Ioannis D. Kostakis

Colorectal Cancer Stem Cells

Colorectal cancer (CRC) is one of the most commonly diagnosed and lethal cancers worldwide. It is a multistep process that requires the accumulation of genetic/epigenetic aberrations. There are several issues concerning colorectal carcinogenesis that remain unanswered, such as the cell of origin and the type of cells that propagate the tumor after its initiation. There are two models of carcinogenesis: the stochastic and the cancer stem cell (CSC) model. According to the stochastic model, any kind of cell is capable of initiating and promoting cancer development, whereas the CSC model suggests that tumors are hierarchically organized and only CSCs possess cancer‐promoting potential. Moreover, various molecular pathways, such as Wingless/Int (Wnt) and Notch, as well as the complex crosstalk network between microenvironment and CSCs, are involved in CRC. Identification of CSCs remains controversial due to the lack of widely accepted specific molecular markers. CSCs are responsible for tumor relapse, because conventional drugs fail to eliminate the CSC reservoir. Therefore, the design of CSC‐targeted interventions is a rational target, which will enhance responsiveness to traditional therapeutic strategies and reduce local recurrence and metastasis. This review discusses the implications of the newly introduced CSC model in CRC, the markers used up to now for CSC identification, and its potential implications in the design of novel therapeutic approaches. STEM CELLS 2012;30:363–371

The Role of Calprotectin in Pediatric Disease

Calprotectin (CP) is a calcium- and zinc-binding protein of the S100 family expressed mainly by neutrophils with important extracellular activity. The aim of the current review is to summarize the latest findings concerning the role of CP in a diverse range of inflammatory and noninflammatory conditions among children. Increasing evidence suggests the implication of CP in the diagnosis, followup, assessment of relapses, and response to treatment in pediatric pathological conditions, such as inflammatory bowel disease, necrotizing enterocolitis, celiac disease, intestinal cystic fibrosis, acute appendicitis, juvenile idiopathic arthritis, Kawasaki disease, polymyositis-dermatomyositis, glomerulonephritis, IgA nephropathy, malaria, HIV infection, hyperzincemia and hypercalprotectinemia, and cancer. Further studies are required to provide insights into the actual role of CP in these pathological processes in pediatrics.

The role of calprotectin in obstetrics and gynecology

The purpose of this article is to create the first complete review concerning the role of calprotectin, a calcium- and zinc-binding protein of the S100/calgranulins family, in obstetrics and gynecology. A Medline search was conducted between 6 and 8 June 2009 using the term calprotectin and its synonyms combined with the following ones: calprotectin, obstetrics and gynecology, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, menstrual cycle, pregnancy, fetal implantation, labor, intra-amniotic inflammation, preeclampsia, HELLP syndrome, Rh(-) incompatibility. We found 46 studies which referred to obstetrics and gynecology. We excluded 11 studies which referred to obstetrics and gynecology but did not include enough information about calprotectin, and another two which referred to calprotectin but were not related to subjects of obstetrics and gynecology. Thus, we ended up with 33 studies which contained sufficient information to extract data for this review. All the articles were written in English. It was found that calprotectin is associated with many physiologic and pathologic processes in obstetrics and gynecology, such as: breast cancer, ovarian cancer, endometrial cancer, cervical cancer, cervical and vaginal physiology, menstrual cycle, pregnancy and labor. The role of calprotectin in these conditions is significant. In conclusion, the role of calprotectin seems to be important in several issues of obstetrics and gynecology. For example, calprotectin could be used as a diagnostic, prognostic or metastatic marker in several types of cancer, as a marker of inflammation and as a pharmaceutical target in many conditions. Further studies must be conducted to elucidate this role.

Comparison Between Minimally Invasive and Open Pancreaticoduodenectomy: A Systematic Review.

Introduction: Minimally invasive approaches (laparoscopic or robotic) are used in various operations. Our aim was to compare them with the open approach in pancreaticoduodenectomy. Methods: We conducted a search for articles published in MEDLINE database comparing minimally invasive (laparoscopic or robotic) with open pancreaticoduodenectomy on June 15, 2014. Results: Our search yielded 136 articles. We excluded 122 articles and we took into consideration 14 (10 for laparoscopic and 4 for robotic pancreaticoduodenectomies). Most cases were related to malignant diseases and tumors treated with minimally invasive operations tended to be smaller. There were relatively high conversion rates in both laparoscopic (0% to 15%) and robotic procedures (4.5% to 10%). There were no significant differences regarding resection margins, rates of pancreatic fistula formation, bile leak, and delayed gastric emptying, reoperation rates, and intraoperative and postoperative mortality. On the contrary, blood loss was less in minimally invasive than open operations, although this difference was not always significant. Moreover, totally laparoscopic and robotic procedures lasted longer than the open ones, whereas hand-assisted laparoscopic procedures did not. However, the findings regarding the number of the retrieved lymph nodes, the length of hospital stay, and costs were inconclusive and controversial. Conclusions: Laparoscopic and robotic pancreaticoduodenectomy are feasible, safe, and oncologically equivalent alternatives to open pancreaticoduodenectomy. Minimally invasive operations have the advantage of the less blood loss, but totally laparoscopic and robotic procedures last longer than open procedures.

Calprotectin: a protein related to cardiovascular risk in adult patients with obstructive sleep apnea.

INTRODUCTION Increased levels of inflammatory mediators, such as hs-CRP, have been detected in patients with obstructive sleep apnea (OSA) and used as cardiovascular risk and disease outcome predictors. Calprotectin is an inflammatory marker regulating atherogenic processes not investigated in adult OSA patients. The aim of the present study as primary objective was to examine the role of calprotectin as an inflammatory molecule, acting through a distinct pathway to the atherogenic process in adult OSA patients and its associations with hs-CRP and the lipidemic profile of the patients. As a secondary objective was the evaluation of the atherogenic markers post-CPAP treatment. MATERIALS AND METHODS Seventy-four participants underwent full overnight polysomnography. Blood samples were collected for calprotectin, hs-CRP, total cholesterol, triglycerides, LDL, HDL and glucose levels. Thirty-two OSA patients were reexamined 6 months post-CPAP treatment. RESULTS Out of 74 participants included in the study, 33 had moderate OSA, 27 had severe OSA and 14 were controls. Calprotectin and hs-CRP were significantly increased in patients with moderate and severe OSA compared to controls (p<0.0001). Calprotectin and hs-CRP levels were positively correlated with apnea-hypopnea index, BMI and total time of sleep with SaO(2)<90% and inversely correlated with SaO(2) minimum and mean values. Calprotectin and hs-CRP levels were significantly improved post-CPAP treatment (p<0.0001). DISCUSSION Calprotectin may serve as a novel and reliable, biomarker of cardiovascular risk severity in OSA patients. The decrease of calprotectin levels post-CPAP treatment combined with hs-CRP amelioration could provide evidence for reduction of cardiovascular risk post CPAP treatment.

Targeting transcription factor corepressors in tumor cells.

By being the “integration” center of transcriptional control as they move and target transcription factors, corepressors fine-tune the epigenetic status of the nucleus. Many of them utilize enzymatic activities to modulate chromatin through histone modification or chromatin remodeling. The clinical and etiological relevance of the corepressors to neoplastic growth is increasingly being recognized. Aberrant expression or function (both loss and gain of) of corepressors has been associated with malignancy and contribute to the generation of transcriptional “inflexibility” manifested as distorted signaling along certain axes. Understanding and predicting the consequences of corepressor alterations in tumor cells has diagnostic and prognostic value, and also have the capacity to be targeted through selective epigenetic regimens. Here, we evaluate corepressors with the most promising therapeutic potential based on their physiological roles and involvement in malignant development, and also highlight areas that can be exploited for molecular targeting of a large proportion of clinical cancers and their complications.

Impact of donor and recipient age difference on long-term allograft survival after living donor renal transplantation: analysis of 478 cases

Either deceased or living‐related renal transplantation constitutes the best therapeutic option for patients with end‐stage renal disease. In this retrospective study, an attempt to identify parameters that affect allograft survival in living donor renal transplantation was made.

Laparoscopic versus open liver resection for hepatocellular carcinoma: initial experience in Greece

Background Liver resection represents the treatment of choice for a small proportion of patients with hepatocellular carcinoma (HCC), amenable to surgery. The remarkable evolution in surgical techniques during the last decades introduced laparoscopic hepatectomy in the operative management of HCC, even in the presence of liver cirrhosis. No comparative study on laparoscopic or open liver resection for HCC has been conducted in Greece yet. Methods Patients undergoing liver resection for HCC by one senior hepatobiliary surgeon in our Institution during the period 11/2011-02/2016 were prospectively sampled and retrospectively analyzed for the purposes of this study. Statistical analysis encompassed Student’s t-test, Fisher’s exact test, the Kaplan-Meier method/log rank test and Cox proportional hazard regression analyses. Results Eleven patients underwent laparoscopic and 21 open liver resection, respectively. Statistical differences between the 2 groups were observed for tumor size (P=0.04), major resections (P=0.01), Pringle maneuver (P=0.008), intraoperative blood transfusion (P=0.03), and duration of operation (P=0.004). Resection margins, and tumor recurrence showed no statistical differences. Three-year postoperative survival after laparoscopic and open hepatectomy was 100%, and 67%, respectively (P=0.06). Regression analysis for patient survival revealed prognostic value for BCLC staging, γ-glutamyl transferase levels, laparoscopic hepatectomy, UICC stage, Dindo-Clavien classification, and hospital stay. Laparoscopic hepatectomy remained as independent predictor of survival by multivariate analysis (P=0.0142). Conclusion Laparoscopic hepatectomy for HCC in chronic liver disease represents a safe and innovative treatment tool in the management of these patients under the presupposition of careful patient selection.

Preoperative serum lactate dehydrogenase levels in colorectal and gastric cancer: a hospital-based case-control study

AIM To reveal correlations between serum lactate dehydrogenase (LDH) levels and various clinicopathological parameters in colorectal and gastric cancer. MATERIALS & METHODS A hospital-based case-control study was conducted by measuring serum LDH levels in 140 patients with colorectal cancer, 40 patients with gastric cancer and 20 hospital controls. RESULTS LDH levels did not differ between patients with colorectal or gastric cancer and hospital controls. In colorectal cancer, LDH values were significantly higher in T4, N2 and/or M1 cases, with high specificities and negative predictive values, but low sensitivities and positive predictive values. On the other hand, there were no significant associations in gastric cancer. CONCLUSION Serum LDH levels are increased in T4, N2 and/or M1 colorectal cancer. Most patients with early-stage cancer have normal LDH values, whereas in advanced stages, some patients have increased LDH values and others have normal values.

Syndromes of impaired ion handling in the distal nephron: pseudohypoaldosteronism and familial hyperkalemic hypertension.

The distal nephron, which is the site of the micro-regulation of water absorption and ion handling in the kidneys, is under the control of aldosterone. Impairment of the mineralocorticoid signal transduction pathway results in resistance to the action of aldosterone and of miner-alocorticoids in general. Herein, we review two syndromes in which ion handling in the distal nephron is impaired: pseudohypoaldosteronism (PHA) and familial hyperkalemic hypertension (FHH). PHA is a rare inherited syndrome characterized by mineralocorticoid resistance, which leads to salt loss, hypotension, hyperkalemia and metabolic acidosis. There are two types of this syndrome: a renal (autosomal dominant) type due to mutations of the mineralocorticoid receptor (MR), and a systemic (autosomal recessive) type due to mutations of the epithelial sodium channel (ENaC). There is also a transient form of PHA, which may be due to urinary tract infections, obstructive uropathy or several medications. FHH is a rare autosomal dominant syndrome, characterized by salt retention, hypertension, hyperkalemia and metabolic acidosis. In FHH, mutations of WNK (with-no-lysine kinase) 4 and 1 alter the activity of several ion transportation systems in the distal nephron. The study of the pathophysiology of PHA and FHH greatly elucidated our understanding of the renin-angiotensin-aldosterone system function and ion handling in the distal nephron. The physiological role of the distal nephron and the pathophysiology of diseases in which the renal tubule is implicated may hence be better understood and, based on this understanding, new drugs can be developed.