Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.

Placebo and other psychological interactions in headache treatment.

We present a theory according which a headache treatment acts through a specific biological effect (when it exists), a placebo effect linked to both expectancy and repetition of its administration (conditioning), and a non-specific psychological effect. The respective part of these components varies with the treatments and the clinical situations. During antiquity, suggestions and beliefs were the mainstays of headache treatment. The word placebo appeared at the beginning of the eighteenth century. Controversies about its effect came from an excessive interpretation due to methodological bias, inadequate consideration of the variation of the measure (regression to the mean) and of the natural course of the disease. Several powerful studies on placebo effect showed that the nature of the treatment, the associated announce, the patients' expectancy, and the repetition of the procedures are of paramount importance. The placebo expectancy is associated with an activation of pre-frontal, anterior cingular, accumbens, and periacqueducal grey opioidergic neurons possibly triggered by the dopaminergic meso-limbic system. In randomized control trials, several arms design could theoretically give information concerning the respective part of the different component of the outcome and control the natural course of the disease. However, for migraine and tension type headache attacks treatment, no three arm (verum, placebo, and natural course) trial is available in the literature. Indirect evidence of a placebo effect in migraine attack treatment, comes from the high amplitude of the improvement observed in the placebo arms (28% of the patients). This figure is lower (6%) when using the harder criterium of pain free at 2 h. But these data disregard the effect of the natural course. For prophylactic treatment with oral medication, the trials performed in the last decades report an improvement in 21% of the patients in the placebo arms. However, in these studies the duration of administration was limited, the control of attacks uncertain as well as the evolution of the co-morbid psycho-pathology. Considering the reviews and meta-analysis of complex prophylactic procedures, it must be concluded that their effect is mostly linked to a placebo and non-specific psychological effects. Acupuncture may have a slight specific effect on tension type headache, but not on migraine. Manual therapy studies do not exhibit difference between manipulation, mobilization, and controls; touch has no proven specific effect. A comprehensive efficacy review of biofeedback studies concludes to a small specific effect on tension type headache but not on migraine. A review of behavioral treatment conclude to an interesting mean improvement but did not demonstrated a specific effect with the exception of a four arm study including a pseudo meditation control group. Expectation-linked placebo, conditioning, and non-specific psychological effects vary according clinical situations and psychological context; likely low in RCT, high after anempathic medical contact, and at its maximum with a desired charismatic healer. The announcements of doctors strongly influence the beliefs of patients, and in consequence their pain and anxiety sensibilities; this modulates the amplitude of the placebo and the non-specific psychological effects and is therefore a major determinant of the therapeutic success. Furthermore, any repetitive contact, even through a placebo, may interfere positively with the psychopathological co-morbidity. One has to keep in mind that the non-specific psychological interactions play a major role in the improvement of the majority of the headache sufferers.

Psychopathology and quality of life burden in chronic daily headache: influence of migraine symptoms.

The aim of this study is to compare the psychopathology and the quality of life of chronic daily headache patients between those with migraine headache and those with tension-type headache. We enrolled 106 adults with chronic daily headache (CDH) who consulted for the first time in specialised centres. The patients were classified according to the IHS 2004 criteria and the propositions of the Headache Classification Committee (2006) with a computed algorithm: 8 had chronic migraine (without medication overuse), 18 had chronic tension-type headache (without medication overuse), 80 had medication overuse headache and among them, 43 fulfilled the criteria for the sub-group of migraine (m) MOH, and 37 the subgroup for tension-type (tt) MOH. We tested five variables: MADRS global score, HAMA psychic and somatic sub-scales, SF-36 psychic, and somatic summary components. We compared patients with migraine symptoms (CM and mMOH) to those with tension-type symptoms (CTTH and ttMOH) and neutralised pain intensity with an ANCOVA which is a priori higher in the migraine group. We failed to find any difference between migraine and tension-type groups in the MADRS global score, the HAMA psychological sub-score and the SF36 physical component summary. The HAMA somatic anxiety subscale was higher in the migraine group than in the tension-type group (F(1,103) = 10.10, p = 0.001). The SF36 mental component summary was significantly worse in the migraine as compared with the tension-type subgroup (F(1,103) = 5.758, p = 0.018). In the four CDH subgroups, all the SF36 dimension scores except one (Physical Functioning) showed a more than 20 point difference from those seen in the adjusted historical controls. Furthermore, two sub-scores were significantly more affected in the migraine group as compared to the tension-type group, the physical health bodily pain (F(1,103) = 4.51, p = 0.036) and the mental health (F(1,103) = 8.17, p = 0.005). Considering that the statistic procedure neutralises the pain intensity factor, our data suggest a particular vulnerability to somatic symptoms and a special predisposition to develop negative pain affect in migraine patients in comparison to tension-type patients.

The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.

[Vitamin B12 deficiency and neurological disorders: a case report and literature review]. / Carence en vitamine B12, ataxie cérébelleuse et troubles cognitifs.

INTRODUCTION: Vitamin B12 deficiency is often associated with neurological disorders of which combined sclerosis of the spinal cord is a common manifestation. CASE REPORT: We report the case of a woman who presented cerebellar ataxia and cognitive deficits associated with leukoencephalopathy on the brain MRI. These symptoms were associated with vitamin B12 deficiency due to Biermer's disease. Vitamin B12 supplementation led to symptom improvement. Later her treatment was discontinued and the patient's clinical status worsened to a bedridden status. CONCLUSION: Ataxia cerebellar dementia and leukoencephalopathy can result from vitamin B12 deficiency. To limit the risks of sequelae, vitamin B12 supplementation should be started at an early stage.

[Primary progressive aphasia: a specific consideration among the neurodegenerative pathology]. / L'aphasie progressive primaire: un cadre à part dans les pathologies neurodégénératives.

INTRODUCTION: Isolated progressive speech and language difficulties are often the first symptom of primary progressive aphasia. EXEGESIS: We report a 63-year-old woman with progressive language impairment that remained isolated for at least two years, related to a greater atrophy within the left hemisphere. There was no impairment in daily living during two years and six months. Progressively, she developed a frontal dementia. CONCLUSION: Isolated language impairment may be the inaugural symptom of a focal form of a neurodegenerative disease. Progressive language deterioration without impairment in daily life activity or behavioral changes must be differentiated from Alzheimer disease. Brain imaging is important for the diagnosis.

[Genetic evolution of poliovirus: success and difficulties in the eradication of paralytic poliomyelitis]. / Evolution génétique du poliovirus: succès et difficultés de l'éradication de la poliomyélite paralytique.

Poliovirus, the aetiological agent of poliomyelitis, is an enterovirus of the Picronaviridae family. Despite the success of the World Health Organisation (WHO) worldwide vaccination campaign against poliomyelitis, poliovirus remains a public health problem in several developing countries, in Africa and Asia in particular. This is partly due to the considerable capacity of poliovirus strains to circulate and spread in populations with insufficient vaccine coverage. In addition, the attenuated strains of the oral polio vaccine (OPV) may rapidly evolve a neurovirulent phenotype, causing rare cases of paralytic poliomyelitis. The recent occurrence of epidemics associated with vaccine-derived poliovirus (VDPV) has highlighted the emergence of recombinant strains with genomes constituted of sequences from OPV strains together with sequences from non-polio enteroviruses. In this review, after briefly describing the molecular biology of poliovirus and the pathogenesis of poliomyelitis, we will provide an overview of the current situation concerning poliomyelitis prophylaxis and the strategies developed to fight this disease. We will also deal with the issue of the possible re-emergence of poliovirus after declaration of the eradication of wildtype poliovirus.

Visual recognition memory differentiates dementia with Lewy bodies and Parkinson's disease dementia.

OBJECTIVE: To compare cognitive impairments in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), to discriminate between the two entities. METHODS: 10 DLB and 12 PDD consecutive patients performed a neuropsychological battery designed to assess several cognitive domains: verbal and visual memory (Delayed Matching to Sample (DMS)-48), language, gnosia, praxia and executive functions. RESULTS: DLB patients had poorer performances in orientation (p<0.05), Trail Making Test A (p<0.05) and reading of names of colours in the Stroop Test (p<0.05). Their scores were also lower in the visual object recognition memory test (DMS-48), in both immediate (p<0.05) and delayed recognition (p<0.05). No differences were observed in the other tests. CONCLUSION: Despite global similarities in cognitive performances between DLB and PDD patients, we observed important differences: in particular, DMS-48, a test of visual object recognition memory and visual storage capacity, was poorer in DLB patients.

Transient global amnesia caused by painless aortic dissection.

Neurological syndromes secondary to acute aortic dissection (AAD) are uncommon and usually consist of focal deficits after an embolic cerebral infarction. This article reports the observation of an AAD with the chief complaint of transient acute memory impairment-that is, a non-usual stroke-like symptom.

[Creation of a regional stroke network in Tours hospital (France): consequences for stroke care and thrombolysis]. / Création d'une filière neuro-vasculaire régionale: évaluation de la prise en charge à 18 mois.

INTRODUCTION: Our university hospital serves a population of 300 000 inhabitants. Stroke is the leading cause of admission in our department of neurology. In June 2003, when the Emergency Department (ED) was closed in our institution, was created an acute stroke network (ASN), comprising 2 beds of direct admission and thrombolysis in the intensive care unit, and 4 beds dedicated to stroke care in the department of neurology, in which standardized stroke care protocols were implemented. OBJECTIVE: The aim of this study was to evaluate changes in stroke care related to the creation of the ASN in terms of delays of arrival, imaging, use of intravenous (IV) thrombolysis, and outcome of patients. We conducted a prospective study during 18 months to evaluate characteristics of patients admitted with suspected stroke or transient ischemic attack (TIA) in the newly created ASN and to assess conditions of treatment with IV thrombolysis in terms of safety and efficacy. We also compared the outcome data before and after the creation of the ASN. METHODS: For each patient admitted in our hospital for suspected stroke or TIA, were prospectively collected clinical and outcome data (age, mode of transport, delay of arrival after the onset of symptoms (OS), treatment with IV thrombolysis, outcome and discharge). This study was conducted in the ED during six months in 2002, and in the ASN during 18 months, for all patients admitted for stroke. RESULTS: Three hundred and sixty four patients were admitted in the ASN. Emergency medical services (EMS) were used in half of cases for transport, and median delay of admission after the OS was 2h and 52 min. Median delay of imaging was 1 h and 45 min. Seventeen patients (8.5 p. 100 of ischemic stroke patients) were treated with IV thrombolysis, with an initial good outcome in 9 patients, 7 with a dramatic recovery). The main reason for therapeutic abstention for untreated patients admitted in the first 3 hours was a mild deficit with a NIHSS<6. Compared with the previous management in the ED, patients in the ASN were younger, had more severe neurological symptoms, the EMS transport was the main mode of transport (versus used in 17 p. 100 of cases in 2002), and the delay of admission was significantly lower: 2 h 52 versus 5 h 10 (p<0.02). After adjustment on the main predictive factors, only patients with hemorrhagic strokes had a better outcome after the creation of the ASN. CONCLUSIONS: Creation of an ASN was associated with a significant decrease of admission and imaging delays, due to a strong collaboration with EMS, and with a better outcome for hemorrhagic stroke patients. Treatment with intravenous thrombolysis in the first 3 hours could be used widely and was efficient and safe. However, the creation of dedicated stroke units for all stroke patients remains necessary to improve quality of care and outcome.

Resectable invasive IPMN versus sporadic pancreatic adenocarcinoma of the head of the pancreas: Should these two different diseases receive the same treatment? A matched comparison study of the French Surgical Association (AFC).

PURPOSE: To compare survival and impact of adjuvant chemotherapy in patients who underwent pancreaticoduodenectomy (PD) for invasive intraductal papillary mucinous neoplasm (IIPMN) and sporadic pancreatic ductal adenocarcinoma (PDAC). METHODS: From 2005 to 2012, 240 patients underwent pancreatectomy for IIPMN and 1327 for PDAC. Exclusion criteria included neoadjuvant treatment, pancreatic resection other than PD, vascular resection, carcinoma in situ, or <11 examined lymph nodes. Thus, 82 IIPMN and 506 PDAC were eligible for the present study. Finally, The IIPMN group was matched 1:2 to compose the PDAC group according to TNM disease stage, perineural invasion, lymph node ratio, and margin status. RESULTS: There was no difference in patient's characteristics, intraoperative parameters, postoperative outcomes, and histologic parameters. Overall survival and disease-free survival times were comparable between the 2 groups. In each group, overall survival time was significantly poorer in patients who did not achieve adjuvant chemotherapy (p = 0.03 for the IIPMN group; p = 0.03 for the PDAC group). In lymph-node negative patients of the IIPMN group, adjuvant chemotherapy did not have any significant impact on overall survival time (OR = 0.57; 95% CI [0.24-1.33]). Considering the whole population (i.e. patients with IIPMN and PDAC; n = 246), patients who did not achieve adjuvant chemotherapy had poorer survival (p < 0.01). CONCLUSIONS: The courses of IIPMN and PDAC were similar after an optimized stage-to-stage comparison. Adjuvant chemotherapy was efficient in both groups. However, in lymph node negative patients, adjuvant chemotherapy seemed not to have a significant impact.

[Poliovirus and apoptosis]. / Poliovirus et apoptose.

Poliovirus is the causal agent of paralytic poliomyelitis. Flaccid paralysis characteritic of poliomyelitis result from the destruction of motor neurons, the specific target cells of poliovirus in the central nervous system (CNS). The development of new animal and cell models has allowed the key steps of the pathogenesis of poliomyelitis to be investigated at the molecular level. In particular, it has been shown that poliovirus-induced apoptosis is an important component of the tissue injury in the CNS of infected mice that leads to paralysis. In this review, the molecular biology of poliovirus and the pathogenesis of poliomyelitis will be briefly described, and then several models of poliovirus-induced apoptosis will be considered ; the role of the cellular receptor of poliovirus, CD155, in the modulation of apoptosis will also be addressed.

[Position-checking by imaging embarked there tomotherapy and the delegation to the radiology technician]. / Contrôle de position quotidien par imagerie embarquée en tomothérapie et de la délégation aux manipulateurs en électroradiologie médicale.

Tomotherapy is a technique of IMRT and IGRT using a linear accelerator and a helical CT-scanner. To reach this targeting of precision, the repositioning of the patient is essential. The use of a contention adapted according to the location of the disease and the morphology of the patient is necessary for the safety of this one and the treatment. Once the patient positioned on the reference table, technicians of imager's team check by the acquisition of helical imagery with the reference CT-scanner the position of the patient, the zone of the PTV and healthy organs in the protected surroundings. At first, adjustment will be made automatically on three planes of the space (axial, sagittal, frontal) and three rotations (pitch, roll and yaw) by the device of treatment, then the technicians of imagery will bring a modification of these recalls manually. After validation, the processing will then be made in complete safety for the patient and the nursing. This check by MVCT is daily before every session of processing. It is made by the technicians of imagery. The radiation oncologist confirms the images at j0, then controls once a week MVCT. Traceability in the file of the patient of the various marks (osseous and\or soft tissue) necessary for the daily gaps will be noted by this one to delegate to the technicians of imagery the validation of the MVCT before every session.

[Psychiatric comorbidity in patients with pseudoseizures: retrospective study conducted in a video-EEG center]. / Comorbidité psychiatrique au cours des événements non épileptiques: étude rétrospective dans un centre de vidéo-EEG.

INTRODUCTION: Pseudoseizures involve a group of paroxysmal behavioral symptoms mimicking an epileptic seizure, but without modifications of cerebral electrical activity. PATIENTS AND METHOD: In this retrospective study focusing on mental disorders, 37 patients with pseudoseizures were recorded during video-EEG procedure. RESULTS: According to DSM-IV criteria, 70 percent of the patients had at least one mental disorder when evaluated. Diagnoses were, in decreasing order of frequency: post-traumatic stress disorders, other anxious disorders, somatoform disorders, dissociative disorders, and mood disorders. CONCLUSION: The strong association between pseudoseizures and post-traumatic stress disorders is discussed. Our results argue in favor of a systematic evaluation of psychiatric comorbidity.

[Cyclosporin-induced toxic neuromyopathy]. / Neuromyopathie toxique induite par la ciclosporine.

INTRODUCTION: Cyclosporine is an immunosuppressive treatment whose side effects limit its usefulness. Among neurological side effects, neuropathies or myopathies have been reported, specially inpatients given combinations of cyclosporine with co-enzyme A reductase inhibitors. CASE REPORT: We report here the case of a 67-year-old woman who developed few months after a kidney graft sensorimotor disorders which progressed rapidly. Since all etiologies of such a disorder were ruled out, the hypothesis of toxicity exclusively induced by cyclosporine was suggested and confirmed by the improvement observed after its withdrawal. CONCLUSION: This observation highlights the fact that cyclosporine may induce neuromyopathies even when given alone at the therapeutic dosage.

A syndrome of REM and non-REM sleep reduction and lateral gaze paresis after medial tegmental pontine stroke. Computed tomographic scans and anatomical correlations in four patients.

A common pattern of reduction in both rapid eye movement and non-rapid eye movement sleep associated with various lateral gaze paralyses was present in four cases of brain-stem stroke. From computed tomographic scan data, clinical inferences, and, in two cases, neuropathologic sections, the common lesions were localized in the medial pontine tegmentum, ie, the inner part of the gigantocellular and pontis centralis caudalis nuclei. These data in humans were compared with lesions obtained experimentally in cats.

SMN1 gene study in three families in which ALS and spinal muscular atrophy co-exist.

Spinal muscular atrophy (SMA) is caused by SMN1 gene deletions or mutations, and ALS is the most frequent motor neuron condition in adults. The authors describe three families in which ALS and SMA coexist. The authors found that no SOD1 mutation was found within these families; all three ALS cases had at least two SMN1 copies; and an abnormal SMN1 gene locus did not explain the co-occurrence of these two motor neuron disorders in these families.

Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI.

We describe the case of a human immunodeficiency virus-infected 34-year-old man with progressive multifocal leukoencephalopathy (PML). His case displayed unusual features, including a bizarre movement disorder, predominant involvement of the subcortical U fibers on neuropathologic examination, and the absence of MRI abnormalities suggestive of PML. Anatomic-clinical correlations are discussed.

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Spectral analysis of the EEG (alpha rhythm) and activity in the left hemisphere: the effects of lateral gaze.

This study tests the effect of maintaining right and left lateral gaze during a writing task which preferentially implicates the left hemisphere using an asymmetry parameter calculated from the spectral power of the alpha rhythm (RP-LP/RP + LP) in a right-handed patient undergoing the same experimental regimen nine times. A six derivation EEG was recorded. Maintaining left lateral gaze (toward the active hemisphere) removes the lateralization found during writing while staring straight ahead whereas maintaining right lateral gaze (toward the side opposite the active hemisphere) results in slightly lower values which are however, not significantly different from those obtained during staring straight ahead. This study adds an electrophysiologic aspect to Kinsbournes's paradigm on gaze position and hemispheric activation.