A Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma

ABSTRACT: BACKGROUND: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered. METHODS: The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56 Gy) followed by surgery and IORT (10-12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. DISCUSSION: The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. Trial Registration : NCT01566123.     

Optical coherence tomography imaging of psoriasis vulgaris: correlation with histology and disease severity

Epidermal thickness (ET) has been suggested as a surrogate measure of psoriasis severity. Optical coherence tomography (OCT) is a recent imaging technology that provides real-time skin images to a depth of 1.8 mm with a micrometre resolution. OCT may provide an accurate in vivo measure of ET. It is, therefore, speculated that OCT may be used in the assessment of psoriasis vulgaris. A total of 23 patients with psoriasis vulgaris were systematically evaluated by OCT imaging and skin biopsy during treatment. Biopsies were graded for disease severity, and additional evaluation was done by the physician via psoriasis area and severity index (PASI) score, and by the patient through measures such as self-administered PASI, psoriasis life stress inventory index and dermatology life quality index. ET was calculated from OCT images. In comparison to normal skin, psoriasis appeared with a more irregular surface with a stronger entrance signal, a serrated dermo-epidermal junction was found and a less signal intensity in the dermis as shown in OCT images. ET measured in untreated plaques was thicker reflecting epidermal hyperproliferation and inflammation. The changes were significantly correlated with the biopsy grading (r ² = 0.41, p = 0.001) and ET significantly decreased with treatment (p = 0.0001). ET correlated significantly with self-reported measures of disease severity, but not with physician-assessed global PASI. The data suggest that OCT may be used to measure ET in psoriasis and the measurements correlate with several other parameters of disease severity. This implies that OCT assessment of psoriatic plaques may provide a useful method for non-invasive in vivo method to follow the evolution of psoriasis lesions.     

The need for improved neutropenia risk assessment in DLBCL patients receiving R-CHOP-21: findings from clinical practice

Febrile neutropenia (FN) risk-assessment and granulocyte-colony stimulating factor (G-CSF) prophylaxis use in clinical practice was evaluated in patients with diffuse large B-cell lymphoma receiving R-CHOP-21. More G-CSF primary prophylaxis was used in patients assessed as high FN risk, but R-CHOP-21 was associated with substantial myelotoxicity in both high- and low-risk groups. In a multivariate analysis, older age, poor performance status, lower baseline hemoglobin, and lack of G-CSF prophylaxis were significantly associated with occurrence of FN in any cycle. Results highlight the need for improved FN risk-assessment and thorough guideline adherence to further reduce FN and better support chemotherapy delivery.     

Atropine for prevention of cardiac dysrhythmias in patients with hepatocellular carcinoma undergoing percutaneous ethanol instillation: a randomized,placebo‐controlled,double‐blind trial

Introduction: Percutaneous ethanol injection (PEI) is an established method in the treatment of hepatocellular carcinoma (HCC). During this procedure, severe cardiac bradyarrhythmias can occur. A preemptive injection of atropine is recommended by professional guidelines to prevent these dysrhythmias. Methods: Patients scheduled for PEI were randomized 1:1 to receive 0.5 mg atropinehydrochloride or placebo in a double‐blind randomized placebo‐controlled trial. Patients were electrocardiogram monitored, which were then analysed by an experienced rhythmologist blinded to the treatment arm. Results: Patients in 40 consecutive PEI sessions were included. During PEI, a significant reduction in the mean heart rate (>15%) was seen in 15% of patients in the placebo group (median, ?37%; range, 15–41%) and in 25% of patients receiving atropine (median, ?20%; range, 16–64%). There was no significant difference between both groups. During PEI, two patients (10%) in the placebo group developed a sinuatrial block (SAB). Four patients in the atropine group (20%) developed arrhythmias: three patients SAB, one of them with escape rhythm and one AV‐bundle block. Blood ethanol levels post‐PEI, amount of instilled ethanol, tumour size and location were not different between patients with or without dysrhythmias. Conclusion: In this randomized‐controlled trial, a preprocedure atropine injection did not prevent the occurrence of bradyarrhythmias. Prophylactic use of atropine might not be effective and therefore cannot be recommended as a routine procedure. Clinicaltrials.gov‐identifier: NCT00575523.     

Mechanisms of gold biomineralization in the bacterium Cupriavidus metallidurans

While the role of microorganisms as main drivers of metal mobility and mineral formation under Earth surface conditions is now widely accepted, the formation of secondary gold (Au) is commonly attributed to abiotic processes. Here we report that the biomineralization of Au nanoparticles in the metallophillic bacterium Cupriavidus metallidurans CH34 is the result of Au-regulated gene expression leading to the energy-dependent reductive precipitation of toxic Au(III)-complexes. C. metallidurans, which forms biofilms on Au grains, rapidly accumulates Au(III)-complexes from solution. Bulk and microbeam synchrotron X-ray analyses revealed that cellular Au accumulation is coupled to the formation of Au(I)-S complexes. This process promotes Au toxicity and C. metallidurans reacts by inducing oxidative stress and metal resistances gene clusters (including a Au-specific operon) to promote cellular defense. As a result, Au detoxification is mediated by a combination of efflux, reduction, and possibly methylation of Au-complexes, leading to the formation of Au(I)-C-compounds and nanoparticulate Au⁰. Similar particles were observed in bacterial biofilms on Au grains, suggesting that bacteria actively contribute to the formation of Au grains in surface environments. The recognition of specific genetic responses to Au opens the way for the development of bioexploration and bioprocessing tools.     

3D volume reconstruction of a mouse brain from histological sections using warp filtering

Sectioning tissues for optical microscopy often introduces upon the resulting sections distortions that make 3D reconstruction difficult. Here we present an automatic method for producing a smooth 3D volume from distorted 2D sections in the absence of any undistorted references. The method is based on pairwise elastic image warps between successive tissue sections, which can be computed by 2D image registration. Using a Gaussian filter, an average warp is computed for each section from the pairwise warps in a group of its neighboring sections. The average warps deform each section to match its neighboring sections, thus creating a smooth volume where corresponding features on successive sections lie close to each other. The proposed method can be used with any existing 2D image registration method for 3D reconstruction. In particular, we present a novel image warping algorithm based on dynamic programming that extends Dynamic Time Warping in 1D speech recognition to compute pairwise warps between high-resolution 2D images. The warping algorithm efficiently computes a restricted class of 2D local deformations that are characteristic between successive tissue sections. Finally, a validation framework is proposed and applied to evaluate the quality of reconstruction using both real sections and a synthetic volume.     

Effect of low-frequency transcranial magnetic stimulation on an affective go/no-go task in patients with major depression: role of stimulation site and depression severity

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a therapeutic tool in major depression. However, a means to assess the effects of a single rTMS session on mood to guide subsequent sessions would be desirable. The present study examined the effects of a single rTMS session on an affective go/no-go task known to measure emotional-cognitive deficits associated with major depression. Ten patients with an acute episode of unipolar major depression and eight partially or completely remitted (improved) patients underwent 1 Hz rTMS over the left and right dorsolateral prefrontal cortex prior to task performance. TMS over the mesial occipital cortex was used as a control. We observed significantly improved performance in depressed patients following right prefrontal rTMS. This beneficial effect declined with decreasing depression severity and tended to reverse in the improved group. Left prefrontal rTMS had no significant effect in the depressed group, but it resulted in impaired task performance in the improved group. Our findings indicate that the acute response of depressed patients to rTMS varies with the stimulation site and depression severity. Further studies are needed to determine whether the present paradigm could be used to predict antidepressant treatment success or to individualize stimulation parameters according to specific pathology.     

Mirtazapine inhibits salivary cortisol concentrations in anorexia nervosa

The antidepressant mirtazapine has been demonstrated to acutely inhibit cortisol concentrations in healthy subjects and depressed patients. Since both depressed and anorectic patients are characterized by hyperactivity of the hypothalamo-pituitary-adrenocortical (HPA) system, the clinical usefulness and the endocrinological effects of mirtazapine were investigated in anorexia nervosa (AN). Five female patients suffering from AN restricting subtype (DSM-IV criteria) were admitted to a closed ward and treated with mirtazapine for three weeks receiving 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 up to the end of the study (day 21). Besides weekly determination of clinical parameters (Body Mass Index [BMI], Hamilton Depression Rating Scale [21-HAMD]), salivary cortisol concentrations were measured before treatment (day - 1), at the beginning of treatment (day 0), after 1 week (day 7), and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 0800 up to 1,400 h. Repeated-measures ANOVA revealed a significant inhibition of salivary cortisol levels during 3-week treatment with mirtazapine (p<0.05) which became obvious already after the first mirtazapine administration (day 0). Moreover, a trend for an increase in BMI was seen (p=0.063), whereas no significant changes in 21-HAMD sum scores could be demonstrated. Double-blind, placebo-controlled studies are needed to clarify the question whether the observed changes in BMI are related to the mirtazapine-induced attenuation of HPA axis activity or whether they are due to monitoring of food intake and purgative behaviour on the closed ward.     

The effect of atypical antipsychotics on pituitary gland volume in patients with first-episode psychosis: A longitudinal MRI study

BackgroundPituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations.AimsTo determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population.MethodPituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naïve, at baseline and after 3 months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication.ResultsThere was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naïve and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r = ? 0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses.ConclusionsAtypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.