Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.     

Exercise Performance of Chronic Heart Failure Patients in the Early Period of Support by an Axial‐Flow Left Ventricular Assist Device as Destination Therapy

Axial‐flow left ventricular assist devices (LVADs) are increasingly used as destination therapy in end‐stage chronic heart failure (CHF), as they improve survival and quality of life. Their effect on exercise tolerance in the early phase after implantation is still unclear. The aim of this study was to evaluate the effect of LVADs on the exercise capacity of a group of CHF patients within 2 months after initiation of circulatory support. Cardiopulmonary exercise test data were collected for 26 consecutive LVAD‐implanted CHF patients within 2 months of initiation of assistance; the reference group consisted of 30 CHF patients not supported by LVAD who were evaluated after an episode of acute heart failure. Both LVAD and reference groups showed poor physical performance; LVAD patients achieved lower workload (LVAD: 36.3 ± 9.0 W, reference: 56.6 ± 18.2 W, P < 0.001) but reached a similar peak oxygen uptake (peak VO₂; LVAD: 12.5 ± 3.0 mL/kg/min, reference: 13.6 ± 2.9 mL/kg/min, P = ns) and similar percentages of predicted peak VO₂ (LVAD: 48.8 ± 13.9%, reference: 54.2 ± 15.3%, P = ns). While the values of the O₂ uptake efficiency slope were 12% poorer in LVAD patients than in reference patients (1124.2 ± 226.3 vs. 1280.2 ± 391.1; P = ns), the kinetics of VO₂ recovery after exercise were slightly better in LVAD patients (LVAD: 212.5 ± 62.5, reference: 261.1 ± 80.2 sec, P < 0.05). In the first 2 months after initiation of circulatory support, axial‐flow LVAD patients are able to sustain a low‐intensity workload; though some cardiopulmonary exercise test parameters suggest persistence of a marked physical deconditioning, their cardiorespiratory performance is similar to that of less compromised CHF patients, possibly due to positive hemodynamic effects beginning to be produced by the assist device.     

Assessment and prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant and in solid organ transplant: A multidisciplinary consensus conference by the Italian GITMO,SITO, and AMCLI societies

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) and solid organ transplantation (SOT) recipients. In view of the uncertainties on the assessment and prevention of CMV infection in both transplant procedures, three Italian scientific societies for HSCT and SOT and for Clinical Microbiology appointed a panel of experts to compose a framework of recommendations. Recommendations were derived from a comprehensive analysis of the scientific literature and from a multidisciplinary consensus conference process. The lack of adequate clinical trials focused on certain diagnostic procedures, and antiviral intervention forced the panel to use the methods of consensus for shaping some recommendations. Recommendations concerning the two types of transplant were given for the following issues: assessment of pretransplant CMV serostatus, immunological monitoring after transplant, CMV prophylaxis with antivirals, CMV preemptive strategy, and CMV prophylaxis with immunoglobulin infusion and with adoptive immunotherapy. The questions raised by and the recommendations resulting from this consensus conference project may contribute to the improvement of certain crucial aspects of the management of CMV infections in allo‐HSCT and in SOT populations.     

A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation

BACKGROUND: Graft shortage makes multiorgan procurement mandatory. We describe the results of a simplified method for the en bloc procurement of multiple organs, which permits isolated transplantation of all abdominal grafts, including the pancreas and the small bowel, to different recipients. METHODS: Three hundred forty-three multiorgan procurements were done with a simplified en bloc technique. RESULTS: None of the 1374 grafts that were procured sustained injuries that potentially precluded transplantation. Seventy-two grafts that were procured from 18 donors (5%) who were diagnosed with a neoplasm were discarded. Overall, 339 grafts that were procured from 325 donors were discarded because of specific contraindications, and 963 grafts (74%) were transplanted. Ninety-seven pancreata were transplanted. In 3 instances the pancreas and the small bowel were procured simultaneously and transplanted to different recipients. A total of 287 liver grafts were also transplanted at 13 different institutions. In 42 instances, the liver was not allocated to our center. Forty liver teams (95%) from 11 different institutions agreed to procure their grafts according to the simplified en bloc technique. Our team performed 18 procurements, and a surgeon from the liver transplantation team, who was assisted by one of the members of our team, performed 22 procurements. In all, 576 kidneys were transplanted, either alone or simultaneously, with other abdominal grafts at 15 different institutions. CONCLUSIONS: This procurement method has high yields, allows pancreas and small-bowel procurement, and can be learned readily.     

Idiopathic focal epilepsies: the “lost tribe”

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010 ), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org ). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.     

Novel insights on the bottom–up rise strength transfer: investigating massed vs. distributed exercise training

Sport Sciences for Health - The purpose of this study is to investigate the Bottom–Up Rise Strength Transfer (BURST) induced by massed vs. distributed-rehabilitative exercise training....     

Hand-assisted videolaparoscopic surgery of the abdominal aorta: preliminary experience with the first 9 cases

Laparoscopic surgery decreases postoperative pain, shortens hospital stay, and returns patients to full functional status more quickly than open surgery in a variety of surgical procedures. This study was undertaken to evaluate laparoscopic techniques as applied to aortic surgery. Nine patients underwent elective hand-assisted laparoscopic surgery, 8 for obliterative disease and 1 for an aneurysm of the abdominal aorta. Five patients had a left aorto-femoral bypass, 3 patients an aorto-bifemoral bypass, and 1 patient an aorto-aortic bypass after aneurysmectomy. There were no laparotomic conversions and all procedures were completed with transperitoneal hand-assisted laparoscopic surgery. Mean aortic clamping time was 39 minutes and mean operative time 194 minutes. Mean blood loss was 500 ml and the mean postoperative hospital stay was 4.2 days without major complications. At control examinations all grafts were patent. Hand-assisted laparoscopic aortic surgery is feasible, safe, and effective. In selected cases it may be a valid surgical procedure in addition to conventional and endovascular surgery. The advantages observed in our patients were minimal tissue trauma, less postoperative pain and faster postoperative recovery.     

Iron indices and vitamin D receptor polymorphisms in hemodialysis patients

Cardiovascular disease caused by accelerated atherosclerosis is the major determinant of morbidity and mortality in chronic kidney disease patients. Vitamin D and its analogs provide survival benefit for hemodialysis (HD) patients. Vitamin D exerts its effects through the vitamin D receptor (VDR) that is coded for by a gene showing several polymorphisms that, in turn, are associated with a variety of diseases and differential responses to vitamin D. In this study, we evaluated the association between 4 VDR polymorphisms (ie, those identified by the restriction enzymes BsmI, ApaI, TaqI, and FokI) and iron indices (serum iron, transferrin, transferrin saturation, and ferritin) in 88 hemodialysis patients routinely treated with vitamin D. The absence or presence of the BsmI, ApaI, TaqI, and FokI restriction sites were denominated B and b, A and a, T and t, F and f, respectively. Our results show that in HD patients with transferrin saturation <20%, the F allele was more frequent than in HD patients with transferrin saturation >20% (P = .03). This relationship may provide a link between VDR alleles and iron and nutritional markers, which are highly predictive variables of cardiovascular morbidity and mortality in hemodialysis patients.     

Inhibition of tyrosine-kinase-mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis

BACKGROUND: The effects of the tyrosine kinase inhibitors, tyrphostin AG126 and AG556 in a murine model of acute pancreatitis are investigated. METHODS: Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as elevation in the serum activities of amylase or lipase. RESULTS: Infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with signs of enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination showed a marked increase in immunoreactivity for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated mice. Pretreatment or posttreatment with tyrphostin AG126 and AG556, 2 different tyrosine kinase inhibitors, significantly reduced the degree of pancreatic inflammation and tissue injury (histologic score). In particular, the treatment with the 2 tyrosine kinase inhibitors reduced the cerulein-induced nitrotyrosine formation and PARP activation in the pancreas as well as the systemic release of tumor necrosis factor alpha. CONCLUSIONS: This study provides the first evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of acute pancreatitis, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of acute pancreatitis.     

BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial

Vitamin D receptor (VDR) gene polymorphisms could be considered one of the factors influencing the efficacy of the anti-osteoporotic treatments. In this multicenter, prospective, randomized and controlled trial we evaluated whether BsmI vitamin D receptor (VDR) genotypes influence the efficacy of antiresorptive treatment regimes (administered alone or in combination) in postmenopausal osteoporotic women. Using restriction endonuclease, we identified the BsmI VDR polymorphism in 1,100 postmenopausal women with osteoporosis. The women were randomized, taking account of genotype, into five treatment groups: (1) alendronate (Aln, 10 mg/day) plus raloxifene (Rlx, 60 mg/day); (2) Aln plus hormone replacement therapy (HRT, 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate); (3) Aln alone; (4) HRT alone; and (5) Rlx alone. Lumbar-spine bone mineral density (BMD) and bone turnover markers were measured at study entry and after 1 year of treatment. Using the general linear model (GLM) repeated-measures procedure, the means of BMD and bone turnover markers significantly differed from baseline after a period of treatment. In particular, the mean change from baseline for BMD was –0.034 (95% confidence interval [CI]: –0.037 to –0.031, P <0.001); for serum osteocalcin (OC) it was 1.369 (95% CI: 1.289 to 1.448, P <0.001); and for urinary deoxypyridinoline (DPD) it was 1.322 (95% CI: 1.242 to 1.401, P <0.001), indicating a considerable variation before and after treatment of these indicators. In all three cases these effects appeared significantly influenced by treatments, genotypes, and the treatments*genotypes interaction term (P <0.001 each, except for the BMD and genotype effect with P =0.02), and not by the investigational centers involved in the study. In conclusion, in postmenopausal osteoporotic women, BsmI VDR genotypes influence the efficacy of antiresorptive drugs particularly when used in combination.