Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma.

Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC50s ranging between 30 and 95 nM. Orthotopic xenografts of GBM10 and the bevacizumab resistant lines GBM6 and GBM39 were established by implantating 3 × 105 cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p < 0.0001). In addition, alisertib administration in these mice decreased phosphorylated aurora-A, induced mitotic arrest and significantly decreased histone H3 phosphorylation in tumors. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.

Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project.

BACKGROUND: In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection. METHODS: In a nested case-control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII(®)). RESULTS: By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0-15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1-64.4). CONCLUSIONS: Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.

Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear. METHODS: We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327,396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use. RESULTS: Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41-0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59-0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ≤ 45 years: HR, 1.46; 95% CI, 1.06-1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk. CONCLUSION: This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.

Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk. METHODS: We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337,802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer. RESULTS: After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83-1.02), although this association was stronger among post-menopausal women (HR, 0.84; 95% CI: 0.74-0.95). Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk. CONCLUSION: Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk.

Use of dietary supplements and medication among postmenopausal women with vasomotor symptoms.

OBJECTIVES: To assess how postmenopausal women with severe vasomotor symptoms who volunteer for an acupuncture trial (ACUFLASH) differ from the general population (the Norwegian Women and Cancer study, NOWAC); and to describe the use of dietary supplements and medication during trial intervention and follow-up. METHODS: Questionnaire data on postmenopausal women regarding demography and use of dietary supplements and medication were compared between the ACUFLASH trial (baseline, 2006-2007, n = 267) and the NOWAC study (2004-2005, n = 331). Additionally, the trial intervention groups, acupuncture and self-care (n = 134) or self-care alone (n = 133), were compared regarding supplements and medication use. RESULTS: The prevalence of dietary supplement use was higher among women with severe vasomotor symptoms (83.9%) than in the population-based sample (74.3%), with particularly extensive use of cod liver oil. The prevalence of medication use was 46.4% in ACUFLASH and 55.0% in NOWAC. Trial participants reported poorer self-reported health, higher education level and tended to be former oral contraceptive users and smokers. At trial baseline, 48.5% of the acupuncture group and 60.3% of the self-care group used dietary supplements (p > 0.05), while 48.5% in the acupuncture group and 45.0% in the self-care group used medication (p > 0.05). Use of supplements for vasomotor symptoms increased significantly in the self-care group at 12 weeks, while it remained unchanged in the acupuncture group. Hormone therapy use increased significantly in both groups after intervention. CONCLUSION: Postmenopausal women suffering severe vasomotor symptoms used more dietary supplements than the general population. They also had poorer self-reported health, but their medication use was similar to that of the general population. Acupuncture did not influence use of dietary supplements in the randomized intervention.

What characterizes substance abusers who commit suicide attempts? Factors related to Axis I disorders and patterns of substance use disorders. A study of treatment-seeking substance abusers in Norway.

OBJECTIVE: The frequency of suicide attempts and clinical characteristics of attempters among poly-substance abusers and alcoholics were examined. METHODS: A consecutive sample (n = 260) of in- and outpatients from two Norwegian counties were assessed by Composite International Diagnostic Interview (Axis I disorders), Millon's Clinical Multiaxial Inventory (Axis II disorders) and the Norwegian National Client Assessment Form. When analysing the association between suicide attempters and the range of predictor variables, logistic regression analysis was conducted. RESULTS: Almost half (47%) of the sample reported lifetime suicide attempts; significantly more frequently in poly-substance abusers (58%) than alcoholics (38%). A substance use disorder with duration of >or=15 years and an early onset (<18 years of age) were independently associated with being a suicide attempter after controlling for Axis I disorders. In addition, eating disorders, agoraphobia and major depression were strongly and independently associated with being a suicide attempter. CONCLUSION: Attempts at preventing suicidal behaviour should not ignore the suicide risk among poly-substance abusers. In addition, prevention of suicidal behaviour demands a treatment programme focusing concomitantly on both addictive behaviour and comorbid psychiatric disorders.

Substance-dependent patients with and without social anxiety disorder: occurrence and clinical differences. A study of a consecutive sample of alcohol-dependent and poly-substance-dependent patients treated in two counties in Norway.

AIMS: (1) To identify clinically important differences between patients with and without social anxiety disorder (SAD) among alcohol-dependent and poly-substance-dependent patients. (2) To explore if primary SAD is a predictor of alcohol-dependency or poly-substance dependency when controlling for other Axes I and II disorders. METHODS: A consecutive sample of in- and outpatient alcohol-dependent (N = 146) and poly-substance-dependent patients (N = 114) from public treatment programmes in two catchment areas was assessed by personal interview, the Composite International Diagnostic Interview and the Millon Clinical Multiaxial Inventory. RESULTS: The frequency of current SAD was 42%; SAD was significantly more frequent among poly-substance-dependent patients (51%) than among alcohol-dependent patients (34%). Patients with SAD do not represent a distinct clinical subgroup, but the occurrence of SAD is combined with the occurrence of other anxiety disorders, affective disorders and personality disorders in both substance groups. The analysis showed a trend towards primary SAD as a predictor for developing poly-substance dependency. CONCLUSIONS: Patients with SAD in both substance groups exhibited more comorbid Axis I and II disorders. They may need specific psychiatric treatment for such disorders in addition to treatment for SAD. Treatment of primary SAD could be a target for preventing poly-substance dependency in young populations.

Gender differences in the prevalence of symptom disorders and personality disorders among poly-substance abusers and pure alcoholics. Substance abusers treated in two counties in Norway.

OBJECTIVE: Gender differences in the prevalence of Axis I and II disorders in poly-substance abusers and pure alcoholics and between these two groups are explored. METHOD: A consecutive sample (n = 260) of in- and out-patients from two Norwegian counties were assessed by CIDI (Axis I disorders) and MCMI-II (Axis II disorders). RESULTS: Major depression, post-traumatic stress disorder (PTSD), and eating disorders were significantly more prevalent in women than in men. A significantly higher prevalence of antisocial, passive-aggressive, and borderline personality disorders (PD) was observed among poly-substance abusers, whereas pure alcoholics were found to have dependent PDs more often. Female poly-substance abusers differed significantly from all other substance abusers by suffering more often from major depression, simple phobia, PTSD and borderline PD. Male poly-substance abusers more often presented antisocial PD and less often Cluster C disorders than all other substance abusers. Female pure alcoholics more often had major depression and Cluster C disorders than all other substance abusers. Male pure alcoholics presented less often with Axis I disorders, major depression, and PTSD, but more often with Cluster A disorders, in particular schizoid PD, than all other substance abusers. CONCLUSION: The pattern of comorbid disorders is clearly different between male and female poly-substance abusers and pure alcoholics. This implies that these four subgroups have important differences in their treatment needs.

Primary and secondary substance misusers: do they differ in substance-induced and substance-independent mental disorders?

AIMS: This study evaluated the primary/secondary distinction among substance misusers according to comorbid mental disorders. METHODS: A consecutive sample (n = 287) of DSM-IV substance dependents from public treatment facilities in two counties in Norway were assessed by the Composite International Diagnostic Interview. According to the debut of the first independent mental disorder, patients were divided into primary substance use disorder (SUD) (17%), secondary SUD (76%) and SUD in the same year as the first mental disorder (7%). RESULTS: A lifetime substance-independent mental disorder was found in 90%. Forty-two per cent had a combination of substance-independent and substance-induced mental disorders. Five per cent had substance-induced mental disorders only. Primary SUD patients comprised less women, and a lower number of substance-independent mental disorders. Secondary SUD patients had more major depression, phobic disorders and obsessive-compulsive disorder. There were no differences between primary SUD and secondary SUD regarding the number of substance-induced disorders or the pattern of substance misuse. CONCLUSIONS: Clinical differences between primary and secondary SUD were small and do not support the distinction.

Hormone replacement therapy in Norwegian women, 1996-1997.

OBJECTIVES: To assess the prevalence of hormone replacement therapy (HRT) among Norwegian women and examine factors related to use. MATERIALS AND METHODS: A random sample of 18,199 Norwegian women aged 45-64 years responded to a postal questionnaire in 1996-1997. The questionnaire included questions about menstruation status and fertility, oral contraceptives (OC) and HRT use, lifestyle, health and socio-economic status. The response rate was 60%. RESULTS: Overall prevalence of ever using systemic or local HRT was 43.9%. Current use was reported by 31.9% of the women. The highest prevalence was in the age group of 55-59 years where 57.4% reported ever use, and 43.1% current use. Mean duration of use among current users was 4.6 years. More than 60% of the women were classified as postmenopausal, two-thirds of them naturally postmenopausal. The prevalence of ever using HRT was 51.8%. Prevalence of use was higher among earlier OC users, smokers, lean women and in households with high income. Among older women, users had a higher educational level than non-users, while this difference disappeared among the youngest of the women. Fixed combinations of estradiol and noretisteroneacetate either cyclic or continuous, are used by six out of ten users. CONCLUSIONS: Our results confirm the increasing trend in sales of estrogens in Norway and suggest that user patterns are changing. More than four out of ten women aged 45-64 years reported ever use of HRT, and one out of three reported current use. Socio-economic differences between users and non-users seem to disappear among women under 55 years of age, but persist in the older age groups. Short time use still dominates.

Carcinoma of the ovary with primary presentation in the choroid.

PURPOSE: An unusual case of choroidal metastases from an ovarian adenocarcinoma is described, and a brief review of the literature is presented. METHODS: Clinical and autopsy findings are presented. RESULTS: After having diagnosed bilateral choroidal metastatic lesions, a clinical investigation and a subsequent laparotomy disclosed bilateral ovarian tumors with histopathological features of mucinous adenocarcinoma. At autopsy the tumor was confirmed to be a primary ovarian mucinous adenocarcinoma with choroidal metastases. CONCLUSION: This article describes what is believed to be the first case report of a primary epithelial carcinoma of the ovary with histopathologically documented metastases to the choroid. Metastatic disease must be considered in the evaluation of patients with choroidal lesions of unknown etiology.

[Local monitoring center for clozapine (Leponex) treatment]. / Lokalt monitoreringssenter for klozapin (Leponex)-behandling.

A local centre for monitoring clozapine therapy has been in operation in the Pharmacy Department at Asgård Hospital in Tromsø since 1994. The centre utilizes an electronic reporting system and is available to clozapine-prescribers in the three northernmost countries in Norway: Nordland, Troms and Finnmark. The system fosters early detection of poor compliance with frequent blood tests and for signs of white blood cell suppression. This is a new concept in Norway and one way of assuring the quality of clozapine treatment. The purpose of the centre is to improve patient safety by facilitating early detection of potentially dangerous white blood cell suppression, thereby avoiding fatal consequences.

Screening for mutations of the apolipoprotein B gene causing hypocholesterolemia.

In this study we have performed analyses of apolipoprotein (apo) B at both the protein and gene level to search for mutations of the apoB gene causing hypocholesterolemia among 71 Norwegian subjects. None of the subjects possessed apoB of abnormal molecular weight as determined by SDS-polyacrylamide gel electrophoresis of lipoproteins in the 1.025 g/ml-1.063 g/ml density range. Screening for mutations in exon 26 of the apoB gene by analysis of single-strand conformation polymorphisms followed by DNA sequencing, revealed seven point mutations of which one is a novel mutation. Five of the mutations were missense mutations and two were sense mutations. A group of 143 hypercholesterolemic, nonfamilial hypercholesterolemia subjects served as a control group for comparisons of gene frequencies. The only statistically significant finding was that mutation 8344T at codon 2712 was more common among those with hypocholesterolemia. This finding is in accord with previous reports.

Lesions of the perirhinal cortex interfere with conditioned excitation but not with conditioned inhibition of fear.

Posttraining lesions of the perirhinal cortex (Prh) have been shown to interfere with the expression of fear. This study assessed whether Prh lesions would also disrupt the inhibition of fear as measured with conditioned inhibition of fear-potentiated startle. Following light + shock, noise-->light-no shock conditioned-inhibition training, rats were given Prh lesions. The lesions interfered with the expression of fear-potentiated startle to the light. To assess whether conditioned inhibition was affected, the rats were given light + retraining without additional noise-->light-training. The noise-conditioned inhibitor retained its ability to inhibit fear-potentiated startle to the retrained light. These results suggest that the areas of the Prh that are essential for the initial expression of conditioned fear are not important for the expression of conditioned inhibition of fear.

Molecular genetics of familial hypercholesterolaemia in Norway.

OBJECTIVES: To characterize mutations in the low density lipoprotein (LDL) receptor gene causing familial hypercholesterolaemia (FH) amongst Norwegian patients. DESIGN: Molecular genetic analyses of the LDL receptor gene have been performed in patients with a clinical diagnosis of FH. SUBJECTS: A total of 742 probands have been studied. Of these, 476 had a diagnosis of definite FH. The rest had a diagnosis of possible FH. RESULTS: Twenty-three different mutations in the LDL receptor gene as well as the apolipoprotein B-3500 mutation have been found. Six of the mutations in the LDL receptor gene are novel mutations. A molecular genetic diagnosis was achieved in 295 of the probands with definite FH (62%) and in 317 probands total. Of the 317 probands, 3% carried the apolipoprotein B-3500 mutation. When family members were included, a total of 624 persons carried a mutation in the LDL receptor gene and 20 carried the apolipoprotein B-3500 mutation. CONCLUSIONS: Approximately 5% of Norwegian FH patients have been provided with a molecular genetic diagnosis. Our data suggest that molecular diagnosis of FH in Norway is feasible and should be implemented in clinical medicine.

[Application of gene technology in the diagnosis of familial hypercholesterolemia]. / Genteknologisk diagnostikk av familiaer hyperkolesterolemi.

Familial hypercholesterolaemia is an autosomal dominant disorder characterized by hypercholesterolaemia, xanthomas and premature coronary heart disease. Treatment of hypercholesterolemia is effective and consists of dietary changes and lipid lowering drugs. Only a minor proportion of familial hypercholesterolaemia patients are adequately treated, however. One explanation for this is assumed to be the relatively vague clinical diagnostic criteria applied. Because familial hypercholesterolaemia is caused by a mutation in the gene encoding the low density lipoprotein (LDL) receptor, mutation analysis of this gene could form the basis for specific diagnosis. 29 different mutations in the LDL receptor gene have been found to cause familial hypercholesterolaemia among Norwegian patients, and a total of 681 patients from 322 unrelated families have been provided with a molecular genetic diagnosis. We conclude that the use of molecular genetic analysis is feasible, and should be used clinically.

Heterozygosity for apolipoprotein A-I(R160L)Oslo is associated with low levels of high density lipoprotein cholesterol and HDL-subclass LpA-I/A-II but normal levels of HDL-subclass LpA-I.

We studied a Norwegian patient and his family, who presented with low HDL-cholesterol. DNA sequence analysis of the apoA-I gene revealed heterozygosity for a mutation in the apoA-I gene that causes a leucine for arginine replacement at residue 160. Compared to unaffected family members, heterozygous carriers of apoA-1 (R160L)Oslo had 60-70% lower mean levels of HDL-cholesterol, 50-60% lower mean levels of apoA-I and 70-80% lower levels of apoA-II. Moreover, the serum concentration of the apoA-II-containing HDL-subclass LpA-I/A-II was decreased by 70% whereas the concentration of the apoA-II-free HDL-subclass LpA-I did not differ from that in unaffected family members. The decrease of LpA-I/A-II was associated with the lack of large LpA-I/A-II. ApoA-I(R160L)Oslo was present at increased concentrations relative to normal apoA-I in plasma, HDL3, and LpA-I. However, only trace amounts of the variant isoform were detectable in immunopurified LpA-I/A-II. Pre beta1-LpA-I contained normal and variant apoA-I isoforms. We conclude that the failure of apoA-I(R160L)Oslo to form LpA-I/A-II causes low HDL-cholesterol in heterozygous carriers of this apoA-I variant.