Pituitary gland volume and psychosocial stress among children at elevated risk for schizophrenia.

BACKGROUND: Pituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress. METHOD: ASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9-12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11-14 years. RESULTS: Neither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment. CONCLUSIONS: The lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

Cannabis use and transition to psychosis in people at ultra-high risk.

BACKGROUND: Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder. METHOD: Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes. RESULTS: Lifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n=98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ(2)1=10.971, p=0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ(2)1=1.061, p=0.303). CONCLUSIONS: In people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer.

BACKGROUND: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. METHODS: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15-30 mg m(-2) per week and cisplatin 15-30 mg m(-2) per week in six planned dose levels (DLs) in 3-6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. RESULTS: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m(-2), cisplatin 15 mg m(-2)) and grade 3 nausea in DL2 (20 mg m(-2), 15 mg m(-2)). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). CONCLUSION: Cisplatin and docetaxel each 30 mg m(-2) per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy.

BACKGROUND: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.

Bullying victimisation and paranoid ideation in people at ultra high risk for psychosis.

BACKGROUND: Bullying victimisation has been suggested to contribute to paranoid ideation in general population samples and recent evidence found that individuals with an ultra high risk (UHR) for psychosis are twice as likely to have been bullied than controls. AIMS: This study sought to examine whether a history of bullying would be associated with higher levels of paranoid ideation in individuals with an UHR and in healthy controls (HCs). METHOD: The study included 64 UHR and 43 HC participants. Following the baseline assessment, participants entered a Virtual Reality (VR) London Underground train. Paranoid ideation was measured immediately after the end of the VR experience. RESULTS: Compared to HCs, UHR participants described higher levels of childhood bullying (OR 5.19, 95% CI=2.21-12.19, p<.001) and experienced more paranoid ideation during VR (χ(2)(1)=21.06, p<.001). Childhood bullying was associated with paranoid ideation during VR in both groups (χ(2)(1)=5.931, p=,021) but prolonged exposure to bullying was not associated with increased paranoid ideation. CONCLUSION: A history of bullying in childhood is particularly common in young adults at high risk for psychosis. However bullying is associated with paranoid ideation in later life, independent of clinical status, consistent with dimensional models of psychotic phenomena.

Neurofibromatosis type 1-associated wild-type gastrointestinal stromal tumor treated with anti-IGF-1R monoclonal antibody.

Gastrointestinal stromal tumors lacking mutations in KIT or PDGFRα are known as wild type (WT) and are less responsive to imatinib. These WT tumors are hypothesized to be dependent on signaling through the insulin-like growth factor 1 receptor (IGF-1R). We report the case of a 29-year-old woman with neurofibromatosis type 1-associated WT GIST treated with an anti-IGF-1R monoclonal antibody. Treatment was ineffective, and the potential basis for lack of response is discussed in the context of IGF-1R expression levels measured within this patients' primary tumor. We suggest that future clinical trials of anti-IGF-1R therapies prospectively determine tumor IGF-1R expression levels for correlation with response to treatment.

Angiotensin II (ATII)-inducible platelet-derived growth factor A-chain gene expression is p42/44 extracellular signal-regulated kinase-1/2 and Egr-1-dependent and mediated via the ATII type 1 but not type 2 receptor. Induction by ATII antagonized by nitric oxide.

Angiotensin II (ATII) and platelet-derived growth factor (PDGF) are two vasoconstrictors implicated in the maintenance of normal vascular homeostasis. PDGF A-chain levels increase in cultured vascular smooth muscle cells (SMCs) exposed to ATII. The molecular mechanisms underlying this induction are not known. We used transient transfection analysis to show that ATII can increase reporter gene activity driven by fragments of the PDGF-A promoter bearing recognition elements for the transcription factor, Egr-1. Nuclear run-off experiments indicate that ATII induces Egr-1 expression at the level of transcription. Gel shift and supershift studies show that Egr-1 protein accumulates in the nuclei of SMCs exposed to ATII and binds to the proximal region of the PDGF-A promoter in a specific, time-dependent manner. ATII induced extracellular-signal regulated kinase (p42/44 ERK) activity as did phorbol 12-myristate 13-acetate. The specific MEK1/2 inhibitor, PD98059, suppressed both PDGF-A and Egr-1 endogenous and promoter-dependent expression inducible by ATII. The ATII type 1 receptor (AT1) antagonist, Losartan, inhibited ATII-induction of p42/44 ERK, as well as Egr-1 and PDGF-A, whereas neither PD123319, an AT2 receptor antagonist, nor wortmannin, an inhibitor of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase, had any effect. ATII-induction of Egr-1 and PDGF-A was blocked by SIN-1, a NO donor. In addition, this pathway was blocked by overexpression of NO synthase. Collectively, these findings demonstrate that ATII activation of the PDGF-A promoter is mediated via the MEK/ERK/Egr-1 pathway and AT1 receptor and that this process is antagonized by NO.

Early growth response factor-1 induction by injury is triggered by release and paracrine activation by fibroblast growth factor-2.

Cell migration and proliferation that follows injury to the artery wall is preceded by signaling and transcriptional events that converge at the promoters of multiple genes whose products can influence formation of the neointima. Transcription factors, such as early growth response factor-1 (Egr-1), with nucleotide recognition elements in the promoters of many pathophysiologically relevant genes, are expressed at the endothelial wound edge within minutes of injury. The mechanisms underlying the inducible expression of Egr-1 in this setting are not clear. Understanding this process would provide important mechanistic insights into the earliest events in the response to injury. In this report, we demonstrate that fibroblast growth factor-2 (FGF-2) is released by injury and that antibodies to FGF-2 almost completely abrogate the activation and nuclear accumulation of Egr-1. FGF-2-inducible egr-1-promoter-dependent expression is blocked by PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-1/2 (MEK-1/2), as well as by dominant negative mutants of ERK-1/2. Inducible ERK phosphorylation after injury is dependent on release and stimulation by endogenous FGF-2. Antisense oligonucleotides directed at egr-1 mRNA suggest that Egr-1 plays a necessary role in endothelial repair after denudation of the monolayer. These findings demonstrate that inducible Egr-1 expression after injury is contingent on the release and paracrine action of FGF-2.