Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies.

2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 1 was used as the precursor for the synthesis of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2. The latter was alkylated with different alkylating agents to produce the S-alkylated products 3-6. Galactosylation of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2 produces a mixture of S- and N-galactosides 8 and 9. The hydrazide 1 is converted to azide 10, coupled with glycine methyl ester hydrochloride and a set of amines to produce the target coupled amides 11-15. New compounds were assigned using NMR and elemental analysis. Compound 12 had potent cytotoxicity with IC50 values of 0.5 and 5.27 µM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC50: 2.14 and 2.48 µM for the mentioned cell lines, respectively. Regarding the molecular target, compound 12 exhibited potent PIM-1 inhibition activity with 97.5% with an IC50 value of 14.3 nM compared to Staurosporine (96.8%, IC50 = 16.7 nM). Moreover, compound 12 significantly activated apoptotic cell death in MCF-7 cells, increasing the cell population by total apoptosis by 33.43% (23.18% for early apoptosis and 10.25% for late apoptosis) compared to the untreated control group (0.64%), and arresting the cell cycle at S-phase by 36.02% compared to control 29.12%. Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells.

Cancer is the most severe disease worldwide. Every year, tens of millions of people are diagnosed with cancer, and over half of those people will ultimately die from the disease. Hence, the discovery of new inhibitors for fighting cancer is necessary. As a result, new indolyl-triazole hybrids were synthesized to target breast and liver cancer cells. The synthetic strategy involves glycosylation of the 4-aryltriazolethiones 3a-b with acetyl-protected α-halosugars in the presence of K2CO3 in acetone to give a mixture of ß-S-glycosides 6a-b, 7a-b, and ß-N-glycosides 8a-b, 9a-b. Chemo-selective S-glycosylation was achieved using NaHCO3 in ethanol. The migration of glycosyl moiety from sulfur to nitrogen (S → N glycosylmigration) was achieved thermally without any catalyst. Alkylation of the triazole-thiones with 2-bromoethanol and 1-bromopropan-2-ol in the presence of K2CO3 yielded the corresponding S-alkylated products. The synthesized compounds were tested for their cytotoxicity using an MTT assay and for apoptosis induction targeting PARP-1 and EGFR. Compounds 12b, 13a, and 13b exhibited cytotoxic activities with promising IC50 values of 2.67, 6.21, 1.07 µM against MCF-7 cells and 3.21, 8.91, 0.32 µM against HepG2 cells compared to Erlotinib (IC50 = 2.51, 2.91 µM, respectively) as reference drug. Interestingly, compounds 13b induced apoptosis in MCf-7 and HepG2 cells, arresting the cell cycle at the G2/M and S phases, respectively. Additionally, the dual enzyme inhibition seen in compound 13b against EGFR and PARP-1 is encouraging, with IC50 values of 62.4 nM compared to Erlotinib (80 nM) and 1.24 nM compared to Olaparib (1.49 nM), respectively. The anticancer activity was finally validated using an in vivo SEC-cancer model; compound 13b improved both hematological and biochemical analyses inhibiting tumor proliferation by 66.7% compared to Erlotinib's 65.7%. So, compound 13b may serve as a promising anticancer activity through dual PARP-1/EGFR target inhibition.

Successful use of venous graft from native liver with hepatocellular carcinoma during living donor liver transplantation with no impact on recurrence rate: A retrospective cohort study.

Introduction: There are still debates regarding using portal vein (PV) from liver with hepatocellular carcinoma (HCC) for vascular reconstruction. This study aimed to assess the feasibility and patency of PV venous graft from an explanted liver with HCC for the reconstruction of the hepatic veins tributaries or PV in living donor liver transplantation (LDLT) and to see if it has any risk on recurrence of HCC. Patient and methods: We conducted a retrospective study on 81 patients with HCC who underwent LDLT from April 2004 to July 2022. Results: Venous graft from native liver PV was used for vascular reconstruction in 31 patients as follows; reconstruction of V5 in 7 patients, V8 in 4 patients, V6 in 3 patients, combined V5 and V8 in 4 patients, V6 with V5/V8 in 5 patients, and as Y shape venous graft for 2 PV reconstruction in 8 patients. The implantation of the new conduit PV graft after reconstruction of the anterior sector tributaries was direct to the IVC in 8 patients, and to the common orifice of the left and middle hepatic veins in 12 patients. The 1 month, 3 months, and 1-year overall patency of the venous graft was 93.5%, 90.3%, and 84%, respectively. Nine patients had recurrent HCC. In multivariate analysis, the independent risk factors for HCC recurrence were AFP >400 ng/mL (HR = 1.47, 95% CI: 1.69-2.31, P = 0.01), moderate/poor differentiated tumor (HR = 3.06, 95% CI: 2.58-6.29, P = 0.02), and microvascular invasion (HR = 2.51, 95% CI: 1.05-1.93, P = 0.01). Using a PV venous graft had no risk factor for HCC recurrence (P = 0.9). Conclusion: The use of PV venous graft of native liver with HCC for venous reconstruction is a feasible and valuable option in LDLT with good patency rates and no risk of HCC recurrence.

Pediatric living donor liver transplantation (LDLT): Short- and long-term outcomes during sixteen years period at a single centre- A retrospective cohort study.

Background and objectives: Pediatric living donor liver transplantation (LDLT) is an effective tool for managing pediatric patients with end-stage liver disease (ESLD) with good long-term graft and patient survival, especially after improvement in peri-operative care, surgical tools and techniques; however, the morbidity and mortality after such a procedure are still a challenging matter. The study aimed to analyze short-and long-term outcomes after pediatric LDLT in a single centre. Methods: We retrospectively analyzed 67 pediatric patients who underwent LDLT in the period from April 2003 to July 2018. The overall male/female ratio was 40/27. Results: Forty-one (61.2%) of patients had ≥1 early and/or late morbidities; the early (less than 3months) and late (≥3months) ones affected 36(53.7%) and 12(17.9%) of them respectively. The 16-year graft and patient survivals were 35(52.2%) while early and late mortalities were 23(34.3%) and 9(13.4%) respectively. Sepsis and chronic rejection were the most frequent causes of early and late mortalities respectively. Moreover, more packed RBCs transfusion units, bacterial infections, and pulmonary complications were independent predictors of poor patient survival. Conclusions: More packed RBCs transfusion units intra-operatively, and post-liver transplant (LT) bacterial infection, sepsis, chronic rejection, as well as pulmonary complications had a negative insult on our patients' outcomes, so proper management of them is mandatory for improving outcomes after pediatric LDLT.

Biliary complications after adult to adult right-lobe living donor liver transplantation (A-ARLLDLT): Analysis of 245 cases during 16 years period at a single high centre- A retrospective cohort study.

Objectives: Biliary complications (BCs) after adult to adult living donor liver transplantation (A-ALDLT) result in poor graft and patient survival. This study aimed to analyze these complications. Methods: We retrospectively analyzed BCs in 245 recipients who underwent A-ALDLT using the right-lobe graft during 16 years period in our centre. The overall male/female ratio was 215/30. Results: One hundred fifty-five BCs affected 102 of our recipients (95 early (≤3months) and 60 late (≥3months)). They were classified as 67/245(27.3%) early bile leak, 10/245(4.1%) early biliary stricture, 44/245(17.9%) late biliary stricture, 4/245(1.6%) early cholangitis, 10/245(4.1%) late cholangitis, 14/245(5.7%) early biloma, and 6/245(2.4%) late cholangitic abscesses. Multiple biliary anastomoses were independently correlated with Post liver transplantation (LT) overall BCs; moreover, post LT hepatic artery thrombosis or stenosis (HAT/S) was an independent predictor of overall BCs, strictures and leaks. The mortality affected 96(39.2%) cases mostly due to sepsis, bleeding and multi-organ failure (MOF). On the other hand, the biliary related mortality was 10.6% of cases. Multiple cholangitic hepatic abscesses were significant predictors of poor graft and patient outcomes. Conclusions: Multiple biliary anastomoses and post LT HAT/S lead to a poor biliary outcome, furthermore, cholangitis, cholangitic abscesses and sepsis lead to poor graft and patient outcomes, so proper management of those variables is mandatory to improve outcomes after A-ARLLDLT.

Short- and long-term outcomes after Kasai operation for type III biliary atresia: Twenty years of experience in a single tertiary Egyptian center-A retrospective cohort study.

Kasai portoenterostomy(KPE) is the treatment of choice for the fatal devastating infantile type III biliary atresia (BA). The study aimed to analyze short-and long-term outcomes after this procedure and their predictors in a tertiary center. METHODS: We retrospectively analyzed 410 infants who underwent KPE for type III BA in the period from February 2000 to December 2019. The overall male/female ratio was 186/224. RESULTS: The early (>6months) complications involved 187(45.6%) of our infants with a higher incidence of early cholangitis that affected 108(26.3%) of them. The jaundice clearance at the 6th post-operative month that reached 138(33.7%) of them had an independent correlation with mild portal tracts ductal and/or ductular proliferation, using postoperative steroids therapy, and absence of early postoperative cholangitis. The early infant mortality that affected 70(17.1%) of our patients was mostly from sepsis. On the other hand, late (<6months) patients complications and mortalities affected 256(62.4%) and 240(58.5%) of patients respectively; moreover, liver failure and sepsis were the most frequent causes of late mortalities in non-transplanted and transplanted cases respectively. Lastly, the long-term (20-year) native liver survival (NLS) that reached 91(22.2%) of patients had an independent correlation with age at operation ≤ 90 days, higher preoperative mean serum alb, portal tract fibrosis grades F0 and F1, absence of intraoperative bleeding, absence of post-operative cholangitis, the occurrence of jaundice clearance at the 6th postoperative month and absence of post-operative portal hypertension (PHN). CONCLUSIONS: Sepsis had a direct effect on early and late patient mortalities after Kasai operation for type III BA; moreover, patient age at operation<90 days, higher fibrosis grades, the occurrence of postoperative cholangitis and PHN, and persistence of post-operative jaundice had negative insult on long-term postoperative outcome. So, it is crucial to modulate these factors for a better outcome.

Fine-tuning of the pharmacological potential of novel thiazolium ionic liquids by anion alteration.

A novel series of thiazolium ionic liquids (TILs) bound to chloride (2a-c), tetrafluoroborate (BF4) (3a-c), and bis-(trifluoromethanesulfonimide) (Tf2N) anions (4a-c) was synthesized and their physicochemical characteristics were investigated using various microanalytical techniques. The pharmacological potential of the new TILs was assessed as chemotherapeutic agents for bacterial infections and ovarian cancer (SKOV-3). Notably, ILs with the same cations become more bactericidal upon their binding with the strongest chaotropic anion (TN2f). The in vitro toxicity of the TILs toward ovarian carcinoma cell lines (SKOV-3) and normal human skin fibroblast cells (HSF) revealed that all tested TILs have the capacity to induce a dose- and time-dependent decline in SKOV-3 cell viability, with Tf2N-linked TILs (4a-c) having a preferable efficacy. In addition, the new compounds showed excellent selectivity for cancer cells (SKOV-3) over healthy cells (HSF). [iPBzTh][Tf2N] (4b) is the most cytotoxic and specific one and may act as a promising anti-ovarian cancer agent.

Prognostic factors for long-term survival after pancreaticoduodenectomy for periampullary adenocarcinoma. A retrospective cohort study.

BACKGROUND: Periampullary adenocarcinoma (PAAC) had a poor prognosis, and pancreaticoduodenectomy (PD) remains the only potentially curative treatment. The study aimed to identify the impact of different clinicopathological factors on long-term survival following PD for PAAC. PATIENTS AND METHODS: This study is a retrospective cohort study for the patients who underwent PD for pathologically proven PAAC from January 2010 to January 2019. Statistical analysis was done using Cox regression multivariate analyses for independent risk factors for survival. RESULT: There were 137 patients with PAAC who underwent PD, 79 patients (57.7%) underwent pylorus-preserving PD. Pancreatico-jejunostomy was done in 108 patients (78.8%). The primary analysis showed that risk factors for poor long-term survival include patients with co-morbidities like hypertension or ischemic heart disease, Carbohydrate Antigen 19-9 > 400U/ml, tumor size > 3 cm, poor tumor differentiation, positive lymph nodes invasion, lymphovascular invasion, and Perineural invasion. Multivariate analysis demonstrated that large tumor size > 3 cm (HR: 0.177, 95%CI: 0.084-0.374, P = 0.002), poorly differentiated tumor (HR: 0.059, 95%CI: 0.020-0.0174, P = 0.016), and perineural invasion in the pathological study (HR: 0.101, 95%CI: 0.046-0.224, P = 0.006) were independent risk factors for poor 5-years survival. The prognosis was better in ampullary adenocarcinoma (5-year survival was 42.1%) than pancreatic adenocarcinoma (5-year survival was 24.3%). The 1, 3, 5 and 7-year overall survival rates were 84.5%, 57.4%, 35.9% and 20.1% respectively. CONCLUSION: It seems from the current study that Tumor size > 3 cm, poor tumor differentiation, and Perineural invasion were independent predictors of poor survival in patients with PAAC.

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation.

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9-13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15-19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22-28. Nucleophilic substitution reactions were used for getting the compounds 29-35 from chloro-thieno[2,3-d]pyrimidine 20. In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.

Risk factors and management of different types of biliary injuries in blunt abdominal trauma: Single-center retrospective cohort study.

BACKGROUND: Biliary injuries after blunt abdominal traumas are uncommon and difficult to be predicted for early management. The aim of this study is to analyze the risk factors and management of biliary injuries with blunt abdominal trauma. METHOD: Patients with blunt liver trauma in the period between 2009 to May 2019 were included in the study. Patients were divided into 2 groups for comparison; a group of liver parenchymal injury and group with traumatic biliary injuries (TBI). RESULTS: One hundred and eight patients had blunt liver trauma (46 patients with liver parenchymal injury and 62 patients with TBI). TBI were; 55 patients with bile leak, 3 patients with haemobilia, and 4 patients with late obstructive jaundice. Eight patients with major bile leak and 12 patients with minor bile leak had been resolved with a surgical drain or percutaneous pigtail drainage. Nineteen patients (34.5%) with major and minor bile leak underwent successful endoscopic retrograde cholangiopancreatography (ERCP). Sixteen patients (29.1%) underwent surgical repair for bile leak. In Multivariate analysis, the possible risk factors for prediction of biliary injuries were central liver injuries (P = 0.032), high grades liver trauma (P = 0.046), elevated serum level of bilirubin at time of admission (P = 0.019), and elevated gamma glutamyl transferase (GGT) at time of admission (P = 0.017). CONCLUSION: High-grade liver trauma, central parenchymal laceration and elevated serum level of bilirubin and GGT are possible risk factors for the prediction of TBI. Bile leak after blunt trauma can be treated conservatively, while ERCP is indicated after failure of external drainage.

Laparoscopic cholecystectomy in patients with liver cirrhosis: 8 years experience in a tertiary center. A retrospective cohort study.

With improved laparoscopic techniques, experience, and availability of newer tools and instruments like ultrasonic shears; laparoscopic cholecystectomy (LC) became a feasible option in cirrhotic patients, the aim of this study was to analyze the outcome of LC in cirrhotic patients. METHODS: We retrospectively analyzed 213 cirrhotic patients underwent LC, in the period from 2011 to 2019; the overall male/female ratio was 114/99. RESULTS: The most frequent Child-Turcotte-Pugh (CTP) score was A, The most frequent cause of cirrhosis was hepatitis C virus (HCV), while biliary colic was the most frequent presentation. The harmonic device was used in 39.9% of patients, with a significant correlation between it and lower operative bleeding, lower blood and plasma transfusion rates, higher operative adhesions rates, lower conversion to open surgery and 30-day complication rates, shorter operative time and post-operative hospital stays where operative adhesions and times were independently correlated. The 30-day morbidity and mortality were 22.1% and 2.3% respectively while overall survival was 91.5%, higher CTP, and model for end-stage liver disease (MELD) scores, higher mean international normalization ratio (INR) value, lower mean platelet count, higher operative bleeding, higher blood, and plasma transfusion rates, longer mean operative time and postoperative hospital stays were significantly correlated with all conversion to open surgery, 30-day morbidities and mortalities. CONCLUSION: LC can be safely performed in cirrhotic patients. However, higher CTP and MELD scores, operative bleeding, more blood and plasma transfusion units, longer operative time, lower platelet count, and higher INR values are predictors of poor outcome that can be improved by proper patient selection and meticulous peri-operative care and by using Harmonic scalpel shears.

Determination of contact force by compression testing of cylindrical specimens.

This paper presents a method for determining values of dynamic parameters of the Hunt and Crossley model in order to estimate the amount of force generated at the point of contact (contact force) in an impact. A two-degree-of-freedom lumped-mass-system based on a non-linear visco-elastic model as proposed by Hunt and Crossley has been widely used to accurately model contact force. The primary difficulty associated with the Hunt and Crossley contact force model is the need to determine the unknown dynamic parameters of the model, which can be obtained by calibrating the model against results from high-speed impact experiments. Spherical impactors have to be placed in the gas-gun barrel for accelerating onto the target specimen. An innovative and inexpensive method proposed in this paper describes the use of compression testing on a test rig employing cylindrical specimens of colliding bodies to obtain the dynamic parameters thereby waiving away the need of costly and time-consuming impact experiments.

Preoperative alkaline phosphatase is a potential predictor of short-term outcome of surgery in infants with biliary atresia.

AIM OF THE STUDY: Biliary atresia (BA) is a fibro-inflammatory cholangiopathy of intra- and extrahepatic biliary radicles. The standard-of-care treatment is surgical restoration of bile flow by Kasai hepatoportoenterostomy (HPE). We aimed to identify the predictors of short-term outcome of the Kasai operation three months postoperatively. MATERIAL AND METHODS: This retrospective study included 107 infants diagnosed with BA by intraoperative cholangiography. All underwent a Kasai operation. The surgical outcome was classified after 3 months post-operatively as successful (bilirubin ≤ 2 mg/dl) or failed (bilirubin > 2 mg/dl). The two groups were compared according to basic clinical, ultrasonographic and histopathological characteristics. RESULTS: Of the studied patients 29 (27.1%) had a successful outcome while 78 (72.9%) had failed Kasai HPE. Of the preoperative characteristics, lower age and lower serum alkaline phosphatase (ALP) were significantly associated with successful surgical outcome (p = 0.009 and < 0.0001, respectively). In addition, surgical type of BA affected the short-term outcome (p = 0.017), while there was no statistically significant difference regarding the other studied parameters between groups. Age of 69.5 days or less was predictive of successful outcome with 74.4% specificity but with low sensitivity (58.6%), and ALP at a cutoff level of 532.5 U/l or less was predictive of successful outcome with 75.9% sensitivity and 74.4% specificity. CONCLUSIONS: Younger age at the time of surgery and lower ALP are good predictors for the short-term outcome of Kasai HPE with better performance of ALP. This may help to anticipate those who can benefit from surgical correction and those who should be given high priority for transplant referral.

Amelioration of titanium dioxide nanoparticle reprotoxicity by the antioxidants morin and rutin.

The present study aimed to examine the ameliorative effects of morin and rutin on the reproductive toxicity induced by titanium dioxide nanoparticles (TiO2NPs) in male rats. A total of seventy adult male Sprague-Dawley rats were randomly divided into seven groups, each comprising ten rats. Nanoreprotoxicity was induced by treating rats with TiO2NPs at a dosage of 300 mg/kg body weight for 30 days. Morin (30 mg/kg body weight) and rutin (100 mg/kg body weight) were co-administered with or without TiO2NPs to rats either individually or combined. Only distilled water was administered to the control group. The results showed that TiO2NPs enhanced oxidative stress, indicated by reduced levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in testicular tissues, and increased levels of the lipid peroxidation marker malondialdehyde (MDA). TiO2NPs significantly reduced the levels of sex hormones (testosterone, FSH, and LH), reduced sperm motility, viability, and sperm cell count, and increased sperm abnormalities, in addition to damaging the testicular histological architecture. TiO2NPs resulted in the downregulation of 17ß-HSD and the upregulation of proapoptotic gene (Bax) transcripts in the testicular tissues. Conversely, morin and/or rutin had a protective effect on testicular tissue. They effectively counteracted TiO2NP-induced oxidative damage and morphological injury in the testis by conserving the endogenous antioxidant mechanisms and scavenging free radicals. Thus, we suggest that morin and rutin could be used to alleviate the toxicity and oxidative damage associated with TiO2NP intake.

Surgical (Open and laparoscopic) management of large difficult CBD stones after different sessions of endoscopic failure: A retrospective cohort study.

OBJECTIVES: For complicated common bile duct stones (CBDS) that cannot be extracted by endoscopic retrograde cholangiopancreatography (ERCP), management can be safely by open or laparoscopic CBD exploration (CBDE). The study aimed to assess these surgical procedures after endoscopic failure. METHODS: We analyzed 85 patients underwent surgical management of difficult CBDS after ERCP failure, in the period from 2013 to 2018. RESULTS: Sixty-seven (78.8%) and 18(21.2%) of our patients underwent single and multiple ERCP sessions respectively. An impacted large stone was the most frequent cause of ERCP failure (60%). Laparoscopic CBDE(LCBDE), open CBDE(OCBDE) and the converted cases were 24.7% (n = 21), 70.6% (n = 60), and 4.7% (n = 4) respectively. Stone clearance rate post LCBDE and OCBDE reached 95.2% and 95% respectively, Eleven (12.9%) of our patients had postoperative complications without mortality. By comparing LCBDE and OCBDE; there was a significant association between the former and longer operative time. On comparing, T-tube and 1ry CBD closure in both OCBDE and LCBDE, there was significantly longer operative time, and post-operative hospital stays in the former. Furthermore, in OCBDE group, choledocoscopy had an independent direction to 1ry CBD repair and significant association with higher stone clearance rate, shorter operative time, and post-operative hospital stay. CONCLUSION: Large difficult CBDS can be managed either by open surgery or laparoscopically with acceptable comparable outcomes with no need for multiple ERCP sessions due to their related morbidities; furthermore, Open choledocoscopy has a good impact on stone clearance rate with direction towards doing primary repair that is better than T-tube regarding operative time and post-operative hospital stay.

Perioperative Thromboelastometry for Adult Living Donor Liver Transplant Recipients with a Tendency to Hypercoagulability: A Prospective Observational Cohort Study.

BACKGROUND: Hypercoagulability can lead to serious thromboembolic events. The aim of this study was to assess the perioperative coagulation status in liver transplant recipients with a tendency to hypercoagulability. METHODS: In a prospective observational study (South African Cochrane Registry 201405000814129), 151 potential liver transplant recipients were screened for thrombophilic factors from October 2014 to June 2017, and 57 potential recipients fulfilled the inclusion criterion of presenting two or more of the following thrombophilic factors: low protein C, low protein S, low anti-thrombin, increased homocystein, increased antiphospholipid IgG/IgM antibodies, increased lupus anticoagulant, and positive Factor V Leiden mutation. Seven patients were excluded from the study because they fulfilled the exclusion criteria of cancelling the liver transplantation, oral anticoagulation, or intraoperative treatment with rFVIIa. Accordingly, 50 patients were included in the final analysis. Thromboelastometry (ROTEM) (EXTEM, INTEM and FIBTEM) and conventional coagulation tests (CCT) were performed preoperatively, during the anhepatic phase, post reperfusion, and on postoperative days (POD) 1, 3 and 7. ROTEM was used to guide blood product transfusion. Heparin was infused (60-180 U/kg/day) postoperatively for 3 days and then was replaced by low-molecular-weight heparin (20 mg/12 h). RESULTS: FIBTEM MCF significantly increased postoperatively above reference range on POD 7 despite normal fibrinogen plasma concentrations (p < 0.05). Both EXTEM and INTEM demonstrated significant changes with the phases of transplantation (p < 0.05), but with no intra- or postoperative hypercoagulability observed. INTEM CT (reference range, 100-240 s) normalized on POD 3 and 7 (196.1 ± 69.0 and 182.7 ± 63.8 s, respectively), despite prolonged aPTT (59.7 ± 18.7 and 46.4 ± 15.7 s, respectively; reference range, 20-40 s). Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) were reported in 12.0% and 2.0%, respectively, mainly after critical care discharge and with high FIBTEM MCF values in 57% on POD 3 and 86% on POD 7. Receiver operating characteristics curve analyses of FIBTEM MCF were significant predictors for thromboembolic events with optimum cut-off, area under the curve and standard error on POD 3 (>23 mm, 0.779 and 0.097; p = 0.004) and POD 7 (>28 mm, 0.706 and 0.089; p = 0.020). Red blood cells (mean ± SD, 8.68 ± 5.81 units) were transfused in 76%, fresh frozen plasma (8.26 ± 4.14 units) in 62%, and cryoprecipitate (12.0 ± 3.68 units) in 28% of recipients. None of the recipients received intraoperative platelet transfusion or any postoperative transfusion. Main transplant indication was hepatitis C infection in 82%. 76% of recipients included in this highly selected patient population showed increased lupus anticoagulant, 2% increased antiphospholipid IgG/IgM antibodies, 20% increased homocysteine, 74% decreased anti-thrombin, 78% decreased protein C, 34% decreased protein S, and 24% a positive Factor V Leiden mutation. Overall 1-year survival was 62%. CONCLUSION: A significant postoperative step-wise increase in FIBTEM MCF beyond the reference range was observed despite normal fibrinogen plasma concentrations, and FIBTEM MCF was a predictor for thromboembolic events in this study population, particularly after POD 3 and 7 on surgical wards when CCTs failed to detect this condition. However, the predictive value of FIBTEM MCF for postoperative HAT and PVT needs to be confirmed in a larger patient population. A ROTEM-guided anticoagulation regime needs to be developed and investigated in future studies.

Surgical management of laparoscopic cholecystectomy (LC) related major bile duct injuries; predictors of short-and long-term outcomes in a tertiary Egyptian center- a retrospective cohort study.

OBJECTIVES: Laparoscopic cholecystectomy - associated bile duct injury is a clinical problem with bad outcome. The study aimed to analyze the outcome of surgical management of these injuries. PATIENTS AND METHODS: We retrospectively analyzed 69 patients underwent surgical management of laparoscopic cholecystectomy related major bile duct injuries in the period from the beginning of 2013 to the beginning of 2018. RESULTS: Regarding injury type; the Leaking, Obstructing, leaking + obstructing, leaking + vascular, and obstructing + vascular injuries were 43.5%, 27.5%, 18.8%, 2.9%, and 7.2% respectively. However, the Strasberg classification of injury was as follow E1 = 25, E2 = 32, E3 = 8, and E4 = 4. The definitive procedures were as follow: end to end biliary anastomosis with stenting, hepaticojejunostomy (HJ) with or without stenting, and RT hepatectomy plus biliary reconstruction with stenting in 4.3%, 87%, and 8.7% of patients respectively. According to the time of definitive procedure from injury; the immediate (before 72 h), intermediate (between 72 h and 1.5months), and late (after1.5 months) management were 13%, 14.5%, and 72.5% respectively. The hospital and/or 1month (early) morbidity after definitive treatment was 21.7%, while, the late biliary morbidity was 17.4% and the overall mortality was 2.9%, on the other hand, the late biliary morbidity-free survival was 79.7%. On univariate analysis, the following factors were significant predictors of early morbidity; Sepsis at referral, higher Strasberg grade, associated vascular injury, right hepatectomy with biliary reconstruction as a definitive procedure, intra-operative bleeding with blood transfusion, liver cirrhosis, and longer operative times and hospital stays. However, the following factors were significantly associated with late biliary morbidity: Sepsis at referral, end to end anastomosis with stenting, reconstruction without stenting, liver cirrhosis, operative bleeding, and early morbidity. CONCLUSION: Sepsis at referral, liver cirrhosis, and operative bleeding were significantly associated with both early and late morbidities after definitive management of laparoscopic cholecystectomy related major bile duct injuries, so it is crucial to avoid these catastrophes when doing those major procedures.

Small for size syndrome difficult dilemma: Lessons from 10 years single centre experience in living donor liver transplantation.

AIM: To analyze the incidence, risk factors, prevention, treatment and outcome of small for size syndrome (SFSS) after living donor liver transplantation (LDLT). METHODS: Through-out more than 10 years: During the period from April 2003 to the end of 2013, 174 adult-to-adults LDLT (A-ALDLT) had been performed at National Liver Institute, Menoufiya University, Shibin Elkoom, Egypt. We collected the data of those patients to do this cohort study that is a single-institution retrospective analysis of a prospectively collected database analyzing the incidence, risk factors, prevention, treatment and outcome of SFSS in a period started from the end of 2013 to the end of 2015. The median period of follow-up reached 40.50 m, range (0-144 m). RESULTS: SFSS was diagnosed in 20 (11.5%) of our recipients. While extra-small graft [small for size graft (SFSG)], portal hypertension, steatosis and left lobe graft were significant predictors of SFSS in univariate analysis (P = 0.00, 0.04, 0.03, and 0.00 respectively); graft size was the only independent predictor of SFSS on multivariate analysis (P = 0.03). On the other hand, there was lower incidence of SFSS in patients with SFSG who underwent splenectomy [4/10 (40%) SFSS vs 3/7 (42.9%) no SFSS] but without statistical significance, However, there was none significant lower incidence of the syndrome in patients with right lobe (RL) graft when drainage of the right anterior and/or posterior liver sectors by middle hepatic vein, V5, V8, and/or right inferior vein was done [4/10 (28.6%) SFSS vs 52/152 (34.2%) no SFSS]. The 6-mo, 1-, 3-, 5-, 7- and 10-year survival in patients with SFSS were 30%, 30%, 25%, 25%, 25% and 25% respectively, while, the 6-mo, 1-, 3-, 5-, 7- and 10-year survival in patients without SFSS were 70.1%, 65.6%, 61.7%, 61%, 59.7%, and 59.7% respectively, with statistical significant difference (P = 0.00). CONCLUSION: SFSG is the independent and main factor for occurrence of SFSS after A-ALDLT leading to poor outcome. However, the management of this catastrophe depends upon its prevention (i.e., selecting graft with proper size, splenectomy to decrease portal venous inflow, and improving hepatic vein outflow by reconstructing large draining veins of the graft).

Hepatic arterial and portal venous complications after adult and pediatric living donor liver transplantation, risk factors, management and outcome (A retrospective cohort study).

OBJECTIVES: Hepatic arterial (HA) and portal venous (PV) complications of recipients after living donor liver transplantation(LDLT) result in patient loss. The aim of this study was to analyze these complications. METHODS: We retrospectively analyzed HA and/or PV complications in 213 of 222 recipients underwent LDLT in our centre. The overall male/female and adult/pediatric ratios were 183/30 and 186/27 respectively. RESULTS: The overall incidence of HA and/or PV complications was 19.7% (n = 42), while adult and pediatric complications were 18.3% (n = 39) and 1.4% (n = 3) respectively. However early (<1month) and late (>1month) complications were 9.4% (n = 20) and 10.3% (n = 22) respectively. Individually HA problems (HA stenosis, HA thrombosis, injury and arterial steal syndrome) 15% (n = 32), PV problems (PV thrombosis and PV stenosis) 2.8% (n = 6) and simultaneous HA and PV problems 1.9% (n = 4). 40/42 of complications were managed by angiography (n = 18), surgery (n = 10) or medically (Anticoagulant and/or thrombolytic) (n = 12) where successful treatment occurred in 18 patients. 13/42 (31%) of patients died as a direct result of these complications. Preoperative PVT was significant predictor of these complications in univariate analysis. The 6-month, 1-, 3-, 5- 7- and 10-year survival rates in patients were 65.3%, 61.5%, 55.9%, 55.4%, 54.5% and 54.5% respectively. CONCLUSION: HA and/or PV complications specially early ones lead to significant poor outcome after LDLT, so proper dealing with the risk factors like pre LT PVT (I.e. More intensive anticoagulation therapy) and the effective management of these complications are mandatory for improving outcome.

Complications and mortality after adult to adult living donor liver transplantation: A retrospective cohort study.

BACKGROUND AND AIMS: Living donor liver transplantation (LDLT) is widely performed for patients to resolve the critical shortage of organs from cadavers. Despite rapid implementation of the procedure, both complications and mortality of LDLT are annoying problems. The aim of this study was to analyze complications and mortality of patients after adult to adult LDLT (A-ALDLT) in a single center. METHODS: Between April 2003 and November 2013, 167 (A-ALDLT) recipients in National Liver Institute, Egypt were included. We retrospectively analyzed complications and mortality in them. RESULTS: The overall incidence of complications was 86.2% (n = 144) and classified as biliary 43.7% (n = 73), vascular 21.6% (n = 36), Small for size syndrome (SFSS) 12.6% (n = 21), Gastrointestinal tract (GIT) 19.8% (n = 33), wound 12.6% (n = 21), chest 19.8% (n = 33), neurological 26.3% (n = 44), renal 21% (n = 35), intra abdominal collection 21.6% (n = 36), recurrent hepatitis C virus (HCV) 16.8% (n = 28), recurrent hepatocellular carcinoma (HCC) 2.4% (n = 4), acute rejection 19.2% (n = 32). 65 (45.1%) of 144 complicated patients died, while 10 (43.5%) of 23 non complicated died. The incidence of whole, in hospital and late mortalities were 44.9%, 28.7% and 16.2% respectively. CONCLUSIONS: Mortality was higher among complicated cases where vascular complications and SFSS had significant effect on it so prevention and treatment of them is required for improving outcome.