CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Cerebral tuberculosis in a patient with systemic lupus erythematosus following cyclophosphamide treatment: a case report.

Central nervous system (CNS) tuberculosis (TB) is a rare but catastrophic event in patients with systemic lupus erythematosus (SLE). Here we report a case of cerebral TB in a patient with lupus myocarditis and nephritis, following cyclophosphamide immunosuppression. To our knowledge this is the first reported case of cerebral TB in SLE in a non-endemic country. A 31-year-old female with SLE and a history of regular travel to Kenya presented to our centre with clinical features of acute heart failure. She was diagnosed with severe lupus myocarditis, and a renal biopsy also confirmed lupus nephritis. Prior to admission, she had also had a cough, fever and weight loss and was under investigation for suspected TB infection. She was treated with ivabradine, beta-blockers and diuretics together with methylprednisolone and cyclophosphamide immunosuppression. Subsequent sputum cultures confirmed TB and she was commenced on triple therapy. Despite this, she developed confusion, dizziness, blurred vision and fluctuating consciousness. Magnetic resonance imaging (MRI) and lumbar puncture revealed CNS TB infection resulting in meningitis. This was later complicated by obstructive hydrocephalus due to TB abscesses. A ventriculoperitoneal (VP) shunt was inserted and TB medications were given intravenously (IV) with dexamethasone. Following a prolonged hospital admission, the patient eventually recovered and rituximab treatment was used to control her SLE. TB infection has been associated with SLE flares. It is likely in this case that TB exacerbated a lupus flare and subsequent immunosuppression resulted in mycobacterial dissemination to the CNS. Systemic and CNS features of TB and SLE are difficult to distinguish and their contemporaneous management represents a diagnostic and therapeutic challenge.

Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease.

Objective The objective of this study was to determine the efficacy of hydroxychloroquine (HCQ) in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases. Methods Under the auspices of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, a multicenter, international, randomized controlled trial (RCT) was initiated, in which persistently aPL-positive but thrombosis-free patients without systemic autoimmune diseases were randomized to receive HCQ or no treatment in addition to their standard regimen. The primary objective was the efficacy of HCQ in preventing the first thrombosis. The secondary objectives were the thrombosis incidence rate, and the effects of HCQ on aPL profile and mortality rate. Patients were risk-stratified based on antiplatelet agent use. The goal was to follow patients every 6 months for 5 years. Results We recruited 20 persistently aPL-positive patients (female: 19, mean age: 46.6 ± 9.9 years, and baseline antiplatelet medication: 14); 9/20 were randomized to HCQ. During the mean follow-up of 1.7 years, no patients developed thrombosis or a serious adverse event. The study was terminated early due to the low recruitment rate, exacerbated by the prolonged manufacturing shortage and significant price increase of HCQ in the United States. Conclusion Given that a small number of patients with a relatively short follow-up were enrolled in our RCT, and no patients developed thrombosis, we cannot accurately assess the effectiveness of HCQ for primary thrombosis prevention in persistently aPL-positive patients with no other systemic autoimmune diseases. Our experience suggests that conducting an international RCT, especially without pharmaceutical support, is an extremely challenging undertaking.

The risk of ischaemic stroke in primary antiphospholipid syndrome patients: a prospective study.

BACKGROUND AND PURPOSE: The most common neurological manifestation of antiphospholipid syndrome (APS) is ischaemic stroke. Identifying patients with APS at high risk for developing any thrombotic event remains a major challenge. In this study, the aim was to identify predictive factors of ischaemic stroke in a cohort of primary APS (PAPS) patients who presented with new onset symptoms suggestive of acute stroke. METHODS: This prospective multicentre study included 36 consecutive PAPS patients who presented with new onset symptoms suggestive of an acute stroke. Patients were prospectively followed up for 12 months. RESULTS: In 10 (28%) out of 36 PAPS patients [mean age 41 years (SD 13.4), 70% female], the suspicion of an acute stroke was confirmed by brain magnetic resonance imaging. Sixty per cent of these patients were <50 years old. Eight of the 10 patients had a history of previous venous thrombosis and were receiving vitamin K antagonist (VKA), with international normalized ratio target 2-3; one patient had a history of a previous arterial event receiving treatment with VKA target international normalized ratio 2-3 plus low dose aspirin; and one patient had a history of previous pregnancy morbidity receiving only low dose aspirin. Time in the therapeutic range for patients receiving VKA was 77.7% (SD 6.6%). Hypercholesterolaemia was significantly higher in patients with confirmed stroke compared to those without (P < 0.05). Similarly, a significantly higher rate of anti-ß2 glycoprotein-I (ß2GPI) antibodies (immunoglobulin G/immunoglobulin M; P < 0.05) and higher adjusted global APS score (aGAPSS) values were found in patients with a confirmed stroke [mean aGAPSS 8.9 (SD 4.7) vs. mean aGAPSS 6.4 (SD 2.5); P < 0.05]. CONCLUSIONS: Patients with PAPS, including young patients, have a high risk of recurrent thrombosis despite anticoagulation treatment. A careful risk assessment is mandatory to identify patients at risk for recurrence.

The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies.

BACKGROUND: Antiphospholipid syndrome is defined by the combination of thrombotic events and/or obstetric morbidity in patients who have tested positive persistently for antiphospholipid antibodies. With good treatment, approximately 70% of pregnant women with antiphospholipid syndrome will deliver a viable live infant. However, current management does not prevent all maternal, fetal, and neonatal complications of antiphospholipid syndrome. OBJECTIVES: This observational, retrospective, single-center cohort study aimed to assess pregnancy outcome in women with antiphospholipid antibodies who were treated with hydroxychloroquine in addition to conventional treatment during pregnancy. STUDY DESIGN: One-hundred seventy pregnancies in 96 women with persistent antiphospholipid antibodies were analyzed: (1) 51 pregnancies that occurred in 31 women were treated with hydroxychloroquine for at least 6 months before pregnancy, and the therapy continued throughout gestation (group A); (2) 119 pregnancies that occurred in 65 women with antiphospholipid antibodies that were not treated with hydroxychloroquine were included as controls (group B). RESULTS: Hydroxychloroquine-treatment was associated with a higher rate of live births (67% group A vs 57% group B; P = .05) and a lower prevalence of antiphospholipid antibodies-related pregnancy morbidity (47% group A vs 63% B; P = .004). The association of hydroxychloroquine with a lower rate of any complication in pregnancy was confirmed after multivariate analysis (odds ratio, 2.2; 95% confidence interval, 1.2-136; P = .04). Fetal losses at >10 weeks of gestation (2% vs 11%; P = .05) and placenta-mediated complications (2% vs 11%; P = .05) were less frequent in group A than group B. Pregnancy duration was longer in group A than group B (27.6 [6-40] vs 21.5 [6-40] weeks; P = .03). There was a higher rate of spontaneous vaginal labor in hydroxychloroquine-treated women compared with group B (37.3% vs 14.3%; P = .01). CONCLUSIONS: Despite the heterogeneity in the 2 groups in terms of systemic lupus erythematosus prevalence and previous pregnancy history, our results support the concept that women with antiphospholipid antibodies may benefit from treatment with hydroxychloroquine during pregnancy to improve pregnancy outcome. The addition of hydroxychloroquine to conventional treatment is worthy of further assessment in a proper designed randomized controlled trial.

Auriculotemporal Neuralgia: Eight New Cases Report.

BACKGROUND: Auriculotemporal neuralgia (ATN) is an infrequent syndrome consisting in strictly unilateral pain in the temporal region associated with nerve tenderness, which can be successfully treated with anesthetic blockade. We analysed clinical characteristics and treatment response in a series of eight patients. METHODS: Series of consecutive patients diagnosed with ATN at Headache Clinics of two university hospitals in Spain. Data on demographic and pain characteristics, as well as response to treatment are presented. RESULTS: Eight patients (seven women). Mean age at onset was 52.8 ± 14.3 years. Pain was strictly unilateral (left-sided in five cases, right-sided in three), and triggered by pressing the preauricular area. Four patients presented background pain, mostly dull in quality, with an intensity of 5.75 ± 1.2 on the verbal analogical scale (VAS). In six, burning exacerbations occurred, ranging from 2 seconds to 30 minutes, with intensity 7.3 ± 1.5 on VAS. Complete relief was achieved with gabapentin in three cases, anaesthetic blockade in three and spontaneously in two. CONCLUSION: ATN is uncommon in headache units. Gabapentin is a good alternative therapeutic option to anesthetic blockade.

Personality traits in patients with cluster headache: a comparison with migraine patients.

BACKGROUND: Cluster headache (CH) has been associated with certain personality traits and lifestyle features, but there are few studies assessing personality profiles in CH. We aimed to analyze personality traits in patients with CH, and to compare them with those found in migraine. METHODS: We included all consecutive patients with CH attending 5 outpatient offices between January and December 2013. Personality traits were evaluated using the Salamanca screening test, a validated inventory assessing 11 personality traits grouped in 3 clusters. We analyzed the test results in this population, and compared them with those of a migraine population previously assessed with the same test. RESULTS: Eighty patients with CH (75 men, 5 women; mean age, 43.2 ± 9.9 years) were recruited. The reference population consisted of 164 migraine patients (30 men, 134 women; mean age 36.4 ± 12.7 years). In CH patients, the most frequent personality traits were anancastic (52.5 %), anxious (47.5 %), histrionic (45 %), schizoid (42.5 %), impulsive (32.5 %) and paranoid (30 %). When compared to migraine patients, paranoid (p < 0.001; χ2 test), and schizoid traits (p = 0.007; χ2 test) were significantly more prevalent in CH patients. In logistic regression analysis the paranoid trait was significantly associated with CH (p = 0.001; OR: 3.27, 95 % CI [1.66-6.43]). CONCLUSION: According to the Salamanca screening test, personality traits included in cluster A (odd or eccentric disorders) are more prevalent in CH patients than in a population of migraineurs. Larger studies are needed to determine whether certain personality traits are related to CH.

Gene profiling reveals specific molecular pathways in the pathogenesis of atherosclerosis and cardiovascular disease in antiphospholipid syndrome, systemic lupus erythematosus and antiphospholipid syndrome with lupus.

OBJECTIVE: To identify shared and differential molecular pathways involved in the pathogenesis of atherosclerosis (AT) and cardiovascular disease (CVD) in systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS) and APS associated with SLE (APS plus SLE). METHODS: 129 patients (42 APS, 31 APS plus SLE and 56 SLE) and 61 healthy donors were included. Microarray expression profiling was performed in monocytes. RT-PCR of selected genes and western blot were used to validate microarray data. Clinical and inflammatory parameters were also analysed. RESULTS: Compared with controls, 555, 1224 and 518 genes were differentially expressed in monocytes from SLE, APS plus SLE and APS patients, respectively. Approximately 25-30% of differentially expressed genes were related to AT and CVD. Each disease displayed a specific AT/CVD/Inflammation-related gene signature. Compared with SLE, APS showed alterations in mitochondria biogenesis and function and oxidative stress. Besides the interferon signature, found in APS plus SLE and SLE patients, various genes mediating atherosclerotic/inflammatory signalling were also differentially expressed in APS plus SLE. IgG-anticardiolipin (aCL) titres independently predicted both atherosclerotic and thrombosis in APS plus SLE. Moreover, a significant correlation of IgG-aCL titres with mRNA levels of certain inflammatory molecules in monocytes was further noticed. In vitro treatment of monocytes with IgG-aCL promoted an increase in the expression of the genes most significantly changed in APS plus SLE versus healthy donors. CONCLUSIONS: Gene expression profiling allows the segregation of APS, APS plus SLE and SLE, with specific signatures explaining the pro-atherosclerotic and pro-thrombotic alterations in these highly related autoimmune diseases.

Hallucinations and aberrant perceptions are prevalent among the young healthy adult population.

INTRODUCTION: Hallucinations are frequent in clinical practice, with an incidence of up to 38.7% in the general population. We aim to determine the prevalence of hallucinations among healthy young adults in our environment. SUBJECTS AND METHODS: We designed an observational study, using as subjects 3rd to 6th year medical students at the Universidad Complutense de Madrid who complete clinical rotations in the Hospital Clínico San Carlos. After a screening questionnaire, an individual interview was conducted via telephone or e-mail to those students who reported hallucinations. We obtained clinical and epidemiological data through a semi-structured clinical interview performed by a third year neurology resident. RESULTS: N=134 (average age was 22.1 years; 77.6% were women). 74 respondents answered affirmatively to one or more screening questions, and 54 completed the follow-up interview. 22.2% described visual phenomena and 64.8%, auditory. The majority reported sleep-related experiences and auditory perceptions related to hyper vigilance, such as hearing the telephone or the doorbell ring when in fact it had not (38.8%). All subjects had good insight into their experiences and none had psychotic symptoms. Two cases were associated with substance abuse. CONCLUSIONS: Hallucinations are frequent among the general population. Traditionally, auditory phenomena have been associated with psychotic pathology, and other studies show a low population incidence (0.6%). However, in our sample, short auditory perceptions with immediate analysis were frequent and not pathological.

Limited vertical tarsal resection in a case of basal cell carcinoma of the lower eyelid.

We present the clinical case of a 71-year-old woman with a history of multiple basal cell carcinomas (BCC) who presented a nodular lesion in practically the entire extension of the free edge of the lower eyelid. The lesion was approached by excision of the palpebral margin with limited vertical resection of the tarsus and Tripier flap with a correct aesthetic and functional result, free histological margins and no recurrence in a 12-month follow-up.

Migraine-triggered hemifacial spasm: three new cases.

BACKGROUND: The occurrence of hemifacial spasm (HFS) during an episode of migraine has been seldom reported. Here we describe three new cases presenting with HFS in association with migraine attacks. CASE RESULTS: Three patients (one woman and two men, aged 31-36 years) developed HFS in close temporal relationship with migraine headaches. All of them started having the muscle spasms after pain onset. Two of them had electromyographic evidence of facial nerve damage, and continued having HFS once the pain abated. CONCLUSIONS: Migraine attacks may be associated with HFS. The appearance of HFS could be related to migraine activity. A mechanism of central hyperexcitability in connection with nociceptive inputs on the trigeminal nucleus caudalis and/or a dilation of vessels compressing the facial nerve at the root exit zone could lead to the development of HFS in predisposed patients. 'Migraine-triggered hemifacial spasm' could possibly be regarded as a complication of migraine.

[SOD1-N196 mutation in a family with amyotrophic lateral sclerosis]. / Mutación SOD1-N19S en una familia de esclerosis lateral amiotrófica.

INTRODUCTION: N19S mutation is produced by substitution in the 139 position of SOD1 and was described by Mayeux in a patient with amyotrophic lateral sclerosis (ALS). He suggested that it did not have a causal effect as it was found in asymptomatic and sporadic cases. Other authors in later articles did not agree. MATERIAL AND METHODS: We describe a family with 4 members with ALS patients and attempt to find the carrier of the N19S mutation of the propositus. Molecular studies were performed on 15 members of the family of a different order. RESULTS: The ALS cases were found in the maternal line of the propositus. The presence of the mutation was detected in 3 people, the other two were asymptomatic. One of patients with ALS in the family, who died previously, did not have the mutation. Two of the sons of this case and another of the other case did not show it. On the other hand, N19S mutation was only present in paternal branch of the propositus, where there were no cases. CONCLUSION: The described family supports the hypothesis by Mayeux and against that mutation N19S has pathological consequences, since mutation is only in the family line where there are no cases with ALS. In consequence, although the described case is included as a familiar form, it cannot be attributed to the mutation, and its relationship with N19S should be considered as casual.

Diagnostic value of quantitative SPECT/CT in assessing active sacroiliitis in patients with axial spondylarthritis and/or inflammatory low back pain.

BACKGROUND: The diagnostic accuracy of bone scintigraphy (BS) increases with SPECT/CT imaging. It would therefore be appropriate to reassess the diagnostic utility of scintigraphy in sacroiliitis with axial spondyloarthritis (SpA). The aim of this study was to compare the diagnostic performance of MRI, SPECT/CT and a combination of both techniques in sacro-iliitis, and to evaluate the correlation between quantitative SPECT/CT indices and quantitative MRI inflammatory lesion scores. METHODS: Thirty-one patients with active SpA and 22 patients with inflammatory low back pain underwent MRI and SPECT/CT of the sacroiliac joints. The diagnostic accuracy of both techniques was calculated using clinical diagnosis as the gold standard. The correlation between MRI and SPECT/CT was calculated by comparing the SPECT/CT activity indices and the Berlin/SPARCC scoring systems for MRI. RESULTS: The sensitivity and specificity values in quantitative SPECT/CT, taking the sacroiliac/promontory ratio of >1.36 as the cut-off value, were close to those from MRI published in the literature. The combination of both techniques increased sensitivity while maintaining high specificity. There was a moderate correlation between SPECT/CT and MRI total scores. This correlation was improved by using solely the MRI inflammation scores. CONCLUSION: Quantitative SPECT/CT showed better diagnostic accuracy than planar scintigraphy and showed a moderate correlation with MRI scores in active sacroiliitis. The combination of both tests increased the diagnostic accuracy. Quanti-tative SPECT/CT could play a relevant role in the diagnosis of active sacroiliitis in patients with high a suspicion of SpA and a negative/inconclusive MRI test or in patients with whom MRI studies cannot be carried out.

Validation of the Spanish-language version of the Montreal Cognitive Assessment as a screening test for cognitive impairment in multiple sclerosis.

BACKGROUND: The neuropsychological batteries traditionally used for the assessment of cognitive impairment (CI) in patients with multiple sclerosis are complex tests requiring a long time to administer. Simpler tests are needed to detect cognitive impairment in daily clinical practice. OBJECTIVE: We aimed to evaluate the diagnostic validity and reliability of the Montreal Cognitive Assessment (MoCA) test as a screening tool for CI in patients with multiple sclerosis, as compared against the Brief Neuropsychological Battery. MATERIAL AND METHODS: We recruited 52 patients with multiple sclerosis (61.5% women; mean age [standard deviation]: 41.7 [11.5] years). We analysed the reliability (internal consistency, interobserver reliability, and test-retest reliability), construct validity (factor analysis, Pearson correlation coefficient, and coefficient of determination), and criterion validity (ROC curve, sensitivity, specificity, total agreement, positive and negative predictive values, positive and negative likelihood ratios, and Fagan nomogram) of the MoCA test in this population. RESULTS: The prevalence of CI was 21.2% according to findings from the Brief Neuropsychological Battery, and 25% according to the MoCA test. The MoCA test showed good internal consistency (Cronbach alpha, 0.822) and interobserver and test-retest reliability (intraclass correlation coefficient 0.80 and 0.96, respectively). The correlation coefficient between total Brief Neuropsychological Battery and MoCA test scores was 0.82. The optimal cut-off point on the ROC curve was 25-26, yielding 91% sensitivity and 93% specificity. CONCLUSION: The MoCA test is a valid and reliable tool for screening for CI in patients with multiple sclerosis.

Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

Calcitonin gene-related peptide in migraine: from pathophysiology to treatment.

INTRODUCTION: It has been observed in recent years that levels of such molecules as calcitonin gene-related peptide (CGRP) and, to a lesser extent, the pituitary adenylate cyclase-activating peptide are elevated during migraine attacks and in chronic migraine, both in the cerebrospinal fluid and in the serum. Pharmacological reduction of these proteins is clinically significant, with an improvement in patients' migraines. It therefore seems logical that one of the main lines of migraine research should be based on the role of CGRP in the pathophysiology of this entity. DEVELOPMENT: The Spanish Society of Neurology's Headache Study Group decided to draft this document in order to address the evidence on such important issues as the role of CGRP in the pathophysiology of migraine and the mechanism of action of monoclonal antibodies and gepants; and to critically analyse the results of different studies and the profile of patients eligible for treatment with monoclonal antibodies, and the impact in terms of pharmacoeconomics. CONCLUSIONS: The clinical development of gepants, which are CGRP antagonists, for the acute treatment of migraine attacks, and CGRP ligand and receptor monoclonal antibodies offer promising results for these patients.

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies.

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.