Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology.

Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.

Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation.

Post liver transplantation (LT) fibrosis has a negative impact on graft function. Cytokine production in the host immune response after LT may contribute to the variable CYP3A-dependent immunosuppressive drug disposition, with subsequent impact on liver fibrogenesis, together with host-related factors. We aimed to investigate whether the cytochrome P4503A5*3 (CYP3A5*3) or TBX21 genotypes impact post-LT liver fibrogenesis. Furthermore, the impact of immunosuppressants on cellular apoptosis has been evaluated using human hepatocytes harvested from cirrhotic explanted livers. We have enrolled 98 LT recipients that were followed for occurrence of liver fibrosis for at least 12 months. There was a statistically significant higher trough level of TAC in patients with homozygous CC-TBX21 genotype (7.83 ± 2.84 ng/ml) vs. 5.66 ± 2.16 ng/ml in patients without this genotype (p = 0.009). The following variables were identified as risk factors for fibrosis ≥2: donor age (p = 0.02), neutrophil to lymphocyte ratio (p = 0.04) and TBX21 genotype CC (p = 0.009). In the cell culture model cytometry analysis has indicated the lowest apoptotic cells percentage in human cirrhotic hepatocytes cultures treated with mycophenolate mofetil (MMF) (5%) and TAC + MMF (2%) whereas the highest apoptosis percentage was registered for the TAC alone (11%). The gene expression results are concordant to cytometry study results, indicating the lowest apoptotic effect for MMF and MMF + TAC immunosuppressive regimens. The allele 1993C of the SNP rs4794067 may predispose to the development of late significant fibrosis of the liver graft. MMF-based regimens have a favourable anti-apoptotic profile in vitro, supporting its use in case of LT recipients at high risk for liver graft fibrosis.

The Impact of Postoperative Complications on Survival after Simultaneous Resection of Colorectal Cancer and Liver Metastases.

BACKGROUND: The aim of this study was to investigate the impact of postoperative complications on the long-term outcomes of patients who had undergone simultaneous resection (SR) of colorectal cancer and synchronous liver metastases (SCLMs). METHODS: We conducted a single-institution survival cohort study in patients with SR, collecting clinical, pathological, and postoperative complication data. The impact of these variables on overall survival (OS) and disease-free survival (DFS) was compared by log rank test. Multivariate Cox regression analysis identified independent prognostic factors. RESULTS: Out of 243 patients, 122 (50.2%) developed postoperative complications: 54 (22.2%) major complications (Clavien-Dindo grade III-V), 86 (35.3%) septic complications, 59 (24.2%) hepatic complications. Median comprehensive complication index (CCI) was 8.70. Twelve (4.9%) patients died postoperatively. The 3- and 5-year OS and DFS rates were 60.7%, 39.5% and 28%, 21.5%, respectively. Neither overall postoperative complications nor major and septic complications or CCI had a significant impact on OS or DFS. Multivariate analysis identified the N2 stage as an independent prognostic of poor OS, while N2 stage and four or more SCLMs were independent predictors for poor DFS. CONCLUSION: N2 stage and four or more SCLMs impacted OS and/or DFS, while CCI, presence, type, or grade of postoperative complications had no significant impact on long-term outcomes.

Definitive Surgery for Liver Trauma in a Tertiary HPB Center (with video).

Background: Surgery for severe liver trauma remains challenging even for HPB surgeons, mainly due the hemodynamical instability, involvement of major vascular and biliary elements, impaired background liver and frequent anatomical variants. In this setting, despite conservative policy, major liver resection is still required in selected cases. Also salvage liver transplantation may be needed. Our study aims to analyze the results after definitive surgery for hepatic injury (HI) in a tertiary HPB center. Methods: Sixty-six patients with HI were admitted and treated in our center between June 2000 and June 2021. The median age was 29 years (mean 35, range 10-76). The male/female ratio was 50/16. According to the American Association for the Surgery of Trauma (AAST) system, HIs were grade II in one patient (1.5%), grade III in 11 pts (16.7%), grade IV in 25 pts (37.9%), and grade V in 29 pts (43.9%); no patient had grade I or VI HI. Results: Fifty-two pts (78.8%) benefitted from surgery and 14 pts (21.2%) from non-operative treatment (NOT). Perihepatic packing was previously performed in 38 pts (73.1%). Surgery consisted in hepatic resections (HR) in 51 pts (77.3%) and liver transplantation in one patient (1.5%). The rate of major HR was 51.9% (27 HRs). The overall major morbidity and mortality rates were 33.3% (20 pts) and 13.6% (9 pts), respectively. For surgery, the major complication rate was 35.3% (18 pts), while for major and minor HR were 40.7% (11 pts) and 29.2% (7 pts), respectively; the mortality rate was 15.7% (8 pts). After NOT, the major morbidity and mortality rates were 14.3% (2 pts) and 7.1% (1 pt), respectively. Conclusions: Hepatic resections, especially major ones and/or involving vascular and biliary reconstructions, as well as non-operative treatment for severe hepatic injuries, are to be carried out in tertiary HPB centers, thus minimizing the morbidity and mortality rates, while having the liver transplantation as salvage option.

A Single Center Experience in Liver Resection and Ablative Techniques: An Analysis of Six Years.

Introduction: We present our 6-year experience with liver surgery and ablative techniques. Method: An observational retrospective analysis from a prospectively maintained database was performed in our department. All the patients with liver resection, liver resection combined with intraoperative ablative techniques and percutaneous ablative techniques were included from January 1st 2014 to December 31st 2020. Results: There were 249 patients analyzed: 273 patients with liver resection, 12 patients with liver resection combined with intraoperative MWA, 9 patients with open surgery MWA, 12 patients with percutaneous MWA, 1 patient with TACE and MWA, 1 patient with TACE and PEI, 10 patients with TACE, and 2 patients with PEI. Conclusion: Liver disease should be managed in specialized centers which can offer a wide range of therapeutic options. With the improvement of the surgical technique and perioperative care, including optimized postoperative complication management, and carried out by well-trained surgeons, liver surgery can be performed with low mortality and acceptable morbidity.

Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Preliminary Experience in a Single Center.

Background: The need to maximize the use of donor organs and the issue of ischemia-reperfusion injury led to the use of thermoregulated oxygenated machine perfusion that improves the function of liver graft prior to transplantation. Among these methods, the HOPE (hypothermic oxygenated perfusion) protocol shows significant benefits. The aim of the paper is to analyze the early experience in using such procedure in a high-volume liver transplantation center. Methods: Normal liver grafts with cold ischemia time â?¥6 hours, marginal grafts and discarded (beyond ECD criteria) grafts were perfused using HOPE. Our selection criteria for dual HOPE (hepatic artery and portal perfusion) were steatosis, at least 3 associated ECD criteria, and discarded grafts. The main criteria to establish graft improvement were the progressive increase of arterial and portal flows, with lactate under 3 mmol/L or, even if over this value, with a decreasing trend during perfusion. Results: Whole liver grafts harvested from 28 donors between February 2016 and June 2021 benefitted from HOPE: 9 otherwise discarded grafts were assessed and considered not fit for transplantation, while the other 19 were ECD or standard grafts that were subsequently transplanted. Dual HOPE was used in 8 out of the 19 procedures (42.1%). We obtained a significant increase of arterial and portal flow (p=0.005 and p=0.001, respectively). In recipients, significant improvement of AST, ALT, INR and lactate values were recorded (p 0.001, p 0.001, p 0.001, and p=0.05, respectively). The rate of major postoperative complications (Dindo-Clavien grade 3) after LT was 26.3%, while the rate of early graft dysfunction was 15.8%. No PRS or acute rejection was recorded. The postoperative mortality rate was 15.8%. After a median follow-up of 9.3 months (range 2-44), the late major complication rate was 15.8%, without mortality. Conclusion: Machine perfusion is nowadays part of current clinical practice. This way, marginal liver grafts (DCD, ECD-DBD) may be safely used for transplantation improving the outcome, thus effectively enhance the use of a persistent scarce pool of donors. For best results, we believe that both techniques of HOPE (mono and dual HOPE) should be used based on specific selection criteria.

Pre and post-liver transplant outcome of cirrhotic patients with acute on chronic liver failure.

Acute on chronic liver failure (ACLF) is a dynamic syndrome, but frequently associated with a high 1 month mortality rate. This is the first study applying the new European Association for the Study of the Liver- chronic liver failure consortium criteria to explore mortality on the waiting list (WL) and early after liver transplantation (LT) in a cohort of Romanian cirrhotic patients that improved or recovered after an episode of ACLF.To assess frequency and waitlist mortality for different grades of ACLF.An observational study was conducted; 257 patients with liver cirrhosis included on the WL between 2015 and 2017 were analyzed. The cumulative incidence of waitlist mortality or removal was calculated for combination of competing events using multivariable competing risks regression.ACLF-1 occurred in 12.07%, ACLF-2 in 7.39% and ACLF-3 in 8.56% of patients. Median Model for End Stage Liver Diseases (MELD) score at the moment of ACLF was 29. The main event while on the WL was death, followed by ACLF; patients with ACLF-3 had a significantly greater subhazard ratio for mortality of 2.25 (1.55-3.26) compared to patients with ACLF-1 or 2. LT proved to be associated with a significantly lower risk of death on the WL at 6 months after inclusion. One and 12 months post-transplant survival of patients with or without ACLF was similar (P = .77).Occurrence of an ACLF episode while on the WL is associated with a significantly high mortality rate, as well as MELD score at inclusion on the WL, renal and liver failure, presence of hepatic encephalopathy. Overall patient short and long term survival after LT is similar to non-ACLF patients in good selected cases.

Surgical treatment for severe liver injuries: a single-center experience.

BACKGROUND: The liver is one of the most frequently injured organs in abdominal trauma. The advancements in diagnosis and interventional therapy shifted the management of liver trauma towards a non-operative management (NOM). Nevertheless, in severe liver injuries (LI), surgical treatment often involving liver resection (LR) and rarely liver transplantation (LT) remains the main option. The present paper analyses a single center experience in a referral HPB center on a series of patients with high-grade liver trauma. METHODS: Forty-five patients with severe LI, that benefitted from NOM (6 pts), LRs (38 pts), and LT (1 pt) performed in our center between June 2000 and June 2019, were included in a combined prospective and retrospective study. The median age of the patients was 29 years (median 33, range 10-76), and the male/female ratio of 33/12. Almost all cases had blunt trauma, except 2 with stab wound (4.4%). RESULTS: LIs classified according to the American Association for the Surgery of Trauma (AAST) system were 13.3% (grade III), 44.2% (grade IV), and 42.2% (grade V); none were grade I, II or VI. The rate of major LR was 56.4% (22 LRs). The median operative time was 200 minutes (mean 236; range 150-420). The median blood loss was 750 ml (mean 940; range 500-6500). Overall and major complication rates were 100% (45 pts) and 33.3% (15 pts), respectively. Overall mortality rate was 15.6% (7 pts). CONCLUSIONS: Severe liver trauma, often involving complex liver resections, should be managed in a referral HPB center, thus obtaining the best results in terms of morbidity and mortality.

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.

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.

Liver Resections in a High-Volume Center: Form Standard Procedures to Extreme Surgery and Ultrasound-guided Resections.

Background: Liver resection (LR) is the treatment of choice for most benign and malignant focal liver lesions, as well as in selected patients with liver trauma. Few other therapies can compete with LR in selected cases, such as liver transplantation in hepatocellular carcinoma (HCC) and ablative therapies in small HCCs or liver metastases. The present paper analyses a single center experience in LR, reviewing the indications of LR, the operative techniques and their short-term results. MATERIAL AND METHOD: Between January 2000 and December 2016, in "œDan Setlacec" Center of General Surgery and Liver Transplantation were performed 3165 LRs in 3016 patients, for pathologic conditions of the liver. In the present series, liver resections for living-donor liver transplantation were excluded. The median age of the patients was 56 years (mean 58 years; range 1-88), with male/female ratio 1524/1492 and adult/pediatric patient ratio 2973/43. Results: Malignant lesions were the main indication for LR (2372 LRs; 74.9%). Among these, colorectal liver metastases were the most frequent indication (952 LRs; 30.1%), followed by hepatocellular carcinoma (575 patients, 18.2%). The highest number of resected tumors per patient was 21, and the median diameter of the largest tumor was 40 mm (mean 51 mm; range 3-250). Major resections rate was 18.6% (588 LRs) and anatomical LRs were performed in 789 patients (24.9%). The median operative time was 180 minutes (mean 204 minutes; range 45-920). The median blood loss was 500 ml (mean 850 ml; range 500-9500), with a transfusion rate of 41.6% (1316 LRs). The morbidity rate was 40.1% (1270 LRs) and the rate of major complications (Dindo-Clavien IIIa or more) was 13.2% (418 LRs). Mortality rate was 4.2% (127 pts). CONCLUSION: LRs should be performed in specialized high-volume centers to achieve the best results (low morbidity and mortality rates).

Comparative Analysis between Simultaneous Resection and Staged Resection for Synchronous Colorectal Liver Metastases - A Single Center Experience on 300 Consecutive Patients.

Introduction: In synchronous colorectal liver metastases (SCLMs), simultaneous resection (SR) of the primary tumor and liver metastases has not gained wide acceptance. Most authors prefer staged resections (SgR), especially in patients presenting rectal cancer or requiring major hepatectomy. Methods: Morbidity, mortality, survival rates and length of hospital stay were compared between the two groups of patients (SR vs. SgR). A subgroup analysis was performed for patients with similar characteristics (e.g. rectal tumor, major hepatectomy, bilobar metastases, metastatic lymph nodes, preoperative chemotherapy). Results: Between 1995 and 2016, SR was performed in 234 patients, while 66 patients underwent SgR. Comparative morbidity (41% vs. 31.8%, respectively, p = 0.1997), mortality (3.8% vs. 3%, respectively, p = 1) and overall survival rates (85.8%, 51.3% and 30% vs. 87%, 49.6% and 22.5%, at 1-, 3- and 5-years, respectively, p = 0.386) were similar between the SR and SgR group. Mean hospital stay was significantly shorter in patients undergoing SR than SgR (15.11 ‚+- 8.60 vs. 19.42 ‚+- 7.36 days, respectively, p 0.0001). The characteristics of SR and SgR groups were similar, except the following parameters: rectal tumor (34.1% vs. 19.7%, respectively, p = 0.0245), metastatic lymph nodes (68.1% vs. 86.3%, respectively, p = 0.0383), bilobar liver metastases (22.6% vs. 37.8%, respectively, p = 0.0169), major hepatectomies (13.2% vs. 30.3%, respectively, p= 0.0025) and neo-adjuvant chemotherapy (13.2% vs. 77.2%, respectively, p 0.0001). A comparative analysis of morbidity, mortality and survival rates between SR and SgR was performed for subgroups of patients presenting these parameters. In each of these subgroups, SR was associated with similar morbidity, mortality and survival rates compared with SgR (p value 0.05). CONCLUSION: In patients with SCLMs, SR provides similar short-term and long-term outcomes as SgR, with a shorter hospital stay. Therefore, in most patients with SCLMs, SR might be considered the treatment of choice.

GOOD TO KNOW: The ALPPS Procedure - Embracing a New Technique.

BACKGROUND: Hepatic resection is the only potentially curative treatment for primary liver tumors and hepatic metastases. The most frightening postoperative complication of extensive hepatectomies is liver failure due to insufficient future liver remnant (FLR). The ALPPS technique (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) effectively increased the resectability of otherwise inoperable liver tumors (primary or secondary malignant liver tumor) by achieving a rapid and an effective hypertrophy of the FLR, which lowers postoperative liver failure risk. AIM: To present the ALPPS classic right trisectionectomy and its technical variants which were invented to decrease the high rate of post-operative morbidity and mortality, reported in early case series. TECHNIQUE: ALPPS involves two stages. The first surgical procedure consists in the ligation of the right portal branch and the partition of the liver at the site of the falciform ligament (insitu splitting). In contrast to a classical hepatectomy, the tumoral hemiliver is left in situ and remains vascularized by the right hepatic artery only. The biliary and systemic venous drainages represented by the right biliary duct and respectively the hepatic veins, are preserved. The second step of the procedure is usually performed within 7 to 15 days after the firststage. The tumoral hemiliver is removed by sectioning the right hepatic artery, the biliary duct and the systemic venous pedicle. Conclusions: The ALPPS technique is a therapeutic method for inoperable liver tumors by standard methods of hepatectomy ± portal vein ligation (PVL). By careful patient selection and technical adjustment to the particular conditions of each case, better outcomes have been achieved, leading toan increasing number of surgeons who perform ALPPS.

Curative Intent Treatment of Hepatocellular Carcinoma - 844 Cases Treated in a General Surgery and Liver Transplantation Center.

Background: The objective of this study is to assess the outcome of the patients treated for hepatocellular carcinoma (HCC) in a General Surgery and Liver Transplantation Center. Methods: This retrospective study includes 844 patients diagnosed with HCC and surgically treated with curative intent methods. Curative intent treatment is mainly based on surgery, consisting of liver resection (LR), liver transplantation (LT). Tumor ablation could become the choice of treatment in HCC cases not manageable for surgery (LT or LR). 518 patients underwent LR, 162 patients benefited from LT and in 164 patients radiofrequency ablation (RFA) was performed. 615 patients (73%) presented liver cirrhosis. Results: Mordidity rates of patient treated for HCC was 30% and mortality was 4,3% for the entire study population. Five year overall survival rate was 39 % with statistically significant differences between transplanted, resected, or ablated patients (p 0.05) with better results in case of LT followed by LR and RFA. Conclusions: In HCC patients without liver cirrhosis, liver resection is the treatment of choice. For early HCC occurred on cirrhosis, LT offers the best outcome in terms of overall and disease free survival. RFA colud be a curative method for HCC patients not amenable for LT of LR.

Dynamics of the Romanian waiting list for liver transplantation after changing organ allocation policy.

AIM: The aim of the present study was to characterize the dynamics of the Romanian waiting list (WL) for liver transplantation (LT) over two periods: 2004-2007 vs. 2008-2011. METHODS: 1,085 patients listed for LT during the time period 2004-2011 were included in our analysis. RESULTS: Death on the WL was significantly higher before 2008 (37% vs. 26.4%, p=0.0001) and risk of dying while on WL was 60% higher. Waiting time on the WL was 75% longer and time until LT was 102% longer before 2008 compared to the second time period (p=0.0001). After 2008, 62.3% of patients were listed for LT with Child Pugh class C compared to 22.1% before 2008 (p<0.0001). CONCLUSION: A significant reduction of mortality has been registered on the Romanian WL for LT after 2008, despite the increased severity of liver disease in patients listed for LT.

Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma - a retrospective study.

AIM: This is a retrospective study of patients with advanced biliary tract carcinoma (BTC), who were treated with different regimens of chemotherapy. METHODS: We studied patients with advanced BTC registered at the Department of Oncology at the Fundeni Clinical Institute between 2004 and 2008. The following data were analyzed: rate of response, progression free survival (PFS) to first and second line of chemotherapy, overall survival (OS) and drug toxicity. Ninety-six patients were eligible having either advanced intra or extrahepatic cholangiocarcinoma, or gallbladder cancer with no prior chemotherapy. RESULTS: Out of 96 patients, 57 (59.4%) received fluoropyrimidines (FP)+cisplatin and 39 (40.6%) gemcitabine (Gem)+/-cisplatin. The median PFS for FP+cisplatin was 5.9 months (95%CI 5-6.9) and for Gem+/-cisplatin 6.3 months (95%CI 5.4-7.1), p=0.661. Median OS for FP+cisplatin was 10.3 months (95%CI 7.5-13.1) and for Gem+/-cisplatin 9.1 months (95%CI 7.0-11.2), p=0.098. On disease progression, 46 patients received second line CT (Gem or FP+/-platinum compounds). Median OS for patients with FP based first line and Gem+/-cisplatin in second line was 19 months (95%CI 8.9-29) higher than for the reverse sequence: 13.2 months (95%CI 12-14.4), but not statistically significant (p=0.830). All patients were evaluated for toxicities. Most patients (75.5%) reported at least one adverse event. CONCLUSION: Our results through direct comparison of FP+cisplatin with Gem+/-cisplatin as first line treatment did not show any statistical differences in terms of rate of response, PFS and OS. However, our study showed that FP+cisplatin as first line and Gem based second line therapy gave a better OS rate.

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.

Pegylated interferon alpha-2a and ribavirin combination therapy in HCV liver transplant recipients. Experience of 7 cases.

BACKGROUND: Hepatitis C virus (HCV) related cirrhosis represents the leading indication for liver transplantation (LT) worldwide and HCV reinfection is the rule among transplant recipients. Combination therapy with interferon and ribavirin is the treatment of choice for established recurrent hepatitis C. AIM: To evaluate the efficacy and safety of the combination of pegylated interferon alpha-2a and ribavirin in LT recipients with histological recurrence of hepatitis C. METHODS: Seven LT recipients with chronic hepatitis C recurrence were treated with peginterferon alpha-2a with an initial intended dose of 180 microg/week and an intended dose of ribavirin 800-1000 mg/day for at least 12 months and followed-up for at least 24 weeks. RESULTS: Early virological response rate was 57.1%. Three patients (42.8%) had end of treatment virological response and all had also sustained viral response (SVR). Five patients had end of treatment biological response, out of which 4 had also sustained biochemical response. Three patients had both SVR and sustained biochemical response. Four patients had end of treatment histological response, out of which 3 patients had also SVR. Cytopenia was the most common adverse event: anemia (57.1%), leucopenia/neutropenia (71.4%), thrombocytopenia (42.8%). CONCLUSION: Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients.

[Laparoscopic left lateral segmentectomy of the liver: indications, technique, results]. / Bisegmentectomia II-III laparoscopica: indicatii, tehnica, rezultate.

INTRODUCTION: The laparoscopic approach of the hepatic lesions located in the left lobe is a frequently used procedure in liver surgery for both benign and malign tumors because of the minimal invasive character, anatomical particularities and modem devices used in hemostasis and biliary-stasis. The purpose of this study is to analyze our experience and report it to the literature data. METHODS AND MATERIAL: The study starts from the basic indications of laparoscopic left lateral segmentectomy, it emphasizes the main operating steps and analyzes the results of this method in a cohort retrospective study in which we included all the laparoscopic resections performed in our center between 1998-2007, both laparoscopic and hand-assisted laparoscopic procedures. We excluded exploratory laparoscopies and the cases in which after the tumor exploration, we decided conversion to open approach in the absence of any intraoperative incidents. RESULTS: Between 1998-2007 we performed 84 laparoscopic hepatic resections out of which 20 were located in the left liver lobe. There were 12 left lateral segmentectomy and in 4 cases we used hand assisted laparoscopy due to bigger tumour dimensions. The hepatic lesions approached laparoscopically were both benign (5 cases out of which 3 hemangioma and 2 adenoma) and malignant (7 cases hepatocellular carcinoma). The tumor diameter ranged between 2-10 cm. The Pringle manoeuvre was never used. CONCLUSIONS: Left lateral segmentectomy can be routinely performed laparoscopically in the absence of any contraindications. This intervention can be accurately performed respecting the limits of oncological security. The results obtained in our center are in accordance with the literature and emphasize the advantages of the minimal invasive approach. On a medium and long term, the results are comparable with those obtained in open surgery.

Combined liver and islet transplantation using steroid-free immunosuppression.

Due to a vicious circle in which HCV favors insulin resistance and, alternatively, insulin resistance facilitates the persistence of HCV, HCV patients have often diabetes associated with liver cirrhosis. We present the case of combined liver and pancreatic islets transplantation performed in a patient with HCV liver cirrhosis associated with insulin-dependent diabetes. This is also the first case of islet allotransplantation in Romania. A 40-year-old male diagnosed with liver cirrhosis due to HCV infection and insulin dependent diabetes underwent combined liver and islet transplantation. Our therapeutic design was based on data provided by both the use of Edmonton immunosuppressive steroid-free protocol in islets cell transplantation and the findings of international studies on the effects of this protocol in liver transplantation for patients with HCV infection. Good metabolic control of the diabetes was obtained. The absence of anti beta cell autoimmunity could explain also the good tolerance for the transplanted islets, proved by the rapid and durable decrease of the insulin need, from 64 U/day to 20 U/day at one month post-transplantation, dose that was maintained for 16 months when the patient died due to recurrent HCV hepatitis. Islet transplantation can be associated to liver transplantation in order to improve the associated diabetes in cirrhotic patients.