Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep.

PURPOSE: To present the long-term follow-up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike-waves during slow wave sleep (CSWS). METHODS: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. KEY FINDINGS: After a mean duration of follow-up of 15.6 years (range, 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long-term outcome correlated best with duration of CSWS. SIGNIFICANCE: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

Treatment motivation in adolescents with psychosis or at high risk: Determinants and impact on improvements in symptoms and cognitive functioning, preliminary results.

Abstract Low motivation is frequent in chronic disorders such as psychosis and may limit treatment efficacy. Although some evidence supports this view in adults, few studies so far have focused on adolescents. We assessed the impact of baseline symptoms, cognitive deficits and cognitive treatment characteristics on treatment motivation (TM), and examined whether TM affected treatment outcome. Twenty-eight adolescents with psychotic disorders participated in 16 sessions of computerized cognitive remediation or games. TM was assessed for each session. Lower TM was predicted by more severe symptoms at baseline, and was associated with smaller improvements in symptoms and both cognitive and psychosocial functioning at the end of the intervention. Experiencing success in the treatment exercises enhanced TM in all patients.

Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes

Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics.

Global surveillance of cancer survival 1995-2009 : analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75 000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. FUNDING: Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

Continuous quantification of HER2 expression by microfluidic precision immunofluorescence estimates HER2 gene amplification in breast cancer.

Chromogenic immunohistochemistry (IHC) is omnipresent in cancer diagnosis, but has also been criticized for its technical limit in quantifying the level of protein expression on tissue sections, thus potentially masking clinically relevant data. Shifting from qualitative to quantitative, immunofluorescence (IF) has recently gained attention, yet the question of how precisely IF can quantify antigen expression remains unanswered, regarding in particular its technical limitations and applicability to multiple markers. Here we introduce microfluidic precision IF, which accurately quantifies the target expression level in a continuous scale based on microfluidic IF staining of standard tissue sections and low-complexity automated image analysis. We show that the level of HER2 protein expression, as continuously quantified using microfluidic precision IF in 25 breast cancer cases, including several cases with equivocal IHC result, can predict the number of HER2 gene copies as assessed by fluorescence in situ hybridization (FISH). Finally, we demonstrate that the working principle of this technology is not restricted to HER2 but can be extended to other biomarkers. We anticipate that our method has the potential of providing automated, fast and high-quality quantitative in situ biomarker data using low-cost immunofluorescence assays, as increasingly required in the era of individually tailored cancer therapy.