Theodoros Liakakos

The assessment of angiogenesis and fibroblastic stromagenesis in hyperplastic and pre-invasive breast lesions.

BackgroundTo investigate the changes of the neoplastic microenvironment during the different morphological alterations of hyperplastic and pre-invasive breast lesions.Methods78 in situ ductal carcinomas of all degrees of differentiation, 22 atypical ductal hyperplasias, 25 in situ lobular carcinomas, 18 atypical lobular hyperplasias, 32 ductal epithelial hyperplasias of usual type and 8 flat atypias were immunohistochemically investigated for the expression of vascular endothelial growth factor (VEGF), smooth muscle actin (SMA) and CD34, while microvessel density (MVD) was counted using the anti-CD31 antibody.ResultsVEGF expression was strongly correlated with MVD in all hyperplastic and pre-invasive breast lesions (p < 0.05). Stromagenesis, as characterized by an increase in SMA and a decrease in CD34 positive myofibroblasts was observed mostly around ducts harboring high grade in situ carcinoma and to a lesser extent around moderately differentiated DCIS. In these two groups of in situ carcinomas, a positive correlation between MVD and SMA (p < 0.05) was observed. On the contrary, CD34 was found to be inversely related to MVD (p < 0.05). No statistically significant changes of the stromal fibroblasts were observed in low grade DCIS neither in any of the other lesions under investigation as compared to normal mammary intra- and interlobular stroma.ConclusionAngiogenesis is observed before any significant fibroblastic stromagenesis in pre-invasive breast lesions. A composite phenotype characterized by VEGF positive epithelial cells and SMA positive/CD34 negative stromal cells, is identified mostly in intermediate and high grade DCIS. These findings might imply for new therapeutic strategies using both anti-angiogenic factors and factors selectively targeting tumor stroma in order to prevent the progression of DCIS to invasive carcinoma.

Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.

Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge.

Improvement of gastric emptying by enhanced recovery after pancreaticoduodenectomy

BACKGROUND Enhanced recovery after surgery (ERAS) has improved postoperative outcomes particularly in colorectal surgery. This study aimed to assess compliance with an ERAS protocol and evaluate its effect on postoperative outcomes in patients undergoing pancreaticoduodenectomy. METHODS Fifty patients who had received conventional perioperative management from 2005 to 2009 (conventional group) were compared with 75 patients who had received perioperative care with an ERAS protocol (fast-track group) from 2010 to 2014. Mortality, complications, readmissions and length of hospital stay were evaluated and compared in the groups. RESULTS Compliance with each element of the ERAS protocol ranged from 74.7% to 100%. Uneventful patients had a significant higher adherence to the ERAS protocol (87.5% vs 40.7%; P<0.001). There were no significant differences in demographics and perioperative characteristics between the two groups. Patients in the fast-track group had a shorter time to remove the nasogastric tube, start liquid diet and solid food, pass flatus and stools, and remove drains. No difference was found in mortality, relaparotomy, readmission rates and overall morbidity. However, delayed gastric emptying and length of hospital stay were significantly reduced in the fast-track group. The independent effect of the ERAS protocol in reducing delayed gastric emptying and length of hospital stay was confirmed by multivariate analysis. CONCLUSION ERAS pathway was feasible and safe in improving gastric emptying, yielding an earlier postoperative recovery, and reducing the length of hospital stay.

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

The role of remote ischemic preconditioning in the treatment of atherosclerotic diseases

Remote ischemic preconditioning (RIPC) is the application of a transient and brief ischemic stimulus to a distant site from the organ or tissue that is afterward exposed to injury ischemia, and has been found to reduce ischemia–reperfusion injury (IRI) in various animal models. RIPC appears to offer two distinct phases of endothelial IRI protection, which are presumably mediated through neuronal and humoral pathways.

Pancreatic neuroendocrine tumors: current opinions on a rare, but potentially curable neoplasm.

Pancreatic neuroendocrine tumors (PNETs) share a unique genetic identity, functional behavior, and clinical course. Compared with tumors of the exocrine pancreas, they are rare and show a different biologic behavior and prognosis. On the basis of data from recent studies, all PNETs, outside of small insulinomas, should be considered potentially malignant and treated accordingly. Untreated tumors have a high possibility to grow locally into adjacent structures or spread to distant organs. Although surgical excision irrespective of tumor functioning or nonfunctioning state remains the cornerstone of therapy, providing the best disease-free and survival rates to date, the understanding of the genetic nature of the disease yields new ‘targets’ to consider in drug development. The aim of this review is to summarize all recent advances of genetic research and new drug development in terms of PNETs, especially their genetic identity and subsequent alterations leading to the development of near or total malignant activity, and the new medical treatment strategies of this potentially curable disease on the basis of therapeutical agents acting, where possible, at the genetic level.

The Greek financial crisis: maintaining medical education against the odds

Greece has been deeply affected by the severe financial crisis that struck the country in 2008, which resulted in government failure to reach financial targets, political instability and poor overall prospects. Higher education was particularly hit because it was seen as an easy target to reduce public expenditure and because it is heavily dependent on increasingly scarce government money. The National and Kapodistrian University of Athens (otherwise known as the University of Athens, UoA), which was founded in 1837, is the oldest institution of higher education in the country, and is closely connected with the history of modern Greece. The UoA School of Medicine (SoM), the largest and most sought after medical school nationally, current accepts about 4% of all applicants who take entry exams in their first undergraduate year. A freeze on recruitment, salary cuts, significant reductions in state contributions to institutional research funding and the failure of the government to meet its financial commitments to joint projects1 ,2 all impacted on the SoM. SoM employees were the first to be affected by the budget cuts. The numbers of workers employed were reduced through normal and early retirement combined with a freeze on hiring new staff, and their salaries were cut through the ‘availability’ measure, according to which civil servants—often administrative staff—are removed from their posts but remain ‘available’ for other posts in the public sector, while being paid a fraction of their salary. The annual state grant to cover the daily operational costs of the SoM was reduced by 71% between 2009 and 2014. Administrative staff are vital to the running of the SoM as procedures are generally …

Determinants of Secondary Hyperparathyroidism in Bariatric Patients after Roux-en-Y Gastric Bypass or Sleeve Gastrectomy: A Pilot Study

Objective. Nutritional deficiencies are common after bariatric surgery. We aimed to assess the prevalence and possible predictors of secondary hyperparathyroidism (SHPT) in bariatric patients. Methods. A total of 95 patients who had undergone Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were assessed after a median of 3 years after surgery. Anthropometric/demographic and weight-loss parameters were compared according to the presence of SHPT, independently for men/premenopausal women and postmenopausal women. Results. SHPT was highly prevalent (men/premenopausal women, 52.1%; postmenopausal women, 31.9%). Among men/premenopausal women, multivariate analysis indicated that SHPT was predicted by (a) 25-hydroxyvitamin D levels (Exp(B) = 0.869, P-value = 0.037), independently of age, sex, smoking; (b) calcium (Exp(B) = 0.159, P-value = 0.033) and smoking, independently of age and sex; (c) magnesium (Exp(B) = 0.026, P-value = 0.046) and smoking, independently of age and sex. Among postmenopausal women, SHPT was predicted by menopausal age independently of age, smoking, and levels of 25-hydroxyvitamin D or calcium. The development of SHPT was not associated with the type of surgery. Conclusions. RYGB and SG exhibited similar effects regarding the regulation of the hypothalamus-pituitary-parathyroid axis after surgery. Vitamin D status and menopausal age appear to determine SHPT on the long term. SHPT should be sought and vigorously treated with calcium and vitamin D supplementation.

Antiplatelet Treatment in Peripheral Arterial Disease: The Role of Novel Antiplatelet Agents

BACKGROUND Acetylsalicylic acid and clopidogrel are two antiplatelet agents currently used in the therapy of peripheral arterial disease. Cilostazol also inhibits platelet aggegration. These agents present limitations that novel antiplatelet agents may overcome. OBJECTIVE The aim of this manuscript is to review current data on the use of novel antiplatelet agents in peripheral arterial disease. METHOD An extensive search in the English medical literature has yielded a number of publications on a number of novel antiplatelet agents; atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel, and prasugrel. RESULTS Data on atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel and prasugrel come mainly from cardiology publications. Limitations, side effects and effectiveness of each of these agents are studied, but their use in peripheral arterial disease is limited, especially for those agents that have not still been approved for this indication. As expected, main side effect of most of these agents is haemorrhage, but other important side effects limit the use of some of these agents in specific subgroups of patients. CONCLUSION Novel antiplatelet agents demonstrate a range of promising characteristics, but further study and clinical trials are necessary for them to be considered safe and effective.

Apolipoprotein J as a predictive biomarker for restenosis after carotid endarterectomy: a retrospective study

Carotid endarterectomy (CEA) is an effective surgical option for stroke prophylaxis in most patients. Restenosis after CEA can lead to re-intervention and adverse events, but the factors predicting restenosis are poorly understood. Apolipoprotein J (ApoJ) is considered to be a novel predictive factor of vascular restenosis and is associated with a large number of processes related to atherosclerosis and cell-cycle phases. The aim of this study was to elucidate the predictive value of Apo J in internal carotid artery (ICA) restenosis following CEA. This retrospective study examined all prospectively collected data for patients who underwent CEA at our surgical department over a 2-year period. The serum ApoJ levels of 100 patients were examined; 56 patients who underwent CEA comprised the vascular group (VG), and 44 patients who underwent minor surgery comprised the control group (CG). ApoJ samples were obtained preoperatively, 24 h after the surgical procedure and at 1, 6 and 12 months thereafter during the follow-up. The preoperative difference in ApoJ levels between the CG and VG was statistically signifcant; the mean values were 39.11±14.16 and 83.03±35.35 μg/mL, respectively. In the VG, the serum ApoJ levels were 112.09±54.40, 71.20±23.70, 69.92±25.76 and 62.25±19.17 μg/mL at postoperative day 1 and at 1, 6 and 12 months post-operatively, respectively, while the ApoJ concentrations of patients in the CG remained unchanged. Further subdivision of the VG into patients with or without restenosis revealed that restenosis patients presented signifcantly higher mean ApoJ values than non-restenosis VG patients. In summary, ApoJ seems to be an important predictor for carotid restenosis at 6 and 12 months postoperatively.