Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2-125) after chemotherapy alone (1 STS) and 19 (95%CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.     

Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: results of a multicenter study

BACKGROUND AND OBJECTIVES: Recurrence after partial liver resection for hepatocellular carcinoma (HCC) is a major cause of death from this disease. To identify risk factors for early death from recurrence after liver resection for HCC. METHODS: All 547 patients in this study had greater than 1 year of follow-up after complete resection of HCC (1980-1999) at one of the four hepatobiliary centers in Japan, France, and the United States. Patients who died of recurrence < or =1 year post-resection and all of those alive at least 1 year were compared. Survival and clinicopathological factors associated with death from recurrence within 1 year of resection were analyzed. RESULTS: Overall postoperative mortality rate was 5%. In the first postoperative year, 123 (22%) patients died. Of these, 53 (43%) died of recurrence, 30 (24%) of postoperative complications, and 40 (33%) of liver failure/hemorrhage. On multivariate analysis, tumor size greater than 5 cm (P < 0.02; odds ratio, 3.0), multiple tumors (P < 0.01; odds ratio, 3.3), and greater than 5 mitoses per 10 high-power fields (P < 0.03; odds ratio, 3) were associated with increased risk of early death due to recurrence. CONCLUSIONS: These findings enable identification of patients with HCC who are at high risk for early death due to recurrence following potentially curative resection who might be candidates for adjuvant therapy trials.     

A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in pancreatic carcinogenesis

MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-beta is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-beta as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.     

Dual HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab

Epidermal growth factor receptor (EGFR) and HER-2 are associated with a poor prognosis in various cancers, including prostate cancer. Inhibition of these receptors may provide a treatment for hormone-refractory prostate cancer. The presence of HER-2 (Western blot) and EGFR (5830 fmol/mg protein, ligand-binding assay) was assessed in the hormone-refractory human prostate cancer cell line, DU-145. Cells were exposed to the selective EGFR-TKI (EGFR tyrosine kinase inhibitor) gefitinib (‘Iressa™; ZD1839) and/or the HER-2-targeted monoclonal antibody trastuzumab (‘Herceptin^®’), for 96 h. Irradiation (RX) at 6 Gy the dose causing 50% growth inhibition, was applied 48 h after the start of drug treatment. There was a dose-related effect on cell survival for both ZD1839 and trastuzumab treatments. Combining ZD1839 and trastuzumab led to less than additive effects on cell survival. Chou and Talalay representations further characterised this less than additive effect on cell survival. The application of ZD1839 led to a marked elevation in the level of the negative regulator of cell division, p27. The ZD1839-trastuzumab combination had less of an impact on p27 expression compared with the effect of ZD1839 treatment alone. The lowest expression of the apoptotic-related protein, Bax, was observed in the presence of the drug combination. There was a significant interaction (synergism) between RX and either ZD1839 or trastuzumab treatments. In contrast, the drug combination with RX resulted in antagonistic cytotoxic effects. These results indicate an antagonistic interaction between EGFR and HER-2 targeting and provide molecular mechanisms supporting this observation. Data from DU-145 cells suggest that dual targeting of EGFR and HER-2 may be inappropriate for the treatment of hormone-refractory prostate cancer, especially in the context of their combination with RX.     

Clonidine in acute aversive inner tension and self-injurious behavior in female patients with borderline personality disorder

BACKGROUND: States of strong aversive inner tension and dissociative symptoms are clinical hallmarks of borderline personality disorder and major reasons for self-injurious behavior, a severe clinical condition for which there are no established pharmacologic treatment options. METHOD: The acute effect of 75 and 150 microg of clonidine administered orally in acute states of strong aversive inner tension and urge to commit self-injurious behavior was examined in 14 female patients meeting DSM-IV criteria for borderline personality disorder. Before and 30, 60, and 120 minutes after administration of clonidine, aversive inner tension and dissociative symptoms were assessed using a self-rating instrument for aversive inner tension and dissociation (Dissociation-Tension-Scale acute), and the urge to commit self-injurious behavior and suicidal ideations were assessed using self-rating Likert scales. Blood pressure and heart rate were monitored during the trial. RESULTS: Aversive inner tension and urge to commit self-injurious behavior before administration of clonidine were strong. After administration of clonidine in both doses, aversive inner tension, dissociative symptoms, urge to commit self-injurious behavior, and suicidal ideations significantly decreased. The strongest effects were seen between 30 and 60 minutes after drug intake and correspond to the pharmacokinetics of clonidine with maximum plasma concentrations after 1 hour. Blood pressure and aversive inner tension and dissociative symptoms were positively correlated before and after administration of clonidine. CONCLUSION: Orally given clonidine may be effective for treatment of acute states of aversive inner tension, dissociative symptoms, and urge to commit self-injurious behavior in female patients with borderline personality disorder. Further placebo-controlled studies with larger populations are needed to confirm this finding.     

Perception of dynamic action in patients with schizophrenia

Neuropsychological studies have revealed that schizophrenic (SZ) patients have severe impairments in the cognitive integration of static and moving perceptual stimuli. Research on knowledge structures has shown that sequences of continuous actions are represented in memory as clusters of goal-directed events in a hierarchical manner. In the present study, we investigated the ability to segment familiar sequences of dynamic goal-directed actions into small and large meaningful units in a group of patients with schizophrenia (N = 16) and a group of healthy control subjects (N = 17). While viewing two videotaped movies, participants were requested to detect the transitions between component events at both low and high levels of the action categorical structure. Both groups detected significantly more events under the small-oriented condition as compared to the large-oriented condition. Differently from normal controls, patients recalled the event scenes in a detailed and fragmentary manner and showed considerable difficulties in detecting large action units. Moreover, low performance on action boundary detection significantly correlated with higher levels of disorganisation symptoms in patients with schizophrenia. A defective conceptual organisation of perceptive action knowledge would help to explain the severe everyday difficulties of these patients both in monitoring their own actions and in understanding others' intentions.     

Decreased social interaction in aged rats may not reflect changes in anxiety-related behaviour

There is evidence that ageing both in humans and animals is accompanied by changes in emotional behaviour. Behavioural studies in rats point to an increase in emotional reactivity and/or anxiety-related behaviour with age. Here we studied social interaction in young adult (3 months) and aged (30 months old) rats using an established test system for anxiety-related behaviour. Using Fos expression as a marker of neuronal activation, we aimed to investigate whether age-related differences in anxiety would be reflected by changes in neuronal activity in brain regions known to be sensitive to fear- and anxiety-related stimuli. Aged rats spent significantly less time (75%) in active social interaction than young rats, without concomitant changes in general locomotor activity. Social interaction enhanced Fos expression both in young and aged rats in several anxiety-related brain areas. Lower Fos response in aged versus young rats was noted in the dorsomedial, dorsolateral and ventrolateral part of the periaqueductal grey, the medial and basolateral amygdala and parvocellular region of the paraventricular hypothalamic nucleus, while no differences in Fos expression were observed in the other regions examined, including the hippocampus, septum or locus coeruleus. These results demonstrate age-related reduction in social interaction, indicative of enhanced anxiety-related behaviour in aged rats. However, since the supposedly increased anxiety level was not accompanied by augmented Fos expression in any of the key brain areas of the fear/anxiety circuitry known to be activated by anxiogenic stimuli, it is suggested that reduced social interaction does not reflect enhanced anxiety in aged rats.     

Background noise does not modify song-induced genic activation in the bird brain

Specialised brain structures allow songbirds to process acoustic signals. One of these brain areas, the NCM (caudomedial neostriatum), shows an immediate-early gene ZENK response when a bird hears a conspecific song. Using a neuro-ethological approach, we investigate if high level of background noise added to conspecific song can modify this song-induced genic activation. We test the ZENK activation in the NCM of adult male Zebra finches Taeniopygya guttata (n = 17) by playing back conspecific signals mixed with different levels of noise, the successful discrimination being reflected by the birds' (n = 6) behavioural responses to these stimuli. From our results, it appears that a high genic activation of the NCM does not necessarily require the audition of an undegraded species-specific signal. Nevertheless, it requires that the signal still contains sufficient information to elicit a behavioural response. The genic activation of the NCM remains thus stable against very high levels of a wide-band background noise, as far as the signal recognition remains possible for the bird.     

Absence of cortical gray matter abnormalities in psychosis of epilepsy: a voxel-based MRI study in patients with temporal lobe epilepsy

The authors retrospectively explored cortical differences between 26 patients with temporal lobe epilepsy and psychosis of epilepsy (POE), 24 patients with temporal lobe epilepsy (TLE) alone, and 20 healthy comparison subjects. Using voxel-based morphometry based on statistical parametric mapping (SPM99), which is an unbiased and fully automated technique to test for morphometric differences, magnetic resonance imaging (MRI) 3D-datasets were acquired and analyzed. There were no significant cortical gray matter differences between the POE and the TLE group. Since cortical pathology is prominent in schizophrenia, POE may be a clinical entity separate from schizophrenia.