is used for treating wastewater that is inhibitory for sufficiently high concentrations. The strategy combines the use of a robust feeding strategy to ensure biodegradation near an optimal unknown concentration value, using only the dissolved oxygen concentration as feedback signal, and a strategy to minimize membrane fouling based on flux and transmembrane pressure measurements during filtration. The strategy was tested on a 10 L laboratory bioreactor treating synthetic wastewater containing 4-chlorophenol as inhibitory model compound and sole source of carbon. Experimental results show the applicability of the proposed strategy.

[Frequency of the IVS4+66A-G polymorphism in the alpha-synuclein gene in patients with Parkinson's disease in north-western Mexico]. / Frecuencia del polimorfismo IVS4+66A-G en el gen alfa-sinucleína en pacientes con enfermedad de Parkinson del noroccidente de México.

INTRODUCTION: Parkinson disease (PD) is the second most common neurodegenerative disease of adult onset. Is a progressive movement disorder including tremor, bradykinesia, rigidity and postural instability, with an age onset between 43 and 66 years. Histopathologically, is characterized by a severe loss of dopaminergic neurons in the substantia nigra and inclusions consisting of insoluble protein aggregates called Lewy bodies, this are comprised in part of alpha-synuclein. The etiology of PD is still not fully understood, but genetic analyses, epidemiologic studies and experimental models of PD are providing important new insights into the pathogenesis of PD. AIM: To determine allelic and genotypic frequencies of polymorphism IVS4+66A-G in the alpha-synuclein gene and to demonstrate its association with PD in northwest Mexican population. SUBJECTS AND METHODS: Genomic desoxyribonucleic acid (DNA) from 51 PD patients and 121 persons without PD were achieved by polymerase chain reaction and analyzed the allelic and genotypic distribution in IVS4+66A-G polymorphism of alpha-synuclein gene. RESULTS: The genotypic frequency of IVS4+66AA was 43.1% in PD patients and 38.8% in control group; IVS4+66GG was 2% in PD patients and 4.1% in control group, whereas 54.9% in PD patients and 57.1% in control group were heterozygous. Statistical differences were not observed between groups (p<0.05). CONCLUSIONS: Association was not observed between the IVS4+66A-G polymorphism and PD.

Idiopathic hypertrophic cranial pachymeningitis successfully treated with weekly subcutaneous methotrexate.

Idiopathic hypertrophic cranial pachymeningitis is a very infrequent disorder. Adequate management is still a matter of debate. We describe the use of low-dose pulse methotrexate in treating a 63-year-old woman with idiopathic hypertrophic cranial pachymeningitis. A weekly scheme with subcutaneous methotrexate was tried. Clinical improvement occurred in one week. Total remission of the clinical and neuro-imaging abnormalities was evident 6 months later, with minimal side effects. The patient is in complete remission after one year of follow-up without treatment. Hence, low-dose weekly subcutaneous methotrexate may be safe and effective in inducing complete and sustained remission of this condition. The experience with subcutaneous methotrexate to treat this entity has never been reported.

[Linear scleroderma en coup de sabre: neurological symptoms, images and review]. / Esclerodermia lineal en coup de sabre. Manifestaciones neurologicas, imagenes y revision

INTRODUCTION: 'Sword stroke' linear scleroderma, which is better known as linear scleroderma en coup de sabre (LSCS), is a rare disease with an uncertain causation that is characterised by progressive craniofacial focal atrophy and is, at least in part, different from Parry-Romberg syndrome (PRS). CASE REPORTS: Here, we report on the cases of 3 patients with LSCS (2 females and 1 male, with a mean age of 40 years). The main neurological symptoms were headache and seizures. Although different alterations were observed in the X-ray images, they were all ipsilateral to the coup de sabre. Histopathological evidence for gliosis and mixed perivascular inflammatory infiltrate was found in the study of a biopsy specimen taken from one female. Cerebrovascular involvement was seen in another patient, as highlighted by the observation of an earlier subclinical cerebellar infarct and occlusion of the superior cerebellar artery in the absence of any other possible causation. CONCLUSIONS: When it affects the central nervous system, the clinical and radiological presentation of LSCS is heterogeneous. Both the imaging studies carried out during the clinical control and the histopathological findings suggest a focal inflammatory process that can be progressive. The arterial involvement is probably due to a non-atherosclerotic, occlusive and chronic inflammatory disease of the peripheral vessels.

[Intracerebral haemorrhage in a referral hospital in the central-western region of Mexico]. / Hemorragia intracerebral en un hospital de referencia de la region centro-occidente de Mexico.

INTRODUCTION: Intracerebral haemorrhage (ICH) has received little attention in studies in Mexico. Isolated reports talk of high frequency, its importance as a disorder among young people, its being mainly located in the lobar regions and a high rate of recurrence. AIMS: The objective of this study was to characterise the clinical, radiological, therapeutic and prognostic spectrum of ICH in a general hospital in the central-western region of Mexico. PATIENTS AND METHODS: The study involved 270 consecutive patients over the age of 15 years with spontaneous ICH who were hospitalised in the Neurology and Neurosurgical Service in the Antiguo Hospital Civil de Guadalajara between the years 2000 and 2002. Their clinical history and progression was known at least on discharge from the hospital. RESULTS: The mean age was 63 years (12% under 40 years old) with no predominance according to gender (53% males). Arterial hypertension was the main risk factor in 69%, followed by obesity in 38%. There were no differences in the Glasgow administered on admission in three pre-established subgroups. The ICH was ganglionic in 64% of cases and lobar in 24%. Arterial hypertension was the principal cause of ICH in 76%. Ventricular aperture was noted in 53%. All the patients were treated in a general ward. Mortality in the acute phase occurred in 49%, although a poor progression was observed in 83%. Overall recurrence was 13%. Outpatient follow-up was poor. CONCLUSIONS: ICH shares most of the features reported in Anglo-Saxon series including aetiology and location. In our population, mortality and recurrence are high with important sequelae. The high frequency of ICH (40%) may represent a bias in the selection of hospitals.

Effect of clopidogrel on platelet aggregation and plasma concentration of fibrinogen in subjects with cerebral or coronary atherosclerotic disease.

Acetylsalicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20% to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30% to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-related antiplatelet drug, with the same mechanism of action; it reduces the expression of the glycoprotein IIb/IIIa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and has a decreased incidence of adverse effects. The effect of one daily dose of 75 mg of clopidogrel on platelet function in 90 subjects was evaluated; 41 with coronary artery disease and 49 with cerebral vascular disease. Before treatment and after 6 and 12 weeks, bleeding time and fibrinogen plasma concentration were also evaluated. There was a reduction in 5-microM ADP-induced platelet aggregation of 38%+/-27% at 6 weeks and 44%+/-29% at 12 weeks in patients with coronary artery disease; 35%+/-41%, 29%+/-59% in the cerebral vascular disease group; and 36%+/-36% and 35%+/-49% in the total group. Reduction of 20 microg/mL collagen-induced platelet aggregation was not significant in any group. Plasma fibrinogen levels did not vary during treatment. Bleeding time was significantly prolonged in all studied groups. There were no hemorrhagic complications; only digestive discomfort in less than 3% of patients. Clopidogrel efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time and is a safe and efficacious antiplatelet drug.

Event-related brain potentials during a continuous performance test (CPT) task in normal children.

BACKGROUND: Continuous Performance Test (CPT) is a commonly used paradigm to assess attention disorders that could involve working memory processes. METHODS: Event-related potentials (ERPs) during a CPT (X-AX) test were obtained in 16 healthy male students, with ages ranging from 9 to 11 years (X = 10.3). In grouped averaged ERPs, an endogenous slow positive potential was recorded in the first task (infrequent letter detection); maximum was at 460 msec with a slight lateralization tendency toward left parietal area. In the second task (target detection with an A as warning signal), an early (maximum at 330 msec) and more acute peak was detected without evidence of any lateralization. RESULTS: Reaction times were significantly shorter for the second task. Electrophysiologic differences between both target conditions showed an early, remarkable, and statistically significant component located at the parietal area at 340 msec. CONCLUSIONS: These ERPs findings could be interpreted as correlates with working memory processes in children.