Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial

Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48.4 months (IQR 42.0-56.5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78.6%) compared with the observation group (4-year disease-free survival 72.2%; hazard ratio [HR] 0.76; 95% CI 0.66-0.87; p<0.0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89.3% vs 87.7%, respectively; HR 0.85; 95% CI 0.70-1.04; p=0.11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22.8 months (range 4.5-52.7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0.68; 95% CI 0.51-0.90; p=0.0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort.

Supplementation of Vitamin E, Vitamin C, and Zinc Attenuates Oxidative Stress in Burned Children: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

The aim of this study was to investigate the effect of supplementation of vitamin E, vitamin C, and zinc on the oxidative stress in burned children. In a prospective double-blind placebo-controlled pilot study, 32 patients were randomized as no supplementation (n = 15) or antioxidant supplementation (n = 17) groups. Supplementation consisted of the antioxidant mixture of vitamin C (1.5 times upper intake level), vitamin E (1.35 times upper intake level), and zinc (2.0 times recommended dietary allowance) administered during 7 days starting on the second day of admittance into the hospital. Energy requirement was calculated by the Curreri equation, and protein input was 3.0 g/kg of ideal body mass index (percentile 50 degrees). Total antioxidant capacity of plasma and malondialdehyde were used to monitor oxidative stress. The time of wound healing was evaluated as the main clinical feature. Patients (age 54.2 +/- 48.9 months, 65.6% males), who exhibited 15.5 +/- 6.7% of total burn area, showed no differences in age and sex, when compared with controls. Intake of the administered antioxidants was obviously higher in treated subjects (P = .005), and serum differences were confirmed for vitamin E and C, but not for zinc (P = .180). There was a decrease in lipid peroxidation (malondialdehyde level) (P = .006) and an increase in vitamin E concentrations in the antioxidant supplementation group (P = .016). The time of wound healing was lower in the supplemented group (P < .001). The antioxidant supplementation through vitamin E and C and the mineral zinc apparently enhanced antioxidant protection against oxidative stress and allowed less time for wound healing. (J Burn Care Res 2009;30:859-866)

Simplified criteria for the diagnosis of autoimmune hepatitis

Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobutins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff >= 6) and 81% sensitivity and 99% specificity (cutoff 2:7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher.

Reliability and validity of the Brazilian-Portuguese version of the Burns Specific Pain Anxiety Scale (BSPAS)

Background: Pain and anxiety are a common problem in all recovery phases after a burn. The Burns Specific Pain Anxiety Scale (BSPAS) was proposed to assess anxiety in burn patients related to painful procedures. Objectives: To assess internal consistency, discriminative construct validity, dimensionality and convergent construct validity of the Brazilian-Portuguese version of the Burns Specific Pain Anxiety Scale. Design: In this cross-sectional study, the original version of the BSPAS, adapted into Brazilian Portuguese, was tested for internal consistency (Cronbach`s Alpha), discriminative validity (related to total body surface area burned and sex), dimensionality (through factor analysis), and convergent construct validity (applying the Visual Analogue Scale for pain and State-Anxiety-STAI) in a group of 91 adult burn patients. Results: The adapted version of the BSPAS displayed a moderate and positive correlation with pain assessments: immediately before baths and dressings (r = 0.32; p < 0.001), immediately after baths and dressings (r = 0.31; p < 0.001) and during the relaxation period (r= 0.31; p < 0.001) and with anxiety assessments (r = 0.34; p < 0.001). No statistically significant differences were observed when comparing the mean of the adapted version of the BSPAS scores with sex (p = 0.194) and total body surface area burned (p = 0.162) (discriminative validity). The principal components analysis applied to our sample seems to confirm anxiety as one single domain of the Brazilian-Portuguese version of the BSPAS. Cronbach`s Alpha showed high internal consistency of the adapted version of the scale (0.90). Conclusion: The Brazilian-Portuguese version of the BSPAS 9-items has shown statically acceptable levels of reliability and validity for pain-related anxiety evaluation in burn patients. This scale can be used to assess nursing interventions aimed at decreasing pain and anxiety related to the performance of painful procedures. (c) 2010 Elsevier Ltd. All rights reserved.

Absence of pathological scarring in the donor site of the scalp in burns: An analysis of 295 cases

Aim: This study aims to describe the incidence of complications on scalp from which a thin split-skin graft was harvested (0.005-0.007 in.) of the donor site in children and adult burn victims. Methods: We reviewed the medical records of 295 burn patients admitted in the Burn Unit of the Clinical Hospital of the Faculty of Medicine of Ribeirao Preto, from January 1998 to December 2007, whose scalps were used as donor site for grafts. Skin-graft thickness varied from 0.005 in. to 0.007 in. The occurrence of pathological healing was evaluated clinically and the time of epithelisation by the main surgeon and a plastic surgeon or a staff nurse. Results: Of the 295 patients whose scalps were used as donor site, 274 were followed from 6 months to 10 years after the procedure (median 18.2 months). Twenty-one patients were lost to follow-up in the first 6 months. No hypertrophic scarring or keloids on the donor site was observed. Five patients (1.82%) presented with folliculitis and two of them were evaluated with small areas of alopecia (0.7%), treated with resection of these areas and primary suture. The average time of epithelisation of the donor site was 7 days. Conclusion: The harvest of thinner split graft from the scalp is a safe procedure. (C) 2009 Elsevier Ltd and ISBI. All rights reserved.

Abdominal compartment syndrome in trauma resuscitation

Purpose of review Swelling is inexorably linked to shock and resuscitation in trauma. In many forms, swelling complicates and interacts with traumatic injury to raise pressures in the abdomen, resulting in intraabdominal hypertension, which may overtly manifest as abdominal compartment syndrome (ACS) driving multiple organ failure. Despite renewed clinical interest in posttraumatic intraabdominal pressure, there remains a chiasm between knowledge of the risks and clinical interventions to mitigate them. This review provides a concise overview of definitions, risk factors, diagnosis and management using an illustrative trauma case. Recent findings Intraabdominal pressure commonly increases following trauma, wherein ACS may manifest earlier than generally appreciated and complicate other insults such as shock and hemorrhage. Contemporary resuscitation strategies may exacerbate intraabdominal hypertension, particularly massive crystalloid resuscitation. Although unproven, the recent transition to crystalloid restriction and high plasma resuscitation strategies may influence the prevalence of ACS. Nonetheless, aggressive intraabdominal pressure monitoring should be mandatory in the critically ill. Despite potential nonoperative options, decompressive laparotomy remains the only definitive but often morbid treatment. Summary ACS results from many dysfunctions acting in concert with each other in self-propagating vicious cycles. Starting with greater awareness, it is imperative that the growing knowledge should be translated into clinical practice.

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Glutamine supplementation does not improve protein synthesis rate by the jejunal mucosa of the malnourished rat

It has been demonstrated that glutamine, a conditionally essential amino acid, improves nitrogen balance, acts as a stimulant of protein synthesis, and decreases proteolysis in myopathic children. In contrast, other studies have shown no beneficial effect of glutamine supplementation on burn victims or critically ill patients. Nonetheless, we hypothesized that glutamine supplementation would increase the fractional protein synthesis rate (FSR) in the jejunal mucosa of malnourished male Wistar rats. Thus, the objective of the present study was to test the effect of daily oral glutamine supplementation (0.42 g kg(-1) d(-1) for 14 days) on the FSR of the jejunal mucosa of healthy and malnourished rats. A 4-hour kinetic study with L-[1-(13)C]leucine was subsequently performed, and jejunal biopsies were obtained 1.5 cm from the Treitz angle and analyzed. Malnourished rats showed a 25% weight loss and increased urinary nitrogen excretion. Plasma amino acid concentration did not differ between groups. (13)C enrichment in plasma and jejunal cells was higher in the malnourished groups than in the healthy group. The FSR (percent per hour) was similar for the control and experimental groups (P > .05), with a mean range of 220%/h to 27%/h. Oral glutamine supplementation alone did not induce higher protein incorporation by the jejunal mucosa in malnourished rats, regardless of total food intake or the presence or absence of glutamine supplementation. (C) 2009 Elsevier Inc. All rights reserved.

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

Aicardi-Goutieres syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

Predictors of word-level literacy amongst Grade 3 children in five diverse languages

Groups of Grade 3 children were tested on measures of word-level literacy and undertook tasks that required the ability to associate sounds with letter sequences and that involved visual, auditory and phonological-processing skills. These groups came from different language backgrounds in which the language of instruction was Arabic, Chinese, English, Hungarian or Portuguese. Similar measures were used across the groups, with tests being adapted to be appropriate for the language of the children. Findings indicated that measures of decoding and phonological-processing skills were good predictors of word reading and spelling among Arabic- and English-speaking children, but were less able to predict variability in these same early literacy skills among Chinese- and Hungarian-speaking children, and were better at predicting variability in Portuguese word reading than spelling. Results were discussed with reference to the relative transparency of the script and issues of dyslexia assessment across languages. Overall, the findings argue for the need to take account of features of the orthography used to represent a language when developing assessment procedures for a particular language and that assessment of word-level literacy skills and a phonological perspective of dyslexia may not be universally applicable across all language contexts. Copyright (C) 2008 John Wiley & Sons, Ltd.

Temperature safety profile of laparoscopic devices: Harmonic ACE (ACE), Ligasure V (LV), and plasma trisector (PT)

Background Reports of iatrogenic thermal injuries during laparoscopic surgery using new generation vessel-sealing devices, as well as anecdotal reports of hand burn injuries during hand-assisted surgeries, have evoked questions about the temperature safety profile and the cooling properties of these instruments. Methods This study involved video recording of temperatures generated by different instruments (Harmonic ACE [ACE], Ligasure V [LV], and plasma trisector [PT]) applied according the manufacturers` pre-set settings (ACE setting 3; LV 3 bars, and the PT TR2 50W). The video camera used was the infrared Flex Cam Pro directed to three different types of swine tissue: (1) peritoneum (P), (2) mesenteric vessels (MV), and (3) liver (L). Activation and cooling temperature and time were measured for each instrument. Results The ACE device produced the highest temperatures (195.9 degrees +/- 14.5 degrees C) when applied against the peritoneum, and they were significantly higher than the other instruments (LV = 96.4 degrees +/- 4.1 degrees C, and PT = 87 degrees +/- 2.2 degrees C). The LV and PT consistently yielded temperatures that were < 100 degrees C independent of type of tissue or ""on""/ ""off"" mode. Conversely, the ACE reached temperatures higher than 200 degrees C, with a surprising surge after the instrument was deactivated. Moreover, temperatures were lower when the ACE was applied against thicker tissue (liver). The LV and PT cooling times were virtually equivalent, but the ACE required almost twice as long to cool. Conclusions The ACE increased the peak temperature after deactivation when applied against thick tissue (liver), and the other instruments inconsistently increased peak temperatures after they were turned off, requiring few seconds to cool down. Moreover, the ACE generated very high temperatures (234.5 degrees C) that could harm adjacent tissue or the surgeon`s hand on contact immediately after deactivation. With judicious use, burn injury from these instruments can be prevented during laparoscopic procedures. Because of the high temperatures generated by the ACE device, particular care should be taken when it is used during laparoscopy.

Microstructural and Ultrastructural Assessment of Inferior Alveolar Nerve Damage Following Nerve Lateralization and Implant Placement: An Experimental Study in Rabbits

Purpose: The present study assessed damage to the inferior alveolar nerve (IAN) following nerve lateralization and implant placement surgery through optical and transmission electron microscopy (TEM). Materials and Methods: IAN lateralization was performed in 16 adult female rabbits (Oryctolagus cuniculus). During the nerve lateralization procedure, one implant was placed through the mandibular canal, and the IAN was replaced in direct contact with the implant The implant was placed in the right mandible, and the left side was used as a control (no surgical procedure) After 8 weeks, the animals were sacrificed and samples were prepared for optical and TEM analysis of IAN structural damage Histomorphometric analysis was performed to determine the number and cross-sectional dimensions of nerve fascicles and myelin sheath thickness between experimental and control grouos. The different parameters were compared by one-way analysis of variance at the 95% significance level Results: Alterations in the perineural and endoneural regions of the IAN, with higher degrees of vascularization., were observed in the experimental group TEM showed that the majority of the myelinated nerve fibers were not affected in the experimental samples. No significant variation in the number of fascicles was observed, significantly larger fascicle height and width were observed in the control group, and significantly thicker myelin sheaths were observed in the experimental samples Conclusion: IAN lateralization resulted in substantial degrees of tissue disorganization at the microstructural level because of the presence of edema However, at the ultrastructural level, small amounts of fiber degeneration were observed. INT J ORAL MAXILLOFAC IMPLANTS 2009,24-859-865