Embryologic Origin of the Primary Tumor and RAS Status Predict Survival after Resection of Colorectal Liver Metastases.

Background and objectives. In colorectal cancers, the embryologic origin of the primary tumor determines important molecular dissimilarities between right-sided (RS) and left-sided (LS) carcinomas. Although important prognostic differences have been revealed between RS- and LS-patients with resected colorectal liver metastases (CLMs), it is still unclear if this observation depends on the RAS mutational status. To refine the impact of primary tumor location (PTL) on the long-term outcomes of patients with resected CLMs, the rates of overall survival (OS), relapse-free survival (RFS) and survival after recurrence (SAR) were compared between RS- vs. LS-patients, according to their RAS status. Material and Methods. All patients with known RAS status, operated until December 2019, were selected from a prospectively maintained database, including all patients who underwent hepatectomy for histologically-proven CLMs. A log-rank test was used to compare survival rates between the RS- vs. LS-group, in RAS-mut and RAS-wt patients, respectively. A multivariate analysis was performed to assess if PTL was independently associated with OS, RFS or SAR. Results. In 53 patients with RAS-mut CLMs, the OS, RFS and SAR rates were not significantly different (p = 0.753, 0.945 and 0.973, respectively) between the RS and LS group. In 89 patients with RAS-wt CLMs, the OS and SAR rates were significantly higher (p = 0.007 and 0.001, respectively) in the LS group vs. RS group, while RFS rates were similar (p = 0.438). The multivariate analysis performed in RAS-wt patients revealed that RS primary (p = 0.009), extrahepatic metastases (p = 0.001), N-positive (p = 0.014), age higher than 65 (p = 0.002) and preoperative chemotherapy (p = 0.004) were independently associated with worse OS, while RS location (p < 0.001) and N-positive (p = 0.007) were independent prognostic factors for poor SAR. Conclusions. After resection of CLMs, PTL had no impact on long-term outcomes in RAS-mut patients, while in RAS-wt patients, the RS primary was independently associated with worse OS and SAR.

The moral status of cerebral organoids.

Organoids are 3D biological structures constructed from stem cells in vitro. They partially mimic the function of real organs. Although the number of articles detailing this technology has increased in recent years, papers debating their ethical issues are few. In addition, many of such articles outline a mere summary of potential ethical concerns associated with organoids, although some have focused on consciousness assessment or organoid use in cystic fibrosis treatment. This article seeks to evaluate the moral status of cerebral organoids and to determine under which conditions their use should be allowed from a bioethical standpoint. We will present an overview of recent steps in developing highly advanced cerebral organoids, followed by an analysis of their ethics based on three factors: human origin, a specific biological threshold (which, once crossed, grants an entity moral status), and the potential to generate human beings. We will also make practical recommendations for researchers working in this biological field.

Diagnosis, morphopathological profile and treatment of mucinous cystadenoma of the pancreas - a single center experience.

AIM: Pancreatic mucinous cystadenoma (MCA) occurs almost exclusively in perimenopausal women and represents between 10% and 45% of cystic neoplasm of the pancreas, being considered a premalignant lesion. MATERIALS AND METHODS: From 1983 to 2017, 31 patients underwent surgery for MCA of the pancreas in our Center. The median age was 47 years (range 17-81 years). All data were obtained retrospectively. RESULTS: The female∕male gender ratio was 14.5∕1. Most of the patients (90.3%) were symptomatic. The most common clinical manifestation was non-specific abdominal pain (58.06%), followed by fatigue and vomiting. The median cyst size was 7 cm, with a range between 2 cm and 15 cm. There were 35 procedures in 31 patients (in four patients the resection was preceded by a drainage procedure). From the 28 resections, most of them (89.28%) were performed by an open approach; a minimal invasive approach was used in three patients (robotic - two; laparoscopic - one). Most of the resections (82.14%) were distal pancreatectomies. In all cases, the final diagnosis was based on histological examination that revealed columnar epithelium and ovarian-type stroma. Postoperative complications occurred in 10 (34.48%) patients. Postoperative mortality was 3.44% (one patient) by septic shock secondary to acute postoperative pancreatitis. CONCLUSIONS: MCAs represent a rare pancreatic pathology with challenging diagnostic and therapeutic implications. Multi-detector computed tomography (MDCT) scan, endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI)∕magnetic resonance cholangiopancreatography (MRCP) are useful in the differential diagnosis with other pancreatic fluid collections and treatment. Oncological surgical resections are recommended. Histopathological examination establishes the final diagnosis. The most common postoperative complication is pancreatic fistula.

Molecular Biomarkers as Predictors for Biliary Complications Following Liver Transplantation. A Prospective Study.

BACKGROUND: The biliary complications (BC) have been always considered the "Achilles' heel" of liver transplantation (LT), being one of the leading causes of postoperative morbidity. AIM: To analyse predictors of BC, by monitoring in the peripheral blood the biomarkers involved in the inflammation and hepatic fibrosis, such as the matrix metalloproteinases (MMP 2, 9) and their tissue inhibitors (TIMP1), the interleukins (IL 2, 8), alfa-TNF, the endothelins and their receptors. METHODS: Thirty LT patients were followed-up prospectively for 5 years. The mRNA for the following biomarkers was quantified in the peripheral blood by qRTPCR and protein expression investigated by ELISA: MMP 2, 9, TIMP1, IL 2, IL 8, TNF-alfa, and endothelins and their receptors. RESULTS: Five patients developed anastomotic stenosis (AS). There was no difference regarding mRNA levels for all studied genes between AS and non-AS patients. Two cytokines were significantly different: pre-LT TNF alpha was higher in the non-AS group and post-LT endothelin-1 at day 7 and month 3 were higher in the AS group. There was a trend for lower levels of serum cytokines for patients without AS compared to patients with AS. CONCLUSION: BC play an important role in the patients' postoperative morbidity and molecular biomarkers prediction should improve their early recognition and treatment.

The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success.

Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list.

Fibrolamellar hepatocellular carcinoma with ovarian metastasis - an unusual presentation.

AIM: Fibrolamellar carcinoma (FLC) has been considered a distinct clinical entity vs. hepatocellular carcinoma, with respect to its epidemiology, etiology, and prognosis. CASE PRESENTATION: We describe the unusual case of a 23-year-old female patient with FLC and ovarian (Krukenberg) and peritoneal metastases, clinically mimicking an ovarian carcinoma. Multiple recurrences occurred despite initial R0 resection and chemotherapy, requiring surgical treatment. The patient survived five years and died from generalized disease. DISCUSSION: The particularities of our case are discussed by comparison with the other two similar cases and other date from the literature. CONCLUSIONS: To our knowledge, the ovarian involvement encountered in our case is the third case published in literature, being explained by the superficial location of the liver tumor.

Pancreatoduodenectomy: Risk Factors of Postoperative Pancreatic Fistula.

BACKGROUND/AIMS: The aim of the present study is the analysis of risk factors of postoperative pancreatic fistula (POPF) and of clinical outcome after pancreatoduodenectomy (PD) in a retrospective multicentric review of the patient cohort. METHODOLOGY: From January 2003 to July 2013 143 patients underwent PD: 138 cases were included and 3 groups were identified according to the different types of anastomosis: Group 1 invaginating end-to-end pancreatojejunostomy, Group 2 end-to-side pancreatojejunostomy with duct-to-mucosa anastomosis, Group 3 end-to-side pancreatogastrostomy. RESULTS: Twenty-one % of patients developed POPF, 16% in Group 1, 27% in Group 2, 12% in Group 3. Forty % grade A, 13% grade B and 47% grade C total POPF. It results that POPF occurred in 16% of hard and in 40% of soft pancreatic texture; in 11.4% of dilated Wirsung versus 30.8% of non dilated (p = 0.007). Overall actuarial 1 and 3 year survival after PD is 69% and 48% respectively. Perioperative mortality is 5.8% overall, 17.85% for grade C. CONCLUSIONS: No differences have been found among surgical anastomosis techniques. Soft tissues seem to increase, while dilated Wirsung seems to decrease POPF rate. The development of POPF increase morbidity but it doesn't affect overall survival, more strictly related to tumour histopathology.

Biliary complications after liver transplantation--523 consecutive cases in two centers.

BACKGROUND/AIMS: Despite various surgical techniques, biliary tract complications (BC) remain a major source of morbidity after liver transplantation (LT). METHODOLOGY: Between April 2000 and November 2008, 523 LTs in 487 recipients (36 re transplantations) were performed as follows: 402 whole deceased donor graft LTs, and 121 partial liver transplantation: 75 living donor liver transplantation, 42 split liver transplantation, and 4 reduced size liver transplantation. RESULTS: Mean follow-up period was 935 days (range 1-3174), 1, 3 and 5-year survival rates were 78.7% 74.2% and 74.2%, respectively. One hundred twenty seven patients--from 487 (26%), developed (after 135 LT) 150 singular BC (in total were 181 BC). Sixty four (of 85) bile leaks (75.29%) were early BC, while 53 (of 63) stenosis (84.1%) were late BC. BC does not influenced significantly patients and graft survival (p > 0.6). From 102 deaths, 8 were due to BC (1.6%) and in only 14 (2.67%) graft loss of 523 LT BC had the main role. Multiple ducts, multiple biliary anastomosis and RYHJ determine BC if compared to a single duct graft. Moreover, ductoplasty, graft type and HAT were independent risk factors. CONCLUSION: Biliary complications are common after LT but are rarely an isolated cause of death.

Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up.

A 46-yr-old female with hepatocellular carcinoma and severe hepatitis B-related liver cirrhosis received a domino liver graft from a 25-yr-old female with homozygous familial hypercholesterolemia (HFHC) in September 2001. Hypercholesterolemia occurred in the graft recipient within one yr after transplantation and was partially controlled by atorvastatin. Three yr after transplantation, an autologous CD34(+) cell transplantation was performed in order to better control the hypercholesterolemia. Only preliminary results of this domino liver transplantation (DLT) were published in 2003, without a long-term analysis of the hypercholesterolemic effects in recipient. Subsequent to DLT, the average plasma cholesterol level in the domino donor rapidly normalized and seven yr after had a value of 182 mg/dL. After seven-yr follow-up, the domino recipient has no hepatocarcinoma recurrence. Moreover, no signs of cardiovascular or atherosclerotic lesions were noted despite an elevated plasma cholesterol level (339 mg/dL after seven yr of follow-up) resistant to drug therapy and stem cell autotransplantation. In conclusion, DLT using a liver graft from a patient with HFHC provides a viable option for marginal recipients.

Costs and efficacy of "on demand" low-dose immunoprophylaxis in HBV transplanted patients: experience in the Romanian program of liver transplantation.

BACKGROUND: HBV in liver transplant (LT) patients is associated with good outcomes and the challenges are primarily focused around optimizing prophylactic regimens with hepatitis B immune globulin (HBIG) and minimizing related costs. AIM: To identify recurrence rates in patients transplanted for HBV or HBV+HDV infection in whom a combined "on demand" low-dose HBIG was used, maintaining low anti-HBs titres (not below 50 IU/L). METHODS: Medical records of 42 patients transplanted for HBV or HBV+HDV induced cirrhosis between April 2000 and September 2007 at Fundeni Clinical Institute were analyzed. Patients received immunoprophylaxis with lamivudine and HBIG (10,000 IU within anhepatic phase and daily within the first postoperative week, followed by 2,500 IU on demand). HBV recurrence rates and survival during follow-up were evaluated using the Kaplan Meier method. RESULTS: HBV recurrence rate was 4.8% after a median of 1.8 years. Three year patient survival rate was 70%. None of the patients died due to liver failure related to HBV recurrence. Using our "on demand" low-dose administration of HBIG, the total mean cost for HBIG and lamivudine for patient per month of survival was 598.3 Eur. The projected monthly cost for the "ideal" schedule/patient was 2,017 Eur. CONCLUSION: Individualization of immunoprophylaxis after LT for HBV related disease according to the lowest protective anti-HBs titers in combination with lamivudine is probably the best approach for non-replicative pre-LT patients in terms of costs and efficacy.

Should we still offer split-liver transplantation for two adult recipients? A retrospective study of our experience.

The role of split-liver transplantation (SLT) for two adult recipients is still a matter of debate, and no agreement exists on indications, surgical techniques, and results. The aim of this study was to retrospectively analyze the outcome of our series of SLT. From May 1999 to December 2006, 16 patients underwent SLT at our unit. We used 9 full right grafts (segments 5-8) and 7 full left grafts (segments 1-4). The splitting procedure was always carried out in situ with a fully perfused liver. Postoperative complications were recorded in 8 (50%) patients: 5 (55%) in full right grafts and 3 (43%) in full left grafts. No one was retransplanted. After a median follow-up of 55.82 months (range, 0.4-91.2), 5 (31%) patients died, and the 1-, 3-, and 5-year overall survival rate for patients and grafts was 69%. We considered as a control group for the global outcome 232 whole liver transplantations performed at our unit in the same period of time. Postoperative complications were recorded in 53 (23%) patients, and after a median follow-up of 57.37 months (mean, 55.11; range, 1-102.83), the 1-, 3-, and 5-year overall patient survival was 87%, 82%, and 80%, respectively. In conclusion, SLT for two adult recipients is a technically demanding procedure that requires complex logistics and surgical teams experienced in both liver resection and transplantation. Although the reported rate of survival might be adequate for such a procedure, more efforts have to be made to improve the short-term outcome, which is inadequate in our opinion. The true feasibility of SLT for two adults has to be considered as still under investigation.

The posterior approach in pancreaticoduodenectomy: preliminary results.

BACKGROUND/AIMS: We present our technical version of pancreaticoduodenectomy by posterior approach that enables a complete dissection of the right side of the mesenteric superior artery and of the portal vein, as well as a complete excision of the retroportal pancreatic process (or lamina), and report the preliminary outcomes of the first 10 selected patients. METHODOLOGY: Between 1 December 2005 and 1 March 2006 10 patients (7 males and 3 females) with a mean age of 60.6 years (range 45-81 years) were operated on using this technique. The patients were diagnosed with carcinoma of the pancreatic head (8 cases), ampullary carcinoma (1 case), and carcinoma of the distal part of the common bile duct (1 case). Invasion of the portal vein occurred in 2 of the 8 cases of carcinoma of the pancreatic head. RESULTS: No significant intraoperative incident was recorded. The mean operative time was 225 minutes (ranging between 180 and 240 minutes) and the mean blood loss was 372,25cc (range 150-800cc). Two cases of carcinoma of the pancreatic head that had a segmental resection of the portal vein needed vascular reconstruction which was performed by Goretex graft interpositing. The pylorus-preserving procedure was used in 2 cases (ampullary carcinoma, and carcinoma of the distal part of the common bile duct, respectively). Postoperative complications consisted of intraabdominal hemorrhage from an arterial source of the pancreatic capsule (on the day of the operation necessitating reoperation for hemostasis) in one case, and pancreatic fistula (that required conservative treatment) in another case. No postoperative diarrhea, delayed gastric emptying episodes or postoperative deaths were recorded. There were no postoperative deaths. The mean length of hospitalization was 12.2 days (range 10-24 days). CONCLUSIONS: The posterior approach in pancreaticoduodenectomy offers an early selection of patients during the operation (in terms of resectability). As compared to the standard procedure, it enables an adequate lymphadenectomy that can be safely performed (by early dissection and isolation of the superior mesenteric artery), and avoids possible intraoperative accidents secondary to anatomical arterial abnormalities. This approach is particularly recommended in cases with portal vein invasion because it allows a "no-touch" resection.