Percutaneous ablation in perivascular-HCC: impact of liver parenchyma and characteristics of vascular structures on the outcomes.

AIM: Percutaneous radiofrequency ablation (RFA) is a standard treatment for small-HCC (<3 cm). However, some features such as proximity to intrahepatic vascular structures (perivascular location) seem to be related to short- and long-term outcomes. The aims of the study were to investigate the features related to ablation success and local tumor progression (LTP) in patients submitted to percutaneous ablation for perivascular-HCC. MATERIALS AND METHODS: From January 2010 to May 2021, 132 perivascular-HCC nodules ablated with US-guided single probe percutaneous RFA were retrospectively analyzed. Univariate analysis and multivariable Cox regression model were used to identify factors that were independently related to ablation success and LTP-free survival. RESULTS: The overall ablation success rate was 71.9% (n=95). Morbidity and mortality rates were 4.0% and 0.0%. The features related to ablation success: nodule size (≤20 mm vs. >20 mm) (OR 2.442, p=0.031), major vascular structures diameter (3-5 mm vs ≥ 5 mm) (OR 2.167, p=0.037) and liver parenchyma (cirrhosis vs no-cirrhosis) (OR 2.373, p=0.033). The following features resulted independently related to better LTP-free survival: nodule size ≤20 mm (HR 2.802, p=0.003), proximity to glissonean pedicles (HR 1.677, p=0.028), and major vascular structure diameter <5 mm (HR 1.987, p=0.041). CONCLUSIONS: Perivascular location confirmed to be a difficult and unfavorable indication for percutaneous ablation for HCC nodules. However, perivascular nodules not suitable for surgery with low-risk features (size <20 mm, proximity to glissonian pedicles and vascular diameter <5 mm) may be treated with RFA with satisfactory outcomes.

Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P < 0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose-response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence.

Contour prognostic model for predicting survival after resection of colorectal liver metastases: development and multicentre validation study using largest diameter and number of metastases with RAS mutation status.

BACKGROUND: Most current models for predicting survival after resection of colorectal liver metastasis include largest diameter and number of colorectal liver metastases as dichotomous variables, resulting in underestimation of the extent of risk variation and substantial loss of statistical power. The aim of this study was to develop and validate a new prognostic model for patients undergoing liver resection including largest diameter and number of colorectal liver metastases as continuous variables. METHODS: A prognostic model was developed using data from patients who underwent liver resection for colorectal liver metastases at MD Anderson Cancer Center and had RAS mutational data. A Cox proportional hazards model analysis was used to develop a model based on largest colorectal liver metastasis diameter and number of metastases as continuous variables. The model results were shown using contour plots, and validated externally in an international multi-institutional cohort. RESULTS: A total of 810 patients met the inclusion criteria. Largest colorectal liver metastasis diameter (hazard ratio (HR) 1.11, 95 per cent confidence interval 1.06 to 1.16; P < 0.001), number of colorectal liver metastases (HR 1.06, 1.03 to 1.09; P < 0.001), and RAS mutation status (HR 1.76, 1.42 to 2.18; P < 0.001) were significantly associated with overall survival, together with age, primary lymph node metastasis, and prehepatectomy chemotherapy. The model performed well in the external validation cohort, with predicted overall survival values almost lying within 10 per cent of observed values. Wild-type RAS was associated with better overall survival than RAS mutation even when liver resection was performed for larger and/or multiple colorectal liver metastases. CONCLUSION: The contour prognostic model, based on diameter and number of lesions considered as continuous variables along with RAS mutation, predicts overall survival after resection of colorectal liver metastasis.

Proof-of-concept validation of the mechanism of action of Src tyrosine kinase inhibitors in dystrophic mdx mouse muscle: in vivo and in vitro studies.

Src tyrosine kinase (TK), a redox-sensitive protein overexpressed in dystrophin-deficient muscles, can contribute to damaging signaling by phosphorylation and degradation of ß-dystroglycan (ß-DG). We performed a proof-of-concept preclinical study to validate this hypothesis and the benefit-safety ratio of a pharmacological inhibition of Src-TK in Duchenne muscular dystrophy (DMD). Src-TK inhibitors PP2 and dasatinib were administered for 5 weeks to treadmill-exercised mdx mice. The outcome was evaluated in vivo and ex vivo on functional, histological and biochemical disease-related parameters. Considering the importance to maintain a proper myogenic program, the potential cytotoxic effects of both compounds, as well as their cytoprotection against oxidative stress-induced damage, was also assessed in C2C12 cells. In line with the hypothesis, both compounds restored the level of ß-DG and reduced its phosphorylated form without changing basal expression of genes of interest, corroborating a mechanism at post-translational level. The histological profile of gastrocnemius muscle was slightly improved as well as the level of plasma biomarkers. However, amelioration of in vivo and ex vivo functional parameters was modest, with PP2 being more effective than dasatinib. Both compounds reached appreciable levels in skeletal muscle and liver, supporting proper animal exposure. Dasatinib exerted a greater concentration-dependent cytotoxic effect on C2C12 cells than the more selective PP2, while being less protective against H2O2 cytotoxicity, even though at concentrations higher than those experienced during in vivo treatments. Our results support the interest of Src-TK as drug target in dystrophinopathies, although further studies are necessary to assess the therapeutic potential of inhibitors in DMD.

Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents.

BACKGROUND AND PURPOSE: Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites. EXPERIMENTAL APPROACH: To determine their contribution to the clinical activity of Mex, p-hydroxy-mexiletine (PHM), hydroxy-methyl-mexiletine (HMM), N-hydroxy-mexiletine (NHM) (phase I reaction products) and N-carbonyloxy beta-D-glucuronide (NMG) (phase II reaction product) were tested on sodium currents (I(Na)) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=-140, -100, -70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline-gap voltage-clamp method. KEY RESULTS: All the hydroxylated derivatives blocked the sodium channel in a voltage- and use-dependent manner. The PHM, HMM and NHM metabolites were up to 10-fold less effective than the parent compound. However, HMM showed a greater use-dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound. CONCLUSIONS AND IMPLICATIONS: Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.

New model for bone resorption study in vitro: human osteoclast-like cells from giant cell tumors of bone.

Cells harvested from 12 human giant cell tumors of bone and kept in culture for several passages were characterized for bone-resorbing capability, total and tartrate-resistant acid phosphatase activity, response to the calciotropic hormone calcitonin, cell proliferation, multinucleation after passages, and presence of calcium sensing. Cells obtained from three tumors presented a complete panel of osteoclast characteristics and maintained their multinuclearity after several passages. Cells from four other tumors increased their cAMP levels after treatment with calcitonin, and the other five apparently consisted of cells of stromal origin. These human cell populations with osteoclast characteristics may provide valid in vitro models for the investigation of osteoclastic differentiation and activity.

Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls.

Childhood sexual abuse is associated with an increased incidence of age-concurrent and adult psychopathology. Little is known, however, about the biological manifestations and sequelae of childhood sexual abuse. In this study, we characterized the hypothalamic-pituitary-adrenal axis of a self-selected sample of sexually abused and control girls recruited from a prospective longitudinal study. Plasma ACTH and total and free cortisol responses to ovine CRH (oCRH) stimulation were measured in 13 sexually abused and 13 control girls, aged 7-15 yr. Psychiatric profiles and 24-h urinary free cortisol (UFC) measures were also obtained. Sexually abused girls had a greater incidence of suicidal ideation (chi 2 = 4.51; df = 1; P < 0.05), suicide attempts (chi 2 = 4.51; df = 1; P < 0.05), and dysthymia (chi 2 = 8.85; df = 1; P < 0.01) than control girls. Sexually abused girls showed significantly lower basal (t = 2.1; df = 24; P < 0.05), and net oCRH stimulated (t = 2.2; df = 24; P < 0.05) ACTH levels and significantly reduced total ACTH responses (t = 2.5; df = 24; P < 0.05) compared with control subjects. Their total and free basal and oCRH-stimulated plasma cortisol levels and 24-h UFC measures, however, were similar to those in controls. The attenuated plasma ACTH with corresponding robust plasma cortisol responses to oCRH stimulation and normal 24-h UFC measures in sexually abused girls suggest a dysregulatory disorder of the HPA axis in these individuals. This may reflect pituitary hyporesponsiveness to oCRH. The ability of sexually abused subjects to correct for the proposed pituitary hyporesponsiveness to CRH may be related to their young age and the presence of intact glucocorticoid feedback regulatory mechanisms.

A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder.

BACKGROUND: Adult posttraumatic stress disorder (PTSD) is associated with decreased hippocampal volumes; however, decreased hippocampal volumes were not seen in pediatric maltreatment-related PTSD. We examined hippocampal volumes longitudinally to determine if a history of childhood traumatic stress alters hippocampal growth during puberty. METHODS: Magnetic resonance imaging was used to measure temporal lobes, amygdala, and hippocampal volumes in nine prepubertal maltreated subjects with pediatric maltreatment-related PTSD and nine sociodemographically matched healthy nonmaltreated yoked control subjects at baseline and after at least 2 years follow-up (during the later stages of pubertal development) using identical equipment and measurement methodology. RESULTS: Temporal lobe, amygdala and hippocampal volumes did not differ between groups at baseline, follow-up, or across time. CONCLUSIONS: Whereas these data are from a small sample, the results do not support hippocampal changes in pediatric maltreatment-related PTSD.

Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.

Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 +/- 24.6 (all values +/- SD) to 64.2 +/- 26.1 pmol/ml and from 46.7 +/- 14.2 to 42.6 +/- 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 +/- 6.5 to 17.4 +/- 5.0 and significantly increased the CSF HVA/5-HIAA ratio.

Right amygdala volume in adolescent and young adult offspring from families at high risk for developing alcoholism.

BACKGROUND: Neurobiological factors have been implicated in the increased susceptibility for developing alcohol dependence that offspring from alcoholic families exhibit. The P300 component of the event-related potential shows developmental changes during childhood and adolescence that appear to be related to risk status. The underlying structural changes that accompany these neurophysiological changes are not well understood. METHODS: Magnetic resonance imaging was used to measure cerebral, amygdala, and hippocampal volumes in 17 high-risk adolescent and young adult offspring from multiplex alcoholism families and 17 age-, gender-, and IQ-matched control subjects without a family history for alcoholism or other substance dependence. Twenty-two of the subjects are part of a longitudinal prospective study and have been followed an average of 7.3 years, making it possible to relate P300 developmental trajectories to structural volumes. RESULTS: High-risk adolescents and young adults showed reduced right amygdala volume in comparison with control subjects. Right amygdala volume was significantly correlated with visual P300 amplitude. CONCLUSIONS: Offspring from families having a high density of alcoholism differ in both neurophysiological and neuroanatomical characteristics that could not be explained by personal drinking history or particular childhood and adolescent psychopathology. Because the amygdala tends to increase in volume during childhood and adolescence, smaller volumes in high-risk children may indicate a developmental delay that parallels delays seen in visual P300 amplitude.

A.E. Bennett Research Award. Developmental traumatology. Part I: Biological stress systems.

BACKGROUND: This investigation examined the relationship between trauma, psychiatric symptoms and urinary free cortisol (UFC) and catecholamine (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal children with posttraumatic stress disorder (PTSD) secondary to past child maltreatment experiences (n = 18), compared to non-traumatized children with overanxious disorder (OAD) (n = 10) and healthy controls (n = 24). METHODS: Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour urine collection for measurements of UFC and urinary catecholamine excretion. Biological and clinical measures were compared using analyses of variance. RESULTS: Maltreated subjects with PTSD excreted significantly greater concentrations of urinary DA and NE over 24 hours than OAD and control subjects and greater concentrations of 24 hour UFC than control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was associated with greater co-morbid psychopathology including depressive and dissociative symptoms, lower global assessment of functioning, and increased incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and UFC concentrations showed positive correlations with duration of the PTSD trauma and severity of PTSD symptoms. CONCLUSIONS: These data suggest that maltreatment experiences are associated with alterations of biological stress systems in maltreated children with PTSD. An improved psychobiological understanding of trauma in childhood may eventually lead to better treatments of childhood PTSD.

A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development.

BACKGROUND: Previous investigations suggest that maltreated children with a diagnosis of posttraumatic stress disorder (PTSD) evidence alterations of biological stress systems. Increased levels of catecholaminergic neurotransmitters and steroid hormones during traumatic experiences in childhood could conceivably adversely affect brain development. METHODS: In this study, 44 maltreated children and adolescents with PTSD and 61 matched controls underwent comprehensive psychiatric and neuropsychological assessments and an anatomical magnetic resonance imaging (MRI) brain scan. RESULTS: PTSD subjects had smaller intracranial and cerebral volumes than matched controls. The total midsagittal area of corpus callosum and middle and posterior regions remained smaller; while right, left, and total lateral ventricles were proportionally larger than controls, after adjustment for intracranial volume. Brain volume robustly and positively correlated with age of onset of PTSD trauma and negatively correlated with duration of abuse. Symptoms of intrusive thoughts, avoidance, hyperarousal or dissociation correlated positively with ventricular volume, and negatively with brain volume and total corpus callosum and regional measures. Significant gender by diagnosis effect revealed greater corpus callosum area reduction in maltreated males with PTSD and a trend for greater cerebral volume reduction than maltreated females with PTSD. The predicted decrease in hippocampal volume seen in adult PTSD was not seen in these subjects. CONCLUSIONS: These data suggest that the overwhelming stress of maltreatment experiences in childhood is associated with adverse brain development.

A pilot study of amygdala volumes in pediatric generalized anxiety disorder.

BACKGROUND: The neurodevelopment of childhood anxiety disorders is not well understood. Basic research has implicated the amygdala and circuits related to these nuclei as being central to several aspects of fear and fear-related behaviors in animals. METHODS: Magnetic resonance imaging was used to measure amygdala volumes and comparison brain regions in 12 child and adolescent subjects with generalized anxiety disorder and 24 comparison subjects. Groups were matched on age, sex, height, and handedness and were also similar on measures of weight, socioeconomic status, and full scale IQ. RESULTS: Right and total amygdala volumes were significantly larger in generalized anxiety disorder subjects. Intracranial, cerebral, cerebral gray and white matter, temporal lobe, hippocampal, and basal ganglia volumes and measures of the midsagittal area of the corpus callosum did not differ between groups. CONCLUSIONS: Although these data are preliminary and from a small sample, the results are consistent with a line of thinking that alterations in the structure and function of the amygdala may be associated with pediatric generalized anxiety disorder.

N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD.

OBJECTIVE: Anterior cingulate dysfunction has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). The authors hypothesized that integrity of the anterior cingulate may be affected in childhood PTSD. METHOD: Single voxel proton magnetic resonance spectroscopy (proton MRS) was used to measure the relative concentration of N-acetylaspartate and creatine, a marker of neural integrity, in the anterior cingulate of 11 children and adolescents who met DSM-IV criteria for PTSD secondary to maltreatment and 11 healthy matched comparison subjects. RESULTS: The ratio of N-acetylaspartate to creatine was significantly lower in the maltreated subjects with PTSD than in the comparison subjects. CONCLUSIONS: The lower N-acetylaspartate/creatine ratio in subjects with PTSD suggests that anterior cingulate neuronal metabolism may be altered in childhood PTSD.

Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression.

The authors measured CSF concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin in nine depressed patients before and after fluoxetine treatment. They found significant decreases in CSF CRH, CSF arginine vasopressin, and Hamilton depression ratings. Thus, the therapeutic effect of this serotonin-uptake inhibitor may be related to diminution of these arousal-promoting neuropeptides.

Hippocampal volume in adolescent-onset alcohol use disorders.

OBJECTIVE: Alcohol use disorders (defined as DSM-IV alcohol dependence or abuse) are prevalent and serious problems among adolescents. As adolescence is marked by progressive hippocampal development, this brain region may be particularly susceptible to the adverse effects of adolescent alcohol use disorders. This study compared the hippocampal volumes of adolescents and young adults with adolescent-onset alcohol use disorders to those of healthy matched comparison subjects. METHOD: Magnetic resonance imaging was used to measure the hippocampal volumes and volumes of comparison brain regions in 12 subjects with alcohol use disorders and 24 comparison subjects matched on age, sex, and handedness. RESULTS: Both left and right hippocampal volumes were significantly smaller in subjects with alcohol use disorders than in comparison subjects. Total hippocampal volume correlated positively with the age at onset and negatively with the duration of the alcohol use disorder. Intracranial, cerebral, and cortical gray and white matter volumes and measures of the mid-sagittal area of the corpus callosum did not differ between groups. CONCLUSIONS: In the mature brain, chronic alcohol use disorders are associated with graded global brain dysmorphology. Although the etiology, neuropsychological consequences, and permanence of these hippocampal findings need to be further examined, these findings suggest that, during adolescence, the hippocampus may be particularly susceptible to the adverse effects of alcohol.

Benzodiazepine withdrawal delirium with catatonic features. Occurrence in patients with partial seizure disorders.

We report the cases of 3 patients with medically intractable seizures in whom withdrawal of treatment with a long-acting benzodiazepine (clorazepate dipotassium, 2 patients; clonazepam, 1 patient) was followed by delirium with catatoniclike features. While an increase in seizure frequency occurred during withdrawal and prior to the onset of behavioral changes, electroencephalograms did not show epileptiform activity during the delirium. We compared these 3 patients with 10 others with intractable seizures in whom antiepileptic therapy was withdrawn without subsequent behavior changes. High-dose benzodiazepine therapy and a history of viral encephalitis may be risk factors for withdrawal delirium.

Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na(+) channels enhancing the antimyotonic activity in vivo.

1. Searching for the structural requirements improving the potency and the stereoselectivity of Na(+) channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid alpha-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. 2. Their ability to block Na(+) currents, elicited from -100 to -20 mV at 0.3 Hz (tonic block) and 2-10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. 3. The alpha-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. 4. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. 5. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. 6. Thus, constraining the chiral centre of tocainide in alpha-proline cycle leads to more potent and stereoselective use-dependent Na(+) channel blockers with improved therapeutic potential.

Thoracic radiotherapy and daily vinorelbine as radiosensitizer in locally advanced non small cell lung cancer: a phase I study.

Experimental studies have shown that vinorelbine is a powerful radiosensitizer in vitro. To date, no reports on clinical activity of the single agent vinorelbine as radiosensitizer have been published. The aim of the present phase I study was to determine the maximum tolerated dose (MTD) of vinorelbine administered daily concurrently with thoracic radiotherapy, with or without amifostine support, in the treatment of locally advanced non small cell lung cancer. In vitro studies have shown that vinorelbine can potentiate the antitumor effects of radiation therapy. Amifostine is a sulphydril compound that has shown to protect normal tissues from chemotherapy and radiotherapy-induced toxicities. Radiotherapy lasted 6 weeks and the total dose was 55 Gy. The daily fraction was 1.8 Gy, administered 5 days a week for 5 weeks and increased to 2.0 Gy during the sixth and last week. Concurrent vinorelbine was administered daily with a planned escalation of the dose from 4, to 5 and 6 mg/m(2). Fourteen patients were enrolled in the study. The first dose of vinorelbine was 4 mg/m(2) and it showed to be feasible without dose-limiting toxicity (DLT). Instead, the second dose level of 5 mg/m(2) was unfeasible because three out of six patients had DLT (grade 4 neutropenia, treatment interruption longer than 2 weeks for prolonged grade 2 neutropenia and treatment interruption longer than 2 weeks for prolonged grade 3 esophagitis together with grade 4 dyspnea). At that time, the study continued adding amifostine to vinorelbine in order to increase its MTD. Amifostine was administered by means of subcutaneous injection 15 min before each radiotherapy fraction at the fixed dose of 300 mg/m(2). However, 5 mg/m(2) of vinorelbine were considered unfeasible even with amifostine support because three out of five patients showed DLT (grade 4 neutropenia, febrile grade 4 neutropenia and grade 3 liver toxicity). Among 14 patients enrolled in the study, eight completed the planned treatment because six patients experienced DLT, which determined treatment interruption. Overall, four partial and two complete responses were observed. Two partial and one complete response were observed in those three patients who had been treated with the first dose of vinorelbine. In conclusion, our data show that the MTD of daily vinorelbine is 4 mg/m(2). Therefore, this is the recommended dose of daily vinorelbine to be administered with concurrent thoracic radiotherapy in a phase II trial. Finally, amifostine administered subcutaneously failed to increase the MTD of daily vinorelbine.

Urinary catecholamine excretion in sexually abused girls.

OBJECTIVE: The objective of this study was to examine urinary catecholamine excretion in a self-selected sample of sexually abused and demographically matched control girls recruited from a prospective, longitudinal study. METHOD: Twenty-four--hour urinary catecholamine and metabolite concentrations of epinephrine, norepinephrine, dopamine, 3-methoxy-4-hydroxyphenylglycol, metanephrine, normetanephrine, vanillylmandelic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in 12 sexually abused and 9 control girls, aged 8 to 15 years. Psychiatric profiles also were obtained. RESULTS: The abused subjects excreted significantly greater amounts of metanephrine, vanillylmandelic acid, homovanillic acid, and total catecholamine synthesis as measured by the sum of epinephrine, norepinephrine, dopamine, and their metabolites compared to values from control subjects. When the means of all significant biochemical measures were adjusted by the covariate effect of height, only homovanillic acid and group interaction remained significant. There were positive trends toward significantly higher urinary excretion of metanephrine, vanillylmandelic acid, and total catecholamine synthesis. Sexually abused girls also had a greater incidence of suicidal ideation, suicide attempts, and dysthymia than control girls. CONCLUSIONS: These findings support the idea that sexually abused girls show evidence of higher catecholamine functional activity compared with controls. The clinical significance of these findings in their similarity to the psychobiology of both post-traumatic stress disorder and major depressive disorder. Results from this pilot study may be of value in understanding the mechanisms of depressive and anxiety disorders and in the clinical treatment of maltreated children.