Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Personality traits and behavioural and psychological symptoms in patients with mild cognitive impairment.

BACKGROUND AND AIMS: Both personality changes and behavioural and psychological symptoms (BPS) may be associated with mild cognitive impairment (MCI) in later life and help identify incipient dementia. We wished to investigate the links between personality and BPS in MCI. METHOD: We studied premorbid personality traits as estimated 5 years back and their changes in 83 control subjects and 52 MCI patients using the revised NEO Personality Inventory for the Five-Factor Model completed by a proxy. Information on BPS was obtained using the Neuropsychiatric Inventory (NPI). Analyses were controlled for current depression and anxiety. RESULTS: Premorbid neuroticism and openness to experience were associated with the total NPI score. The changes in neuroticism, extraversion, openness to experiences, and conscientiousness were associated with apathy and affective symptoms. CONCLUSIONS: Personality changes and BPS occur in MCI. The occurrence of affective BPS and apathy is associated with both premorbid personality traits and their changes.

Treatment of central retinal vein occlusion-related macular edema with intravitreal bevacizumab (Avastin): preliminary results.

PURPOSE: To assess the safety and efficacy of treatment of macular edema secondary to central retinal vein occlusion (CRVO) with intravitreal bevacizumab. PATIENTS AND METHOD: The ongoing prospective study included 8 consecutive patients (8 eyes) with macular edema secondary to CRVO (6 non ischemic and 2 ischemic), treated with intravitreal injection of 1.25 mg (0.05 mL) of bevacizumab. Main outcome was best corrected visual acuity (BCVA) and central foveal thickness (CFT) measured by optical coherence tomography monthly during one year. Retreatment criteria include decrease of BCVA, persistence of macular edema on angiograms and increase of CFT. RESULTS: Mean age of the eight patients was 68 years (range: 50-82 years). Mean duration of symptoms before injection was 98 days (range: 3-289). Mean follow-up was 3.25 months. At baseline, mean BCVA was 0.84 logMar and mean baseline CFT was 771 microm. Mean BCVA was 0.36 and mean CFT thickness was 275 microm (n = 8) at month 1, 0.41 and 411 microm at month 2 (n = 7), 0.3 and 344 microm at month 3 (n = 6), 0.3 and 397 microm at month 4 (n = 5), respectively. In 75 % of patients, a single injection was not sufficient, and retreatment needed. No serious adverse events were observed. CONCLUSIONS: Treatment of macular edema secondary to CRVO with intravitreal bevacizumab injection of 1.25 mg was well tolerated and associated with marked macular thickness reduction and BCVA improvement in all patients. A trend towards reduction of foveal thickness and improvement of visual acuity was observed in both acute and chronic CRVO.

Clinician characteristics, communication, and patient outcome in oncology: a systematic review.

OBJECTIVE: The aim of this study was to review the literature on clinician characteristics influencing patient-clinician communication or patient outcome in oncology. METHODS: Studies investigating the association of clinician characteristics with quality of communication and with outcome for adult cancer patients were systematically searched in MEDLINE, PSYINFO, PUBMED, EMBASE, CINHAL, Web of Science and The Cochrane Library up to November 2012. We used the preferred reporting items for systematic reviews and meta-analyses statement to guide our review. Articles were extracted independently by two of the authors using predefined criteria. RESULTS: Twenty seven articles met the inclusion criteria. Clinician characteristics included a variety of sociodemographic, relational, and personal characteristics. A positive impact on quality of communication and/or patient outcome was reported for communication skills training, an external locus of control, empathy, a socioemotional approach, shared decision-making style, higher anxiety, and defensiveness. A negative impact was reported for increased level of fatigue and burnout and expression of worry. Professional experience of clinicians was not related to communication and/or to patient outcome, and divergent results were reported for clinician gender, age, stress, posture, and confidence or self-efficacy. CONCLUSIONS: Various clinician characteristics have different effects on quality of communication and/or patient outcome. Research is needed to investigate the pathways leading to effective communication between clinicians and patients. Copyright © 2013 John Wiley & Sons, Ltd.

A 10-year experience in paediatric spontaneous cerebral hemorrhage: which children with headache need more than a clinical examination?

INTRODUCTION: When a child is seen in a clinic with a headache, stroke is certainly not the first on the list of differential diagnoses. In western countries, stroke is typically associated with adults and the elderly. Although rare, haemorrhagic strokes are not exceptional in the paediatric population, as their incidence is around 1/100 000/year. Prompt diagnosis is essential, since delayed treatment may lead to disastrous prognosis in these children. MATERIALS AND METHODS: This is a retrospective review of paediatric cases with spontaneous cerebral haemorrhage that presented in two university hospitals in the last ten years. The experience of these primary and tertiary referral centres comprises 22 consecutive cases that are analysed according to aetiology, presenting symptoms, treatment and outcome. RESULTS: 77% of the children diagnosed with haemorrhagic stroke presented with headaches. 41% of them had a sudden onset, while 9% developed headaches over a period of hours to weeks. While 9% presented only with headaches, the majority had either subtle (diplopia, balance problems) or obvious (focal deficits, unilateral weakness and decreased level of consciousness) concomitant neurological signs. 55% had an arteriovenous malformation (AVM), 18% had an aneurysm and 14% had a cavernous malformation. In 14% the aetiology could not be determined. The majority of haemorrhages (82%) were supratentorial, while 18% bled into the posterior fossa. All children underwent an emergency cerebral CT scan followed by specific investigations. The treatment was dependent on the aetiology as well as the mass effect of the haematoma. In 23% an emergent evacuation of the haematoma was performed. Two children (9%) died, and 75% had a favourable clinical outcome. CONCLUSION: Headaches in children are a common problem, and a small minority may reveal an intracranial haemorrhage with poor prognosis if not treated promptly. Although characterisation of headaches is more difficult in a paediatric population, sudden, unusual or intense headaches should lead to imaging work-up. Any neurological finding, even one as subtle as hemianopsia or dysmetria, should alarm the physician and should be followed by emergency imaging investigation. If the cerebral CT reveals a haemorrhage, the child should be referred immediately to a neurosurgical referral centre without further investigation. The outcome is grim for children presenting in coma with fixed, dilated pupils. The long-term result overall for children after spontaneous intracranial haemorrhage is not dismal and depends critically on specialised management.

Psychodynamic interventions in cancer care I: psychometric results of a randomized controlled trial.

OBJECTIVE: This study aimed to assess the effectiveness of psychodynamic interventions in cancer care. METHODS: Between 2006 and 2009, each consecutive outpatient of the Oncology Center of the University Hospital of Lausanne was invited to participate in a trial evaluating the effects of psychological support. Accepting patients were randomly assigned to an immediate intervention or a delayed intervention [4-month waiting list]. Patients who declined support were asked to participate in an observational group [OG]. Socio-demographic and medical data, anxiety, and depression [HADS], psychological distress [SCL-90], alexithymia [TAS] and quality of life [EORTC] were recorded at baseline, and at 1, 4, 8, and 12-months follow-up. RESULTS: Of the 1973 approached patients, 1057 were excluded, 530 refused, and 386 were included with 196 of them participating in the OG. Of the patients in the intervention group [IG] [N = 190], 94 were randomized to the immediate intervention and 96 to the delayed intervention group (dIG). IG patients were younger, predominantly female, and had more psychological symptoms compared with those in the OG. Although patients of the IG and OG showed significant improvement in quality of life from baseline to 12-months follow-up, other outcomes [anxiety, depression, psychological distress, and alexithymia] remained unchanged. CONCLUSIONS: The intervention was not effective with regards to psychometric outcome. The results have to be interpreted in light of the study design [untargeted intervention], the low levels of psychiatric symptoms, dropout of symptomatic patients, and the high prevalence of alexithymia.

Personality traits and behavioral and psychological symptoms in patients at an early stage of Alzheimer's disease.

OBJECTIVE: The origins of behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) are still poorly understood. Focusing on individual personality structure, we explored the relationship between premorbid personality and its changes over 5 years, and BPS in patients at an early stage of AD. METHOD: A total of 54 patients at an early stage of AD according to ICD-10 and NINCDS-ADRDA criteria and 64 control subjects were included. Family members filled in the Neuropsychiatric Inventory Questionnaire to evaluate their proxies' current BPS and the NEO Personality Inventory Revised twice, the first time to evaluate the participants' current personality and the second time to assess personality traits as they were remembered to be 5 years earlier. RESULTS: Behavioral and psychological symptoms, in particular apathy, depression, anxiety, and agitation, are frequent occurrences in early stage AD. Premorbid personality differed between AD patients and normal control, but it was not predictive of BPS in patients with AD. Personality traits clearly change in the course of beginning AD, and this change seems to develop in parallel with BPS as early signs of AD. CONCLUSIONS: Premorbid personality was not associated with BPS in early stage of AD, although complex and non-linear relationships between the two are not excluded. However, both personality and behavioral changes occur early in the course of AD, and recognizing them as possible, early warning signs of neurodegeneration may prove to be a key factor for early detection and intervention. Copyright © 2012 John Wiley & Sons, Ltd.

Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era.

PURPOSE: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. EXPERIMENTAL DESIGN: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. RESULTS: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19-83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6-3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4-51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. CONCLUSIONS: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. Clin Cancer Res; 18(16); 4458-64. ©2012 AACR.

Primary pineal tumors: outcome and prognostic factors-a study from the Rare Cancer Network (RCN).

PURPOSE: To better define outcome and prognostic factors in primary pineal tumors. MATERIALS AND METHODS: Thirty-five consecutive patients from seven academic centers of the Rare Cancer Network diagnosed between 1988 and 2006 were included. Median age was 36 years. Surgical resection consisted of biopsy in 12 cases and resection in 21 (2 cases with unknown resection). All patients underwent radiotherapy and 12 patients received also chemotherapy. RESULTS: Histological subtypes were pineoblastoma (PNB) in 21 patients, pineocytoma (PC) in 8 patients and pineocytoma with intermediate differentiation in 6 patients. Six patients with PNB had evidence of spinal seeding. Fifteen patients relapsed (14 PNB and 1 PC) with PNB cases at higher risk (p = 0.031). Median survival time was not reached. Median disease-free survival was 82 months (CI 50 % 28-275). In univariate analysis, age younger than 36 years was an unfavorable prognostic factor (p = 0.003). Patients with metastases at diagnosis had poorer survival (p = 0.048). Late side effects related to radiotherapy were dementia, leukoencephalopathy or memory loss in seven cases, occipital ischemia in one, and grade 3 seizures in two cases. Side effects related to chemotherapy were grade 3-4 leucopenia in five cases, grade 4 thrombocytopenia in three cases, grade 2 anemia in two cases, grade 4 pancytopenia in one case, grade 4 vomiting in one case and renal failure in one case. CONCLUSIONS: Age and dissemination at diagnosis influenced survival in our series. The prevalence of chronic toxicity suggests that new adjuvant strategies are advisable.

Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.

OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively. METHODS: A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists. MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography. RESULTS: After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome. CONCLUSIONS: Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.

Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences.

One of the most relevant concerns in long-term survivors of paediatric acute lymphoblastic leukaemia (ALL) is the development of neuropsychological sequelae. The majority of the published studies report on patients treated with chemotherapy and prophylactic central nervous system (CNS) irradiation, little is known about the outcome of patients treated with chemotherapy-only regimens. Using the standardised clinical and neuropsychological instruments of the SPOG Late Effects Study, the intellectual performance of 132 paediatric ALL patients treated with chemotherapy only was compared to that of 100 control patients surviving from diverse non-CNS solid tumours. As a group, ALL and solid tumour survivors showed normal and comparable intellectual performances (mean global IQ 104.6 in both groups). The percentage of patients in the borderline range (global IQ between 70 and 85) was comparable and not higher as expected (10% cases and 13% controls, expected 16%). Only 2 (2%) of the former ALL and 1 (1%) of the solid tumour patients were in the range of mental retardation (global IQ<70). Former known risk factors described in children treated with prophylactic CNS irradiation, like a younger age at diagnosis of ALL and female gender, remained valid in chemotherapy-only treated patients. The abandonment of prophylactic CNS irradiation and its replacement by a more intensive systemic and intrathecal chemotherapy led to a reduction, but not the disappearance of late neuropsychological sequelae.