CD44v6 as innovative sarcoma target for CAR-redirected CIK cells.

Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR+.CIK). We set a patient-derived experimental platform. CAR+.CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR+.CIK were characterized and assessed in vitro against multiple histotypes of patient-derived STS. The anti-sarcoma activity of CAR+.CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR+.CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti-CD44v6 antibody. CAR+.CIK produced higher amounts of IL6 and IFN-γ compared to control CIK. CAR+.CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities. We report first evidence of CAR+.CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR+.CIK in clinical trials against high grade STS.

Inositol and acne.

Acne, once considered as a mere esthetic problem, is now recognized as a disease that can cause major disturbances of the psychological and emotional sphere. Currently, the treatment of acne is focused on one or more pathogenic factors: hormonal stimulation and sebaceous hypersecretion, disorder of keratinization, colonization of Propionibacterium acnes and inflammation. The aim of the paper was to evaluate the use of inositol in patients with moderate acne.

Headache in school age.

Headache, especially migraine and tension-type headache, is one of the most frequently reported somatic complaints by children and adolescents. Different population-based studies have been conducted to study the correlation between headache and lifestyles in pediatric age, nevertheless, the obtained results are often controversial and these relationship still remain unclear. Likewise, is still strongly debated the burden of headache during school age, its impact on school performances and on quality of life of children and their families. Consequently, larger studies are necessary to evaluate the degree of disability due to pediatric headache. We summarize the ongoing knowledge about these concepts, with the intent to provide useful data to neurologists but also to primary care providers, to further improve the management of pediatric headaches by preventing the headache progression, the disabling effects associated and improving the long-term outcome.

Post-traumatic headaches: an epidemiological overview.

Post-traumatic headache (PTH) is the most common secondary headache disorder, corresponding to approximately 4 % of all symptomatic headaches. PTH, a cardinal feature of the post-concussive syndrome, usually shows a phenotype similar to migraine or tension-type headache. However, rare cases of PTH similar to trigeminal autonomic cephalalgias have been described. Many studies have investigated PTH prevalence and potential risk factors for its development and maintenance. In general population, the majority of PTH patients is female and has been involved in vehicle-related accidents. Generally, headache gradually disappears over few weeks or months; however, PTH could become persistent and very disabling in a minority of patients. This brief review will focus on PTH epidemiological aspects.

Controversies in migraine treatment: opioids should be avoided.

The use of opioids for migraine is still controversial. Evidence-based guidelines do not recommend opioids as first-line treatment of migraine attacks, while clinical and epidemiological surveys demonstrate that the use of opioids is associated with more severe headache-related disability, symptomology and comorbidities, and greater health-care resource utilization. There are concerns that opioids may be misused or abused, leading to opioid abuse or dependence and migraineurs are particularly prone and at risk for the development of chronic daily headache from opioids overuse. Since clinical and preclinical studies evidence a pathophysiological role of opioids in migraine progression, opioids should be avoided in migraine patients.

Basilar-type migraine patients responsive to lamotrigine: a 5-year follow-up.

Five years ago we reported the case of three patients affected by basilar-type migraine (BM) responsive to lamotrigine. At that time, proven treatment options for BM are rather limited and lamotrigine has been tested in BM patients because it was a widely tested treatment for migraine with aura. That positive 1-year experience leaded us to suggest that lamotrigine could be a preventive therapeutic option for BM patients, with and without menstruation association. We now report the five-year follow-up of the same patients to confirm and underlie the possible role of lamotrigine to induce BM attacks remission.

Migraine and movement disorders.

A large series of clinical and experimental observations on the interactions between migraine and the extrapyramidal system are available. Some previous studies reported high frequency of migraine in some basal ganglia (BG) disorders, such as essential tremor (ET), Tourette's syndrome (TS), Sydenham's chorea and more recently restless legs syndrome (RLS). For example, the frequency of migraine headache in a clinic sample of TS patients was found nearly fourfold more than that reported in the general population. To the best of our knowledge, no controlled studies have been conducted to determine a real association. ET and migraine headache have been considered comorbid diseases on the basis of uncontrolled studies for many years. In a recent Italian study, this comorbid association has been excluded, reporting no significant differences in the frequency of lifetime and current migraine between patients with ET and controls. Among mostly common movement disorders, RLS has been recently considered as possibly comorbid with migraine. Studies in selected patient groups strongly suggest that RLS is more common in migraine patients than in control populations, although no population-based study of the coincidence of migraine and RLS has yet been identified. The exact mechanisms and contributing factors for a positive association between migraine and RLS remain unclear. A number of possible explanations have been offered for the association of RLS and primary headache, but the three most attractive ones are a hypothetical dopaminergic dysfunction and dysfunctional brain iron metabolism, a possible genetic linkage and a sleep disturbance. More recently, the role of BG in pain processing has been confirmed by functional imaging data in the caudate, putamen and pallidum in migraine patients. A critical appraisal of all these clinical and experimental data suggests that the extrapyramidal system is somehow related to migraine. Although the primary involvement of extrapyramidal system in the pathophysiology of migraine cannot as yet be proven, a more general role in the processing of nociceptive information and/or maybe part of the complex behavioral adaptive response that characterizes migraine may be suggested.

Migraine and metabolism.

Migraine is a chronic disorder with complex pathophysiology involving both neuronal and vascular mechanisms. Migraine is associated with an increased risk of vascular disorders, such as stroke and coronary heart disease. Obesity and diabetes are metabolic disorders with a complex association with migraine. Insulin resistance, which represents the main causal factor of diseases involved in metabolic syndrome, is more common in patients with migraine. A better understanding of the relationship between metabolic syndrome and migraine may be of great clinical interest for migraine management.

Headache, eating and sleeping behaviors and lifestyle factors in preadolescents and adolescents: preliminary results from an Italian population study.

Several dietary and lifestyle habits can be associated with headaches or with their progression to chronic forms in adults. We report the results of the first population study performed in Italy on a sample of preadolescent and adolescent students to assess the possible association between headache and specific habits and lifestyle factors. Preliminary data from 800 questionnaires showed that 365 subjects had headaches, which were of moderate-severe intensity, associated with anorexia, and caused absence from school in more than 50 % of students. The main finding was the evidence of a clear association between headache and irregular intake of meals (especially irregular breakfast) and sleep disturbance with significant differences when subjects with and without headache were compared. If confirmed, these results are likely to influence clinical practice as well to address educational programs in preadolescents and adolescents.

Polytherapy for migraine prophylaxis.

Migraine is a chronic neurological disorder with episodic manifestations, progressive in some individuals. Preventive treatment is recommended for patients with frequent or disabling attacks. A sizeable proportion of migraineurs in need of preventive treatment does not significantly benefit from monotherapy. This short review evaluates the role of pharmacological polytherapy in migraine prevention.

Triptans: over the migraine.

Migraine is a chronic, recurrent, disabling condition that affects millions of people worldwide. Proper acute care treatment for migraineurs is based on triptans, a class of specific medications approved over 20 years ago. Triptans are serotonin (5-HT1B/1D) receptor agonists that are generally effective, well tolerated and safe. Seven triptans are available worldwide, although not all are available in every country, with multiple routes of administration, giving to doctors and patients a wide choice. Despite the similarities of the available triptans, pharmacological heterogeneity offers slightly different efficacy profiles. Triptans are not pain medications, they are abortive migraine medications which cannot prevent migraines. In addition to migraine attacks, triptans are also helpful for cluster headaches. If they are useful in other primary headaches rather than migraine and cluster headache it is yet to be addressed. In the literature there are only limited controlled clinical data to support a migraine-selective activity for triptans. Reports are available about efficacy of triptans to stop attacks of other types of primary headache, such as tension type headache, hypnic headache and other rare forms of primary headaches. On the other hand, sumatriptan failed to treat the indomethacin-responsive primary headache disorders like chronic paroxysmal hemicrania and hemicrania continua, nor was it effective in the myofascial temporal muscle pain or in atypical facial pain. Why triptans are effective in so different types of primary headaches remain unclear. Up to date, it is not clear whether the antimigrainous activity of the triptans involves an action only in the periphery or in the CNS as well. Probably we should consider triptans as "pain killers" and not only as "migraine killers". We clearly need additional studies on triptans as putative analgesics in well-accepted animal and clinical models of acute and chronic somatic pain.

Remarks on an educational training course on headache.

In the last years several studies have been performed on migraine; however, only few topics have changed the clinical practice. Among these, there are physiopathological insights (e.g., allodynia and gastric stasis) or therapeutical evidences (e.g., topiramate) that become very important in the management of migraine and could clarify the different response to the therapies. The aim of a training school on headache should be to link research to practice without transferring contradictory data. To teach is not only to support notions with simple data: we think that knowledge has to be used according to the condition of the patient and the situation in which the migraineurs live.

Autonomic and cerebrovascular abnormalities in mild COPD are worsened by chronic smoking.

Patients with chronic obstructive pulmonary disease (COPD) may develop hypercapnia and hypoxia, two main determinants of cerebral blood flow. The current authors tested whether cerebrovascular regulation was altered in mild COPD, modified by manoeuvres acutely improving autonomic cardiovascular modulation or influenced by smoking habit. In 15 eucapnic normoxic mild COPD patients (eight smokers) and 28 age-matched controls (14 smokers), midcerebral artery blood flow velocity (MCFV), end-tidal carbon dioxide tension (P(ET,CO2)), arterial oxygen saturation (S(a,O2)), ECG and blood pressure at rest were monitored during progressive hypercapnic hyperoxia, isocapnic hypoxia, slow breathing and oxygen administration. MCFV, arterial baroreflex and dynamic MCFV-blood pressure relationships were compared by phase analysis. COPD and control smokers showed higher MCFV (when corrected for P(ET,CO2)), lower cerebrovascular resistance index and lower sensitivity to hypercapnia than nonsmokers, with equal sensitivity to S(a,O2) and similar phase analysis. Arterial baroreflex was depressed in all COPD patients. Slow breathing and oxygen administration improved baroreflex sensitivity and reduced MCFV in all COPD patients. Patients with mild chronic obstructive pulmonary disease show autonomic dysfunction. Chronic smoking induces cerebral vasodilation and impairs cerebrovascular control. All abnormalities can be partly corrected by improving the cardio- and cerebrovascular autonomic modulation, suggesting that functional autonomic abnormalities are already present at an early stage of disease.

Influence of respiratory instability during neurocardiogenic presyncope on cerebrovascular and cardiovascular dynamics.

OBJECTIVE: To analyse the influence of breathing activity on cerebrovascular dynamics during presyncope. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: 38 subjects developing neurocardiogenic syncope (syncope group), and 61 age-matched control subjects with negative tilt. INTERVENTIONS: Middle cerebral artery mean blood flow velocity (MCFV), continuous non-invasive blood pressure (BP), end-tidal CO(2) (CO(2)-et) and minute ventilation were measured before and during 45' 60 degrees tilting. MAIN OUTCOME MEASURES: Respiratory and cerebrovascular variability, cerebrovascular resistance (CVR)-absolute and corrected for CO(2)-et at 40 mm Hg (CVR-40)-and dynamic cerebrovascular regulation (CVR-dyn: transfer function phase analysis between MCFV and BP), obtained during supine rest (baseline), first 5 minutes of tilt (early tilt), early- and late presyncope (first and second half, respectively, of 4 minutes preceding syncope in syncope group, and equivalent time in controls). RESULTS: Tilting induced a mean (SE) CVR decrease in controls (baseline 1.20 (0.04); late presyncope 1.12 (0.06) mm Hg x s/cm, p<0.05) but not in the syncope group (baseline 1.09 (0.04); late presyncope 1.09 (0.06) mm Hg x s/cm, p = NS). However, CVR-40 showed similar reduction in both groups (controls: from 1.15 (0.04) to 0.96 (0.04) mm Hg x s/cm; syncope group: from 1.01 (0.04) to 0.83 (0.04) mm Hg x s/cm, p = NS). CVR-dyn of the two groups was also similar (p = NS). Respiratory variability increased in the syncope group, from early tilt to late presyncope (p<0.05 or better), preceding hyperventilation and being significantly correlated with an increase in MCFV and BP variability (p<0.01). CONCLUSIONS: During presyncope, the development of respiratory instability and hypocapnia impairs MCFV, thus facilitating the onset of syncope despite preserved cerebrovascular regulation.

Functional neuroimaging and headache pathophysiology: new findings and new prospects.

In the last ten years pathophysiology of primary headaches has received new insights from neuroimaging studies. Positron emission tomography (PET) showed activation of specific brain structures, brainstem in migraine and hypothalamic grey in trigeminal autonomic cephalalgias. This brain activation suggests it may intervene both in a permissive or triggering manner and as a response to pain driven by the first division of the trigeminal nerve. Voxel-based morphometry has suggested that there is a correlation between the brain area activated specifically in acute cluster headache - the posterior hypothalamic grey matter - and an increase in grey matter in the same region. New insights into mechanisms of head pain have emerged thanks to neuroimaging obtained in experimentally induced headaches, and during peripheral and central neurostimulation.

Deep brain stimulation in craniofacial pain: seven years' experience.

Cluster headache (CH) is a primary headache with excruciatingly painful attacks that are strictly unilateral. About 10% of cases experience no significant remission, and about 15% of these do not respond to medication, so surgery is considered. Neuroimaging studies show that the posterior inferior hypothalamus is activated during CH attacks and is plausibly the CH generator. We report on 16 chronic CH patients, with headaches refractory to all medication, who received long-term hypothalamic stimulation following electrode implant to the posterior inferior hypothalamus. After a mean follow-up of 23 months, a persistent pain-free to almost pain-free state was achieved in 13/16 patients (15/18 implants; 83.3%) a mean of 42 days (range 1-86 days) after monopolar stimulation initiation. Ten patients (11 implants) are completely pain-free. A common side effect was transient diplopia, which limited stimulation amplitude. In one patient, a small non-symptomatic haemorrhage into the 3rd ventricle occurred following implant, but regressed 24 h later. Persistent side effects are absent except in one patient with bilateral stimulation, in whom stimulation was stopped to resolve vertigo and worsened bradycardia, but was resumed later without further problems. Hypothalamic stimulation is an effective, safe and well tolerated treatment for chronic drug-refractory CH. It appears as a valid alternative to destructive surgical modalities, and has the additional advantage of being reversible.

Headache and spontaneous low cerebrospinal fluid pressure syndrome.

We examined 59 consecutive patients presenting between 1993 and 2006 at our centre diagnosed with headache associated with spontaneous intracranial hypotension syndrome (SIH). Thirty-six (61%) patients were women; the mean age was 47 years (range 20-68). Cerebral MRI with contrast confirmed SIH in all patients. Headache characteristics were obtained by direct semistructured interview; in a minority of cases information was completed retrospectively through a phone call. All SIH patients suffered from headache. Early recognition of SIH may avoid dangerous worsening due to delayed diagnosis. Orthostatic headache, the main symptom, suggests the diagnosis.

Basilar-type migraine responsive to lamotrigine: three case reports.

Basilar-type migraine (BM) has been recognised in the revised International Classification of Headache Disorders as a distinct clinical entity (subtype of migraine with aura), characterised by disturbing migraine aura clearly originating from the brainstem or from both hemispheres simultaneously affected. It differs from familial and sporadic hemiplegic migraines by the absence of motor deficit. Lamotrigine has been shown to be effective in preventing migraine aura symptoms in typical aura and in some cases of BM. We tried lamotrigine in three female cases of BM.

Skin prick-test reactivity to aeroallergens and allergic symptoms in an urban population of central Italy: a longitudinal study.

BACKGROUND: Cross-sectional studies report an increasing prevalence of allergic diseases, such as rhinitis and asthma. Not thoroughly known, instead, is the natural history of allergic sensitization and the progress of the allergic disease-related symptoms. AIM: The purpose of this study was to evaluate longitudinally the skin reactivity for the most common aeroallergens and the allergic symptoms in an urban population living in Perugia, a town of central Italy with a low-level of air pollution exposure. METHODS: In the 1998-1999 period 788 subjects were tested for skin reactivity to a panel of aeroallergens and underwent the administration of a questionnaire. These same subjects were part of a cohort of 1200 subjects who participated in a previous epidemiological study performed in 1984-1985 using the same tools. Subjects were aged between 14 and 64 years at the time of the first survey. RESULTS: In the present survey 196 subjects (24.9%) had skin reactivity to at least one aeroallergen, while in the previous survey 143 subjects (18.1%) had skin prick-test reactivity. The increase of the skin reactivity between the two observations was highly significant (P<0.001) and was mainly observed in subjects <40-years old. The greatest increment in skin reactivity was seen to Dermatophagoides pteronyssinus (house dust mite) allergen. Data obtained from questionnaires showed that subjects who declared allergic symptoms increased from 341 (43.3%) to 380 (48.2%). However, the increase was significant (P<0.01) only in subjects who had a positive association between allergic symptoms and prick-test reactivity and was greater for rhino-conjunctivitis than for asthma-related symptoms. CONCLUSIONS: In a cohort of urban population of the centre of Italy, exposed to a low and stable level of air pollution, the sensitization to common aeroallergens increased with time, mostly in people <40-years of age. The greatest increment was found for indoor allergens such as Dermatophagoides pteronysimus. A significant increase in allergic symptoms, mainly related to rhino-conjunctivitis, was observed only in the presence of positive prick test.

Adult abdominal migraine: a new syndrome or sporadic feature of migraine headache? A case report.

Abdominal migraine is one of the variants of migraine headache typically occurring in children and coded as 1.3.2 in the revised edition of IHS classification within the group 'Childhood periodic syndromes that are commonly precursors of migraine'. The affected children frequently develop typical migraine later in their life. We report a case of a 23 years old woman affected by attacks of recurrent abdominal pain accompanied by migraine. Abdominal pain attacks started in the adolescence and persisted without headache until the patient was 21. At this time, she experienced migraine pain accompanied by nausea, photophobia and phonophobia and associated to acute abdominal pain. Neuroimaging investigations and laboratory testing excluded any underlying organic disease. Complete remission of abdominal attacks was obtained during 4-month treatment period with pizotifen. Attacks fulfil IHS diagnostic criteria for 'abdominal migraine', although of late onset. This case report suggests that 'abdominal migraine' is a migraineous disorder to be hypothesized in adult patients after having disclosed any organic disease. As reported in the literature, 'adult abdominal migraine' is a sporadic migraine subtype in adult patients and it is not to be considered as a new migraineous syndrome.