George C. Zografos

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection

IntroductionAlthough major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time.MethodsThe statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer.ResultsExpression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis.ConclusionsMajor differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

Current concerns and challenges regarding tailored anti-angiogenic therapy in cancer

raise serious questions concerning the efficacy and safety of these VEGF antagonists. Overall survival (OS) improvement is the fundamental principle of any new therapy. Instead of improving, could anti-angiogenic agents, specifically bevaci-zumab, actually reduce OS? Although this provocative finding requires confirmation, a potential decrease in OS by administra-tion of the widely used drug bevacizumab in a metastatic setting has a central role in treatment decision making. Why is pro-gression-free survival (PFS) selected as a primary end point in several clinical trials, less appropriate than OS? Is the identifica-tion of new biomarkers for patient selec-tion essential to prove the clinical utility of anti-angiogenic therapy only in specific subgroups of patients and not generally in all patients? Over the last decade, molecularly tar-geted therapy has developed rapidly. Adding targeted agents to traditional sur-gery, radiotherapy and chemotherapy rep-resents the major hope in the war against solid cancers. The concept is scientifically rational. Targeting signaling pathways that are deregulated and responsible for can-cer progression and metastasis can lead to effective cancer treatment. However, most Phase III trials without marker-based selection of patients were negative. This treatment failure raises the sugges-tion of a change in drug development and clinical trial design towards personalized genotype–phenotype predictions

Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease

BackgroundRecent evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) expression is induced in many types of human cancer, while detection of its complex with matrix metalloproteinase-9 (MMP-9) is correlated with cancer disease status. We aim to evaluate the serum expression of MMP-9, NGAL and their complex (MMP-9/NGAL) during the diagnostic work-up of women with breast abnormalities and investigate their correlation with disease severity.MethodsThe study included 113 women with non-palpable breast lesions undergoing vacuum-assisted breast biopsy for histological diagnosis, and 30 healthy women, which served as controls. Expression levels of MMP-9, NGAL and their complex MMP-9/NGAL were determined in peripheral blood samples with immunoenzymatic assays.ResultsWomen with invasive ductal carcinoma exhibited significantly increased levels of MMP-9, NGAL and MMP-9/NGAL compared to healthy controls (MMP-9: p < 0.003, NGAL: p < 0.008 MMP-9/NGAL: p < 0.01). Significant correlations were observed between MMP-9 and NGAL serum levels and breast disease severity score (r = 0.229, p < 0.006 and r = 0.206, p < 0.01, respectively), whereas a non-significant correlation was found for their complex. MMP-9, NGAL and their complex MMP-9/NGAL levels were not correlated with either Body Mass Index (BMI) or age of patients.ConclusionThese findings suggest that the serum measurement of MMP-9 and NGAL may be useful in non-invasively monitoring breast cancer progression, while supporting their potential role as early biomarkers of breast disease status.

Reinforcing the staple line during laparoscopic sleeve gastrectomy: prospective randomized clinical study comparing two different techniques. Preliminary results.

BackgroundSleeve gastrectomy involves the creation of small gastric reservoir based on lesser curvature of the stomach, which is fashioned by a longitudinal gastrectomy that preserves the antrum and pylorus together with its vagal innervation. The main complications in the early postoperative course are bleeding and gastric leak. In order to reduce these complications the staple line can be reinforced in many different ways. The purpose of this study was to randomly compare two different techniques in laparoscopic sleeve gastrectomy (LSG): buttressing the staple line at the gastroesophageal junction (angle of Hiss) with Gore Seamguard and staple-line suturing with PDS 2.0.MethodsBetween July 2009 and July 2010, 90 patients were prospectively and randomly enrolled in the two different techniques of handling the staple line during LSG. Forty-eight of these patients belonged in group A (application of Gore Seamguard) and 42 in group B (application of a continuous suture). Operative and postoperative complications were recorded.ResultsPostoperative leak affected two patients in group A (4.2%) and bleeding occurred in one patient of group A (2%). Total complication rate was 6.2% for group A. No major surgical complication occurred in group B. The differences between the two groups did not reach statistical significance.ConclusionsNo significant difference is evidenced in terms of bleeding and postoperative leak between the two techniques of enhancing the staple line in LSG. Suturing of the staple line may be more time consuming but costs are considerably less.

Morbid Obesity and Sleeve Gastrectomy: How Does It Work?

Laparoscopic sleeve gastrectomy is known to be a safe and effective procedure for treating morbid obesity and is performed with increasing frequency both in Europe and the USA. Despite its broad use, many questions about the remaining gastric tube diameter, its long-term efficacy, its effects on gastric emptying, and the hormones involved still remain to be answered. In order to use such a relatively new surgical procedure wisely, it is essential for every surgeon and physician to understand how sleeve gastrectomy acts in obesity and what its potential benefits on the patients’ metabolism are. This review focuses on the most important pathophysiologic questions referred to sleeve gastrectomy on the literature so far, in an attempt to evaluate the different issues still pending on the subject.

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT–PCR). The overall concordance between kRT–PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT–PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development

Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

Predictive value of procalcitonin for bowel ischemia and necrosis in bowel obstruction.

BACKGROUND To our knowledge, the predictive value of procalcitonin for bowel strangulation has been evaluated in only 2 experimental studies that had conflicting results. The objective of this study was to evaluate the value of procalcitonin for early diagnosis of intestinal ischemia and necrosis in acute bowel obstruction. METHODS We performed a prospective study of 242 patients with small- or large-bowel obstructions in 2005. A total of 100 patients who underwent operation were divided into groups according to the presence of ischemia (reversible and irreversible) and necrosis, respectively, as follows: ischemia (n = 35) and nonischemia groups (n = 65) and necrosis (n = 22) and nonnecrosis groups (n = 78). Data analyzed included age, sex, vital signs, symptoms, clinical findings, white blood cell count, base deficit, metabolic acidosis, procalcitonin levels on presentation, the time between symptom onset and arrival at the emergency department and the time between arrival and operation, and the cause of the obstruction. RESULTS Procalcitonin levels were greater in the ischemia than the nonischemia group (9.62 vs 0.30 ng/mL; P = .0001) and in the necrosis than the non-necrosis group (14.53 vs 0.32 ng/mL; P = .0001). Multivariate analysis identified procalcitonin as an independent predictor of ischemia (P = .009; odds ratio, 2.252; 95% confidence interval, 1.225-4.140) and necrosis (P = .005; odds ratio, 2.762; 95% confidence interval, 1.356-5.627). Using receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) of procalcitonin for ischemia and necrosis was 0.77 and 0.87, respectively. A high negative predictive value for ischemia and necrosis of procalcitonin levels <0.25 ng/mL (83% and 95%, respectively) and a positive predictive value of procalcitonin >1 ng/mL were identified (95% and 90%, respectively). CONCLUSION Procalcitonin on presentation is very useful for the diagnosis or exclusion of intestinal ischemia and necrosis in acute bowel obstruction and could serve as an additional diagnostic tool to improve clinical decision-making.

Precursors and preinvasive lesions of the breast: the role of molecular prognostic markers in the diagnostic and therapeutic dilemma

Precursors and preinvasive lesions of the breast include atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular neoplasia (LN). There is a significant debate regarding the classification, diagnosis, prognosis and management of these lesions. This review article describes the current theories regarding the pathogenesis and molecular evolution of these lesions. It reviews the implication of a variety of molecules in the continuum of breast lesions: estrogen receptors (ER-alpha and ER-beta), c-erb-B2 (Her2/neu), p53, Ki-67, bcl-2, E-cadherin, transforming growth factor-beta (TGF-beta), p27 (Kip1), p16 (INK4a), p21 (Waf1), vascular endothelial growth factor (VEGF). With respect to the aforementioned molecules, this article reviews their pathophysiological importance, and puts the stress on whether they confer additional risk for invasive breast cancer or not. This knowledge has the potential to be of importance in the therapeutic decisions presenting in the common clinical practice.

Modified Radical Mastectomy With Axillary Dissection Using the Electrothermal Bipolar Vessel Sealing System

HYPOTHESIS The use of the electrothermal bipolar vessel sealing system is feasible, safe, and effective in modified radical mastectomy with axillary dissection in terms of lymph vessel sealing, hemostasis, and perioperative complications. DESIGN Prospective study. SETTING University surgical department. PATIENTS Between January 1, 2003, and December 31, 2003, 60 patients with locally advanced breast cancer (T2 or T3) admitted for modified radical mastectomy with axillary dissection were included in this study. The entire procedure was performed by the same surgical team using the electrothermal bipolar vessel sealing system. MAIN OUTCOME MEASURES Final outcome, operative time, hospitalization stay duration, intraoperative blood loss, postoperative mastectomy and axillary drainage volume and duration, and postoperative complications (seroma, bleeding, skin burn, hematoma, lymphedema, pneumothorax, and wound infection or necrosis). RESULTS The mean (SD) intraoperative blood loss was 45 (12) mL, and the mean (SD) operative time was 105 (7) minutes. No postoperative bleeding, seroma, hematoma, lymphedema, or other complications occurred. The mean (SD) mastectomy and axillary drainage volumes were 20 (8) and 155 (35) mL, respectively, and the mean (SD) drainage durations were 1.3 (0.2) and 2.7 (0.5) days, respectively. The mean (SD) hospital stay was 3.7 (0.6) days. CONCLUSIONS In this first report (to our knowledge) of modified radical mastectomy with axillary dissection using the electrothermal bipolar vessel sealing system, the technique was feasible, safe, and effective. The device simplified the surgical procedure, while achieving efficient lymph vessel sealing and hemostasis. Compared with historical data regarding the conventional or harmonic scalpel, this technique seems to result in reduced operative time, perioperative blood loss, drainage volume and duration, and incidence of seroma or lymphedema. Prospective randomized controlled studies are necessary to evaluate the effect of this technique on perioperative complications.