Dana Tomescu

Assessment of Gene Expression Profiles in Peripheral Occlusive Arterial Disease

BACKGROUND Molecular events responsible for the onset and progression of peripheral occlusive arterial disease (POAD) are incompletely understood. Gene expression profiling may point out relevant features of the disease. METHODS Tissue samples were collected as operatory waste from a total of 36 patients with (n = 18) and without (n = 18) POAD. The tissues were histologically evaluated, and the patients with POAD were classified according to Leriche-Fontaine (LF) classification: 11% with stage IIB, 22% with stage III, and 67% with stage IV. Total RNA was isolated from all samples and hybridized onto Agilent 4×44K Oligo microarray slides. The bioinformatic analysis identified genes differentially expressed between control and pathologic tissues. Ten genes with a fold change ≥ 2 (1 with a fold change ≥ 1.8) were selected for quantitative polymerase chain reaction validation (GPC3, CFD, GDF10, ITLN1, TSPAN8, MMP28, NNMT, SERPINA5, LUM, and FDXR). C-reactive protein (CRP) was assessed with a specific assay, while nicotinamide N-methyltransferase (NNMT) was evaluated in the patient serum by enzyme-linked immunosorbent assay. RESULTS A multiple regression analysis showed that the level of CRP in the serum is correlated with the POAD LF stages (r(2) = 0.22, P = 0.046) and that serum NNMT is higher in IV LF POAD patients (P = 0.005). The mRNA gene expression of LUM is correlated with the LF stage (r(2) = 0.45, P = 0.009), and the mRNA level of ITLN1 is correlated with the ankle-brachial index (r(2) = 0.42, P = 0.008). CONCLUSIONS Our analysis shows that NNMT, ITLN1, LUM, CFD, and TSPAN8 in combination with other known markers, such as CRP, could be evaluated as a panel of biomarkers of POAD.

First report of cytokine removal using CytoSorb® in severe noninfectious inflammatory syndrome after liver transplantation

Introduction Emergency transplantation of a donor liver that is not matched for the major blood antigens can produce marked immune-mediated cytokine release that can cause donor graft loss. Control of the inflammatory response may be a key element in treatment. Methods We present the case of a 46-year-old man with primary graft nonfunction after liver transplantation who underwent emergency retransplantation with an ABO-incompatible graft. A severe inflammatory response syndrome (SIRS) was noted in the perioperioperative period of retransplantation. The patient was successfully treated for this condition with a new hemoadsorption column (CytoSorb®), in combination with continuous venovenous hemofiltration (CVVH) throughout the intraoperative and early postoperative period. Results During and after each treatment a significant and rapid decrease of pro- and anti-inflammatory cytokines was observed, especially for interleukin-6 (IL-6), IL-10 and monocyte chemotactic protein 1 (MCP-1). Reduction of cytokines was associated with normalization of cardiac output and systemic vascular resistance, and improved liver function. Conclusions We believe this is the first case in which hemoadsorptionin combination with CVVH has been used to manage SIRS in a patient with primary graft nonfunction undergoing emergency retransplantation.

Living Donor Liver Transplantation for Unresectable Liver Adenomatosis Associated with Congenital Absence of Portal Vein: A Case Report and Literature Review

Patient: Female, 21 Final Diagnosis: Unresectable liver adenomatosis associated with congenital absence of portal vein Symptoms: — Medication: — Clinical Procedure: Living donor liver transplantation Specialty: Transplantology Objective: Rare disease Background: Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. Case Report: We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. Conclusions: We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter.

Rapid Recovery of Liver Transplantation Recipients by Implementation of Fast-Track Care Steps: What Is Holding Us Back?

A body of scientific studies has shown that early extubation is safe and cost-effective in a large number of liver transplant (LT) recipients including pediatric patients. However, fast-track practices are not universally accepted, and debate still lingers about whether these interventions are safe and serve the patients’ best interest. In this article, we focus on reasons why physicians still have a persistent, although diminishing, reluctance to adopt fast-track protocols. We stress the importance of collection/analysis of perioperative data, adoption of a consensus-based standardized protocol for perioperative care, and formation of LT anesthesia focused teams and leadership. We conclude that the practice of early extubation and fast-tracking after LT surgery could help improve anesthesia performance, safety, and cost-effectiveness.

Prothrombotic State in a Patient With Acute Liver Failure: The Question of Anticoagulation

A 35-year-old male with acute liver failure due to acute hepatitis B virus infection was admitted to the intensive care unit with significant hepatocellular injury, cholestasis, abnormal standard coagulation tests, normal rotational thromboelastometry indices, and without signs of bleeding. He underwent emergency liver transplantation without requiring blood product transfusions or procoagulant treatments. The postoperative course was complicated by deep vein thrombosis and impending hepatic artery thrombosis treated with unfractionated heparin, aspirin, and intravenous prostacyclin. The patient survived and made a full neurological recovery. This case revealed the presence of a prothrombotic state due to a rebalanced coagulation system in a patient with liver dysfunction that was not identifiable by standard coagulation tests. This case emphasizes that identifying and treating coagulopathy is very difficult in liver failure patients and requires specific diagnostic and therapeutic strategies.

Resection of Concomitant Hepatic and Extrahepatic Metastases from Colorectal Cancer - A Worthwhile Operation?

Background: The benefit of hepatic resection in case of concomitant colorectal hepatic and extrahepatic metastases (CHEHMs) is still debatable. The purpose of this study is to assess the results of resection of hepatic and extrahepatic metastases in patients with CHEHMs in a high-volume center for both hepatobiliary and colorectal surgery and to identify prognostic factors that correlate with longer survival in these patients. METHOD It was performed a retrospective analysis of 678 consecutive patients with liver resection for colorectal cancer metastases operated in a single Centre between April 1996 and March 2016. Among these, 73 patients presented CHEHMs. Univariate analysis was performed to identify the risk factors for overall survival (OS) in these patients. Results: There were 20 CHMs located at the lymphatic node level, 20 at the peritoneal level, 12 at the ovary and lung level, 12 presenting as local relapses and 9 other sites. 53 curative resections (R0) were performed. The difference in overall survival between the CHEHMs group and the CHMs group is statistically significant for the entire groups (p 0.0001), as well as in patients who underwent R0 resection (p 0.0001). In CHEHMs group, the OS was statistically significant higher in patients who underwent R0 resection vs. those with R1/R2 resection (p=0.004). Three variables were identified as prognostic factors for poor OS following univariate analysis: 4 or more hepatic metastases, major hepatectomy and the performance of operation during first period of the study (1996 - 2004). There was a tendency toward better OS in patients with ovarian or pulmonary location of extrahepatic disease, although the difference was not statistically significant. CONCLUSION In patients with concomitant hepatic and extrahepatic metastases, complete resection of metastatic burden significantly prolong survival. The patients with up to 4 liver metastases, resectable by minor hepatectomy benefit the most from this aggressive onco-surgical management.

Effects of Fibrinogen Levels and Platelet Counts on Viscoelastic Testing in Cirrhotic Patients

Abstract Introduction. Cirrhotic patients have been considered for decades to have a pro-haemorrhagic pattern and were treated as such based on the results from standard coagulation tests. The aim of our study was to determine the effects of platelet count and fibrinogen levels on rotational thromboelastometry (ROTEM) parameters. Methods. We prospectively included 176 patients with End-Stage Liver Disease (ESLD) admitted to our Intensive Care Unit prior to liver transplantation. Collected data consisted of severity scores, liver, renal and standard coagulation tests, fibrinogen levels, platelet counts and ROTEM parameters. Four ROTEM assays were performed (ExTEM, InTEM, ApTEM and FibTEM) and the following parameters included: CT – clotting time, CFT – clot formation time, MCF – maximum clot firmness, ML – maximum lysis, alpha angle, TPI – thrombin potential index, MaxV - maximum velocity of clot formation (MaxV), MaxVt - time to MaxV, MCE - maximum clot elasticity and AUC - area under the curve. Results. Statistical analysis demonstrated a linear correlation between platelet counts and ExTEM TPI (R2 linear =0.494), ExTEM MaxV (R2 linear =0.253), ExTEM MCE (R2 linear = 0.351) and ExTEM MCF (R2 cubic = 0.498). Fibrinogen levels correlated linearly with ExTEM MCF (R2 linear = 0.426), ExTEM TPI (R2 linear = 0.544), ExTEM MaxV (R2 linear = 0.332), ExTEM MCE (R2 linear = 0.395) and non-linearly with ExTEM CFT (R2 cubic = 0.475). Conclusion. Fibrinogen levels and platelet counts had an important effect on both standard and derived ROTEM parameters. Further analysis is required in order to determine clinically oriented cut-off values below which severe coagulopathy would develop.

Perioperative Stress-Induced (Takotsubo) Cardiomyopathy in Liver Transplant Recipients

Abstract A comprehensive analysis of published cases of Takotsubo cardiomyopathy, occurred in liver transplant recipients in the perioperative period, has been attempted in this review. Predisposing factors, precipitating events, potential physiological mechanisms, acute and post-event management have been discussed.

Intraoperative Ultrasound Guided Liver Resections: A Single Center Experience

Background: Liver resection (LR) is the standard treatment for most focal liver lesions. Intraoperative ultrasound (IOUS) improves their diagnosis and guides the liver resection. The present paper analyses our experience in IOUS guided LR, reviewing the indications, surgical techniques, and the short-term results. Material and Method: 198 LRs guided by IOUS in 186 patients operated in our center between January 2013 and December 2017 were included in a combined prospective and retrospective study. The median age of the patients was 60 years (mean 57, range 16-79), with a male/female ratio of 109/77, and adult/pediatric patient ratio of 185/1. Results: Malignant lesions were the main indication for IOUS guided LR (164 LRs; 82.8%); among these, colorectal liver metastases were the main indication (66 LRs; 33.3%), followed by hepatocellular carcinoma (44 cases, 22.2%). The mean number of tumors was 3 (range 1-16), and the median diameter of the largest tumor was 40 mm (mean 51; range 3-240). IOUS found new lesions in 22.3% of cases operated for liver metastases (46 LRs), and changed the surgical strategy in 41.9% of cases (83 LRs). Major resection rate was 18.2% (36 LRs); anatomical LRs were performed in 18 cases (9.1%). The median operative time was 330 minutes (mean 334; range 90-920). The median blood loss was 700 ml (mean 900; range 250-9500), with a transfusion rate of 54.8% (108 LRs). Overall and major complication rates were 46.5% (92 LRs) and 7.6% (15 LRs), respectively, while the mortality rate was 2% (4 pts). Conclusion: IOUS should be fully integrated in the modern liver surgery, providing improved diagnosis and optimal resection guidance, increasing resectability and surgical safety, with low perioperative morbidity and mortality.

Let’s Talk About Sepsis

The current definition of sepsis is based on comparatively contemporary knowledge. However, the disease process is not fully understood and treatment still profoundly challenging. Definitions and guidelines have changed over the recent years, and clinicians are always interested to know what the new and current thoughts on the subject are. Many papers have been published in the medical press, reporting on definitions, scores, models, cytokines, therapies, new trends, statistics, campaigns, including a sepsis anniversary day-which is not celebrating but fighting against sepsis. Together they signify the enormous interest in the subject. The American College of Chest Physicians and the Society of Critical Care Medicine met in 1992 and gave the first definition of sepsis and associated organ failure [1]. Eleven years later, American intensivists met European intensivists to evaluate if there was a need for a new definition of sepsis [2]. In 2016 a new and second definition of sepsis was proposed which stated that “sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs” [3]. This new definition better illustrates the fact that when we talk about sepsis, we referring to the body’s inadequate response to an infection. In effect, the body injures its own tissues and organs in a fight to overcome an “enemy”, resulting in self-destruction. Several models, aimed at understanding sepsis, have been proposed. I think the predisposition, insult, response, organ dysfunction concept (PIRO) that stages sepsis in a similar manner to the tumour, nodes, metastasis (TNM) cancer staging is of interest [4]. This is an exciting perspective, as the sepsis process is described as a dynamic one, with an extension degree that finally affects organs and ultimately results in death. The model involves compiling a complex picture of the patients, taking into account variables present before the insult, genetic factors, co-morbidities and age. Moreover, the host’s response is assessed with regard to all clinical features of sepsis, [5] including the presence of damage/danger-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), resolution-associated molecular patterns (RAMPs), numerous biomarkers [6,7], specific and non-specific pathways of inflammation. Using such a model, the physician is assisted in assessing the probable effects on organs which may result in failure, death or resolution. The insult or infection is also extensively expressed in order to target appropriate therapy as soon and as efficiently as possible. The interesting fact is that a lot of novel genetic predisposing factors have been discovered, and future development in the field of genomics and proteomics are subject to further research [8]. Another interesting model that leads to a better understanding of sepsis is the persistent inflammation, immunosuppression, and catabolism syndrome, or PICS concept [9-11]. This model is also dynamic, as it indicates a fluid pathway that that can progress to an adequate host response with resolution of the injury, or to death subsequent to an inadequate host response. The novel concept, embedded in this model, is a predictable, rapid unfavourable fatal outcome occurs rapidly if the insult is severe and the host response is inadequate. However, with most patients seen in an intensive care unit (ICU) death is insidious and occurs when clinicians were hoping to save the patient. The last category of patients have a prolonged ICU stay, suffering multiple infectious episodes, a baseline elevated chronic and persistent inflammatory state, cachexia and sarcopenia, with wounds that do not heal. They typically require a degree of organ support. I will not elaborate on the inflammatory process per se. However, sepsis affects practically all aspects of endothelial cell (EC) function and the inflammatory process targets the endothelium that is altered in sepsis [12]. This is considered to be the critical factor in