Living donor liver transplant in Romania – 116 cases experience

Centrul de Chirurgie Generală și Transplant Hepatic “Dan Setlacec”, Institutul Clinic Fundeni, Bucureşti, România, Al XII-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova cu participare internațională 23-25 septembrie 2015Introducere: Cererea pentru transplantul hepatic în Romania este în continuă creștere în timp ce penuria de donatori de organe persistă. Timpul lung de așteptare pentru un transplant de ficat şi disfuncţia hepatică progresivă aferentă așteptării a motivat multe familii să ia în considerare donarea de organe. Material și metode: În anul 2000 a fost realizat primul transplant hepatic ortotopic cu ficat întreg de către echipa I.Popescu et al. la Institutul Clinic Fundeni din Bucureşti, urmat de transplantul de ficat de la donator viu (LDLT) mai târziu în acelaşi an, ajungând în aprilie 2015 la un total de 116 de transplanturi cu ficat de la donator viu. LDLT a fost realizată cu hemificat drept la 78 pacienți, secțiune laterală stânga – la 26 pacienți, hemificat stâng – la 7 pacienți, hemificat stâng în bloc cu segmentul 1 – la 3 pacienți, şi dual graft – la 2 pacienți. Rezultate: Rata de morbidități majore a fost de 53,4% (62 pacienți), rata generală de retransplant a fost de 11,3% (13 pacienți). Rata de supraviețuire generală la 1-, 3-, şi 5 ani a fost de 88,8%, 82,5%, respectiv, 79,2%. Concluzii: Scopul nostru a fost de a reduce rata mortalității pe lista de așteptare prin scurtarea timpului de aşteptare pentru TH prin asigurarea grefelor necesare. Avantajele LDLT includ posibilitatea de a fi efectuate în regim programat şi cu un timp de aşteptare scurt pentru primitor, în timp ce indicaţiile de transplant pot fi extinse (ex: HCC în afara criteriilor Milano).Introduction: The request for Liver Transplant (LT) in Romania continues to increase while the donor pool size remains inadequate. The long waiting time for a liver transplant and the progressive liver dysfunction that occurs in this time has motivated many families to consider living donation. Material and methods: In 2000, the first successful LT (with whole graft) was carried out by I.Popescu et al. at Fundeni Clinical Institute in Bucharest, followed by the first living donor liver transplantation (LDLT) (successful) later the same year, reaching 116 living donors liver transplants by April 2015. LDLT was performed with right hemiliver in 78 pts, left lateral section in 26 pts, left hemiliver in 7 pts, left hemiliver with segment 1 in 3 pts, and dual graft LDLT in 2 pts: one received a right hemiliver and a left lateral section (17), and one received a left hemiliver and a left lateral section. Results: Major morbidity rates were 53.4% (62 pts) Overall retransplantation rate was 11.3% (13 pts). Long-term overall 1-, 3-, and 5- year estimated survival rates were 88.8%, 82.5%, and 79.2%, respective. Conclusions: Our main goal was to continuously reduce the drop-out rate on waiting list (due to mortality and morbidity) by shortening the waiting time for LT insured by providing the necessary grafts. Advantages of LDLT include the ability to be performed on an elective basis, with optimal timing and no waiting time for the recipient, while the indications for transplantation may be extended (i.e. HCC beyond Milan criteria)

15 years of Romanian national program of liver transplant – a retrospective analysis of 648 patients operated

Centrul de Chirurgie Generală şi Transplant Hepatic “Dan Setlacec”, Institutul Clinic Fundeni, Bucureşti, România, Al XII-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova cu participare internațională 23-25 septembrie 2015Introducere: Transplantul hepatic (TH) a devenit metoda de elecție în tratamentul bolilor hepatice în stadiu terminal, cu peste 20.000 de proceduri anuale la nivel mondial. Scopul acestui studiu este de a analiza rezultatele programului de transplant hepatic românesc după 15 ani de activitate. Material și metode: Între aprilie 2000 și aprilie 2015, 648 de pacienți au fost transplantați cu ficat în România. Raportul pe sexe a fost 382 (m) / 266 (f), în timp ce raportul adulți/copii a fost de 588/60, cu o vârstă medie de 45 de ani. Indicațiile principale pentru TH au fost: ciroza de etiologie VHB (176 pct; 27,1%), HCC (128 pct; 19,7%), și ciroza de etiologie VHC (118 pct; 18,2%). Transplantul hepatic de la donator cadaveric a fost efectuat la 532 pacienți (82,1%): 512 pct cu ficat întreg, 16 pct – cu ficat split, 2 pct – cu ficat redus, transplant-domino – la 2 pct. Transplantul de ficat de la donator viu a fost efectuat la 116 pct (17,9%). Rezultate: Mortalitatea perioperatorie a fost de 7,9% (51 pct). Rata de retransplant a fost de 4,6% (30 pct). Supraviețuirea la 1, 3 și 5 ani pe termen lung a fost estimată la 88,8%, 82,5% și respectiv 79,2%. Timpul de așteptare pentru TH a scăzut semnificativ în timp. Mortalitatea pe un an pe lista de așteptare a scăzut semnificativ, de la 31,4% la 11,8%. Concluzii: Programul de transplant hepatic în România se adresează atât cauzelor de insuficiență hepatică acută și cronică, cât și tumorilor hepatice la adulți și copii, fiind folosite toate tehnicile chirurgicale. Amploarea programului a crescut constant în timp, ceea ce a adus la scurtarea timpului și a ratelor de mortalitate pe lista de așteptare.Background: Liver transplantation (LT) is the treatment of choice for end-stage liver diseases, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT after 15 years of activity. Methods: Between April 2000 and April 2015, 648 patients received 678 LTs in Romania. Male/female ratio was 382/266, while adult/pediatric ratio was 588/60, with a mean age range 7 months – 68 yr. Main LT indications in the adult population were HBVrelated cirrhosis (176 pts; 27.1%), hepatocellular carcinoma (128 pts; 19.7%), and HCV-related cirrhosis (118 pts; 18.2%). DDLT (death donor liver transplant) was performed in 532 pts (82.1%): whole LT in 512 pts, split LT in 16 pts, reduced LT in 2 pts, and domino LT in 2 pts. LDLT (living donor liver transplant) was performed in 116 pts (17.9%). Results: Perioperative mortality was 7.9% (51 pts). Retransplantation rate was 4.6% (30 pts). Long-term overall 1-, 3-, and 5- year estimated survival rates were 88.8%, 82.5%, and 79.2%, respectively. Median waiting time for LT decreased significantly over time. One-year overall mortality on waiting list also decreased significantly over time from 31.4% to 11.8%. Conclusions: The liver transplantation program in Romania addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques. The program constantly increased over time, leading to less time and lower mortality rate on the waiting list with the results similar to those of other centers

Pediatric liver transplant in Romania – 60 cases experience

Centrul de Chirurgie Generală şi Transplant Hepatic “Dan Setlacec”, Institutul Clinic Fundeni, Bucureşti, România, Al XII-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova cu participare internațională 23-25 septembrie 2015Introducere: În ultimele două decenii transplantul hepatic pediatric a devenit o soluţie viabilă pentru copiii cu boală hepatică în stadiu terminal. Deşi cazurile pediatrice reprezintă aproximativ 11% din totalul pacienţilor de pe lista de aşteptare din România, utilizarea grefelor de la donator în viață, a grefelor split și a celor reduse a oferit posibilitatea transplantării mai multor pacienţi pediatrici şi adolescenţi, reducând astfel numărul de pacienţi de pe lista de aşteptare şi demonstrând rezultate similare în comparaţie cu transplantul de ficat la adult. Material și metode: Între martie 2004 şi aprilie 2015 un numar de 60 de pacienți pediatrici au fost transplantați hepatic de echipa I.Popescu et al. la Institutul Clinic Fundeni din Bucureşti. Principalele indicaţii pentru transplantul pediatric au fost anomaliile biliare congenitale (atrezie biliară, ductopenie) (12 pacienți; 20%), boala Wilson (11 pacienți; 18,3%), glicogenoză (8 pacienți; 13,3%), şi fibrozele hepatice congenitale (7 pacienți; 11,7%). Rezultate: La copii şi adolescenţi ratele de supraviețuire pe termen lung la 1, 3, şi 5 ani au fost de 91,9%, 88,5%, respectiv 88,5% (0-17 ani). Concluzie: Transplantul de ficat pentru bolile hepatice în stadiul terminal la copii a devenit o soluţie viabilă, donatorul viu fiind principala sursă de grefe hepatice. Avantajele transplantului hepatic de la donator în viață includ posibilitatea de a fi efectuate în regim programat într-un cadru optim şi timp de aşteptare scăzut pentru primitor.Introduction: In the last two decades pediatric liver transplantation became a viable solution for children with End stage liver disease. Although pediatric cases represent about 11% of the total patients on the waiting list in Romania, the utilization of living-related donors livers, cut down “reduced” and split liver grafts has provided more liver grafts for pediatric patients thus reducing the number of the patients on the waiting list and had shown results similar in comparison with adult liver transplant. Material and methods: Between March 2004 and April 2015, 60 children pts were liver transplanted by I.Popescu et al. at Fundeni Clinical Institute in Bucharest. The main indication for transplantation were congenital biliary anomalies (biliary atresia, hypoplasia or ductopenia) (12 pts; 20%), Wilson’s disease (11 pts; 18.3%), glycogenosis (8 pts; 13.3%), and congenital liver fibrosis (7 pts; 11.7%). Results: In pediatric patients, long-term 1-, 3-, and 5-year estimated survival rates were 91.9%, 88.5%, and 88.5% (0-17 yrs). Conclusion: Liver transplant for end stage liver disease in children has became a viable curative solution, living donor liver transplant being the main source of liver grafts

Mitochondrial permeabilization engages NF-kappa B-dependent anti-tumour activity under caspase deficiency

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies

Generalized cerebral atrophy seen on MRI in a naturally exposed animal model for creutzfeldt-jakob disease

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance imaging has been used in the diagnosis of human prion diseases such as sCJD and vCJD, but patients are scanned only when clinical signs appear, often at the late stage of disease. This study attempts to answer the questions "Could MRI detect prion diseases before clinical symptoms appear?, and if so, with what confidence?"</p> <p>Methods</p> <p>Scrapie, the prion disease of sheep, was chosen for the study because sheep can fit into a human sized MRI scanner (and there were no large animal MRI scanners at the time of this study), and because the USDA had, at the time of the study, a sizeable sample of scrapie exposed sheep, which we were able to use for this purpose. 111 genetically susceptible sheep that were naturally exposed to scrapie were used in this study.</p> <p>Results</p> <p>Our MRI findings revealed no clear, consistent hyperintense or hypointense signal changes in the brain on either clinically affected or asymptomatic positive animals on any sequence. However, in all 37 PrP^Scpositive sheep (28 asymptomatic and 9 symptomatic), there was a greater ventricle to cerebrum area ratio on MRI compared to 74 PrP^Scnegative sheep from the scrapie exposed flock and 6 control sheep from certified scrapie free flocks as defined by immunohistochemistry (IHC).</p> <p>Conclusions</p> <p>Our findings indicate that MRI imaging can detect diffuse cerebral atrophy in asymptomatic and symptomatic sheep infected with scrapie. Nine of these 37 positive sheep, including 2 one-year old animals, were PrP^Scpositive only in lymph tissues but PrP^Scnegative in the brain. This suggests either 1) that the cerebral atrophy/neuronal loss is not directly related to the accumulation of PrP^Scwithin the brain or 2) that the amount of PrP^Scin the brain is below the detectable limits of the utilized immunohistochemistry assay. The significance of these findings remains to be confirmed in human subjects with CJD.</p

Let-7 MicroRNA Family Is Selectively Secreted into the Extracellular Environment via Exosomes in a Metastatic Gastric Cancer Cell Line

Background: Exosomes play a major role in cell-to-cell communication, targeting cells to transfer exosomal molecules including proteins, mRNAs, and microRNAs (miRNAs) by an endocytosis-like pathway. miRNAs are small noncoding RNA molecules on average 22 nucleotides in length that regulate numerous biological processes including cancer pathogenesis and mediate gene downregulation by targeting mRNAs to induce RNA degradation and/or interfering with translation. Recent reports imply that miRNAs can be stably detected in circulating plasma and serum since miRNAs are packaged by exosomes to be protected from RNA degradation. Thus, profiling exosomal miRNAs are in need to clarify intercellular signaling and discover a novel disease marker as well. Methodology/Principal Findings: Exosomes were isolated from cultured cancer cell lines and their quality was validated by analyses of transmission electron microscopy and western blotting. One of the cell lines tested, a metastatic gastric cancer cell line, AZ-P7a, showed the highest RNA yield in the released exosomes and distinctive shape in morphology. In addition, RNAs were isolated from cells and culture media, and profiles of these three miRNA fractions were obtained using microarray analysis. By comparing signal intensities of microarray data and the following validation using RT-PCR analysis, we found that let-7 miRNA family was abundant in both the intracellular and extracellular fractions from AZ-P7a cells, while low metastatic AZ-521, the parental cell line of AZ-P7a, as well as other cancer cell lines showed no such propensity. Conclusions/Significance: The enrichment of let-7 miRNA family in the extracellular fractions, particularly, in the exosome

Anti-angiogenic effect of high doses of ascorbic acid

Pharmaceutical doses of ascorbic acid (AA, vitamin C, or its salts) have been reported to exert anticancer activity in vitro and in vivo. One proposed mechanism involves direct cytotoxicity mediated by accumulation of ascorbic acid radicals and hydrogen peroxide in the extracellular environment of tumor cells. However, therapeutic effects have been reported at concentrations insufficient to induce direct tumor cell death. We hypothesized that AA may exert anti-angiogenic effects. To test this, we expanded endothelial progenitor cells (EPCs) from peripheral blood and assessed, whether or not high dose AA would inhibit EPC ability to migrate, change energy metabolism, and tube formation ability. We also evaluated the effects of high dose AA on angiogenic activities of HUVECs (human umbilical vein endothelial cells) and HUAECs (human umbilical arterial endothelial cells). According to our data, concentrations of AA higher than 100 mg/dl suppressed capillary-like tube formation on Matrigel for all cells tested and the effect was more pronounced for progenitor cells in comparison with mature cells. Co-culture of differentiated endothelial cells with progenitor cells showed that there was incorporation of EPCs in vessels formed by HUVECs and HUAECs. Cell migration was assessed using an in vitro wound healing model. The results of these experiments showed an inverse correlation between AA concentrations relative to both cell migration and gap filling capacity. Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects. This study supports further investigation into non-cytotoxic antitumor activities of AA

Cellular therapies for treating pain associated with spinal cord injury

Spinal cord injury leads to immense disability and loss of quality of life in human with no satisfactory clinical cure. Cell-based or cell-related therapies have emerged as promising therapeutic potentials both in regeneration of spinal cord and mitigation of neuropathic pain due to spinal cord injury. This article reviews the various options and their latest developments with an update on their therapeutic potentials and clinical trialing