Search

A study to find that if manual Thrombus aspiration was more effective as compared to normal conventional treatment during primary percutaneous coronary intervention (PCI) is conducted. Results indicate that Thrombus aspiration was more effective in the treatment of PCI than conventional methods.

Introduction This study aims to evaluate the applicability and prognostic value of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) histopathological response score in extremity soft tissue sarcoma (ESTS) patients treated with neoadjuvant hyperthermic isolated limb perfusion (HILP) and delayed surgical resection. Methods Patients treated between 1991 and 2016 were included. The histopathological tumor response was established in accordance with the EORTC-STBSG response score. The distribution of patients was assorted according to the 5-tier histopathological response score for tumor grade, histological subtype and HILP regimen. Predictors for local recurrence free survival (LRFS) and overall survival (OS) were identified through Kaplan-Meier and Cox regression analyses. Results Ninety-one patients were included and their resection specimens were reanalyzed. Which resulted in 11 Grade A (12.1%), ten Grade B (11.0%), 15 Grade C (16.5%), 22 Grade D (24.2%) and 33 Grade E (36.3%) responses found among the series. The histopathological response was significantly influenced by the HILP regimen used, p = 0.033. Median follow-up was 65.0 (18.0–157.0) months. The histopathological response was not associated with LRFS nor OS. Resection margins, HILP regimen and adjuvant radiotherapy were associated with LRFS. Patients' age, tumor grade, tumor size and histological subtype were predictors for OS. Conclusions The EORTC-STBSG response score is applicable for determining the histopathological response to neoadjuvant ESTS treatment. However, this response does not seem to predict LRFS nor OS in locally advanced ESTS. [ABSTRACT FROM AUTHOR]

ABSTRACT So far only mutations in the filamin A gene ( FLNA) have been identified as causing familial mitral valve prolapse (MVP). Previous studies have linked dysregulation of the transforming growth factor beta (TGF-β) cytokine family to MVP. We investigated whether mutations in the TGF-β receptors genes type I ( TGFBR1) and II ( TGFBR2) underlie isolated familial MVP cases. Eight families with isolated familial MVP were evaluated clinically and genetically. Ventricular arrhythmias were present in five of the eight families and sudden cardiac death occurred in six patients. Tissue obtained during mitral valve surgery or autopsy was available for histological examination in six cases; all demonstrated myxomatous degeneration. A previously described FLNA missense mutation (p.G288R) was identified in one large family, but no mutations were discovered in TGFBR1 or TGFBR2. An FLNA missense mutation was identified in one family but we found no TGFBR1 or TGFBR2 mutations. Our results suggest that TGFBR1 and TGFBR2 mutations do not play a major role in isolated myxomatous valve dystrophy. Screening for FLNA mutations is recommended in familial myxomatous valvular dystrophy, particularly if X-linked inheritance is suspected. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: EUS is a standard staging procedure in esophageal cancer. For adequate staging, FNA of suspicious lymph nodes is recommended. Based on optimal staging, sophisticated treatment can be applied more properly. The working channel of the endoscope can potentially be contaminated by cancer cells derived from the luminal surface of esophageal cancer during EUS-guided FNA, which may result in false-positive cytology results of EUS-guided FNA of celiac lymph nodes. Objective: To determine whether passing an endoscope through intraluminal esophageal cancer can lead to contamination of the working channel with tumor cells. Design: An ex vivo assessment of contamination of endoscope working channels. Setting: University hospital. Patients: This study involved 13 patients with esophageal cancer. Intervention: Working channels of endoscopes that had been used in patients with intraluminal esophageal cancer were studied immediately after EUS. A routine ex vivo FNA was performed through the endoscope on 8 patients. The same procedure was performed through the endoscope on 5 other patients after the working channel had been cleaned by extensive flushing. Main Outcome Measurements: Semiquantitative scoring of cytology smears. Results: Six of 8 specimens contained carcinoma cells. No contamination by carcinoma cells or normal cells was observed when the working channel was flushed with tap water prior to the sham FNA procedure. Limitations: This was an ex vivo study of a limited group of patients. Conclusion: The working channel of the endoscope can be contaminated during the EUS-guided FNA procedure. Cancer cell contamination can be avoided by flushing the endoscope. [Copyright &y& Elsevier]

Although current cytomorphology-based cervical cancer screening has reduced the incidence of cervical cancer, Pap-smears are associated with high false positive and false negative rates. This has spurred the search for new technologies to improve current screening. New methodologies are automation of Pap-smear analysis, addition of new biological or molecular markers to traditional cytology or using these new markers to replace the current screening method. In this overview we will summarize data on cervical cancer epidemiology and etiology and the current cervical cancer screening approach. Available data on new screening approaches, such as quantitative cytochemistry, detection of loss of heterozygosity (LOH) and hypermethylation analysis will be reviewed. We discuss the potential of these approaches to replace or augment current screening. When available, data on cost–effectiveness of certain approaches will be provided. In short, Human Papillomavirus (HPV) DNA detection stands closest to implementation in nation-wide screening programs of all markers reviewed. However, specificity is low in women aged <35 years and the psychological effects of knowledge of HPV positivity in absence of cervical (pre) malignant disease are important drawbacks. In our opinion the results of large clinical trials should be awaited before proceeding to implement HPV DNA detection. New technologies based on molecular changes associated with cervical carcinogenesis might result in comparable sensitivity, but improved specificity. Hypermethylation analysis is likely to be more objective to identify patients with high grade squamous intra-epithelial lesions (HSIL) or invasive cancer with a higher specificity than current cytomorphology based screening. [ABSTRACT FROM AUTHOR]

Background: Recent studies show that erythropoietin (EPO) plays a protective role in brain ischemia. In this condition, administration of EPO protects neurons from ischemic damage. Recently, it has been shown that in patients with chronic heart failure (CHF), EPO treatment improved cardiac function. In the present study we assessed the role of EPO and EPO-receptor (EPO-R) in the heart. Methods and results: We studied the presence and functionality of the EPO-R in isolated rat hearts in the Langendorff set-up. Hearts were perfused for 20 min with 10 U/ml EPO or vehicle. Immunohistochemistry revealed the presence of the EPO-R on endothelial cells, fibroblasts and to a lesser extent cardiomyocytes. Furthermore, perfusion with EPO resulted in a 50% increase in the phosphorylated MAP kinases p42/p44. To evaluate the protective role of EPO in cardiac ischemia, we performed low-flow (0.6 ml/min) ischemia/reperfusion experiments in isolated rat hearts. Administration of EPO (10 U/ml) reduced the cellular damage by 56% (P<0.05) during reperfusion, diminished apoptosis by 15% (P<0.05) and resulted in a significantly improved recovery of left ventricular pressure (P=0.02) and coronary flow (P=0.01). Conclusion: The present data suggest that a functional EPO-R is present in rat adult cardiac tissue and that exogenous EPO administration improves cardiac function after ischemia/reperfusion injury. [Copyright &y& Elsevier]

1. Compound B (1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ehtyl-1,3-dihydro-2H-benzimidazol-2-one, CompB) is a nociceptin/orphanim FQ (N/FQ) antagonist showing high selectivity for the NOP (ORL1) receptor over classical opioid receptors. We studied the effect of subcutaneous CompB administration on the release of mesolimbic dopamine (DA) and the expression of hedonia in mice. 2. CompB (0.3-30 mg kg-1) dose dependently stimulated mesolimbic DA release as measured by in vivo freely moving microdialysis, without any change in locomotor activit. However, itracerebroventricular administered N/OFQ (endogenous agonist of the NOP receptor, 6 nmol) did not influence CompB- (10 mg kg -1) induced DA release, despite clearly suppressing release when adminstered alone. 3. Studies using NOP receptor knockout mice and no-net flux microdialysis revealed mildly, but not statistically significantly higher endogenous DA levels in mice lacking the NOP receptor compared to wild-type mice. Administration of CompB (10 mg kg-1) induced identical increases in mesolimbic DA release in wild-type and NOP receptor knockout mice. 4. CompB was rewarding in approximately the same dose range in which CompB induced major increases in mesolimbic DA release when assayed using a conditioned place preference paradigm. The rewarding effect of CompB (30 mg kg-1) was maintained in NOP receptor knockout mice. The results show that CompB stimulated mesolimbic DA release and is rewarding by an action independent of the NOP receptor, the precise site of which in unclear. Consequently, caution should be exercised when interpreting the results of studies using this drug, particularly when administered by a peripheral route. [ABSTRACT FROM AUTHOR]

Objective: To study the effects of increased levels of myocardial angiotensin II type 1 (AT1) receptor on microvascular growth following myocardial infarction (MI). Methods: MI was created in transgenic rats (TGR) with a cardioselective overexpression of the AT1 receptor. We used Sprague–Dawley (SD) rats as controls. Some of the rats were treated with the selective AT1 receptor blocker losartan (Los). Rats were sacrificed after 3 weeks. Results: MI caused left ventricular (LV) hypertrophy and LV dysfunction in both SD and TGR, which was prevented by AT1 receptor blockade. Furthermore, MI decreased microvessel density in the non-infarcted myocardium (SD MI: 1653±37/mm2, P<0.01 vs. sham-operated controls), however, microvessel density decreased significantly more in TGR with MI (1298±33/mm2, P<0.01 vs. SD MI). AT1 receptor blockade restored microvessel density (SD MI Los: 2046±195/mm2; TGR MI Los: 1742±47/mm2; P<0.01 vs. untreated). The differences in microvessel density were still present after correction for LV hypertrophy. The increase in microvessel density after AT1 receptor blockade was not accompanied by increased myocardial vascular endothelial growth factor (VEGF) levels. Microvessel density correlated with parameters of myocardial stretch, such as LV end-diastolic pressure (−0.681, P<0.001) and N-ANP (−0.424, P=0.01). Conclusions: Microvessel density after MI is decreased when the AT1 receptor is overexpressed, and this is amenable to AT1 receptor blockade. This suggests that efficacy of AT1 receptor blockers post-MI may not only be due to attenuation of LV remodeling, but also to a stimulatory effect on angiogenesis. [Copyright &y& Elsevier]

Cardiovascular gene therapy is a promising new approach for a variety of diseases. As far as gene therapy aimed at the myocardium is concerned a new transcutaneous delivery method may be into the pericardial sac. Objective: To evaluate the safety and applicability of the percutaneous pericardial delivery route for drug- or gene-therapy. Methods: A percutaneous pericardial access device called a perducer® was used to deliver either Indian ink or methylene blue to the pericardium of male yorkshire pigs under hemodynamic surveillance. Animals were sacrificed after either 3 h or 3 days. Post mortem distribution of the injectate was evaluated macroscopically and microscopically. Results: With the perducer®, the pericardial cavity was punctured in 10 pigs without hemodynamic complications. Although traces of dye could be seen in the pleural cavity in pigs sacrificed after 3 h, no evidence for dissemination was found in myocardial, lung, mediastinal lymph node and liver tissue in pigs sacrificed after 3 days. In two additional pigs the pericardium was punctured with the same perducer® technique under simultaneous thoracoscopic monitoring. Visualization of the surface of the pericardium facilitated the procedure because pericardial fat could be avoided. Conclusion: Obtaining access to the pericardium with the perducer® technique is safe and feasible. In addition thoracoscopic guidance may improve success rate and offers the possibility of on line surveillance. [Copyright &y& Elsevier]

Background – Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently. Methods – We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results – Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion – All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes. Unlabelled Image • Role of TPM1 variants in cardiomyopathy development are relatively understudied • Comprehensive clinical evaluation shows the heterogeneous cardiomyopathy phenotype • First description of compound heterozygote TPM1 E62Q/M281T in a child with RCM • Reduced CaT amplitudes and structural changes occur irrespective of TPM1 variants [ABSTRACT FROM AUTHOR]

Abstract: Background: Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour mainly affecting children and adolescents. Since survival of high-risk patients remains poor, new treatment options are awaited. The aim of this study is to investigate anaplastic lymphoma kinase (ALK) and insulin-like growth factor-1 receptor (IGF-1R) as potential therapeutic targets in RMS. Patients and methods: One-hundred-and-twelve primary tumours (embryonal RMS (eRMS)86; alveolar RMS (aRMS)26) were collected. Expression of IGF-1R, ALK and downstream pathway proteins was evaluated by immunohistochemistry. The effect of ALK inhibitor NVP-TAE684 (Novartis), IGF-1R antibody R1507 (Roche) and combined treatment was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in cell lines (aRMS Rh30, Rh41; eRMS Rh18, RD). Results: IGF-1R and ALK expression was observed in 72% and 92% of aRMS and 61% and 39% of eRMS, respectively. Co-expression was observed in 68% of aRMS and 32% of eRMS. Nuclear IGF-1R expression was an adverse prognostic factor in eRMS (5-year survival 46.9±18.7% versus 84.4±5.9%, p =0.006). In vitro, R1507 showed diminished viability predominantly in Rh41. NVP-TAE684 showed diminished viability in Rh41 and Rh30, and to a lesser extent in Rh18 and RD. Simultaneous treatment revealed synergistic activity against Rh41 and Rh30. Conclusion: Co-expression of IGF-1R and ALK is detected in eRMS and particularly in aRMS. As combined inhibition reveals synergistic cytotoxic effects, this combination seems promising and needs further investigation. [Copyright &y& Elsevier]

Summary: The evaluation of response to radiotherapy in patients with laryngeal cancer is a challenge because of the difficulty to differentiate between post-therapy changes and recurrent or residual tumor. Positron emission tomography is a non-invasive imaging tool that may be helpful in this differentiation. In this study, [18F]-fluoro-3′-deoxy-l-thymidine ([18F]FLT), a proliferation tracer is compared with 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]FDG). Patients with primary laryngeal cancer, scheduled to undergo radiotherapy were included in this study. Patients underwent both [18F]FLT-PET and [18F]FDG-PET shortly before radiotherapy. Ten patients underwent [18F]FLT-PET and [18F]FDG-PET 2–3months after radiotherapy. Scans were analyzed visually for areas of increased tracer uptake. The standardized uptake value (SUV) was measured as a semi-quantitative value of tracer uptake. Fourteen patients, all male, were included in this study. Both [18F]FLT-PET and [18F]FDG-PET showed increased tracer uptake in 12 out of 14 patients (86%). [18F]FDG uptake was significantly higher than [18F]FLT uptake (SUVmax: 4.5 vs. 2.4 (P =0.002); SUVmean: 3.4 vs. 1.9 (P =0.002)). After radiotherapy, 3 patients had histologically proven residual or recurrent laryngeal cancer. [18F]FDG was true positive in 2 out of 3 patients, whereas [18F]FLT showed increased tracer uptake in only one. Of the remaining 7 patients, [18F]FLT was true negative in all, whereas [18F]FDG showed increased uptake in one (false positive). [18F]FLT-PET is feasible in visualizing laryngeal cancer and its evaluation of treatment. The overall uptake of this tracer is significantly lower as compared with [18F]FDG, but tumor to background ratios are comparable. [Copyright &y& Elsevier]

Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP).From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype.BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes.The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype. [ABSTRACT FROM AUTHOR]