The Impact of Chemotherapy and Transforming Growth Factor-ß1 in Liver Regeneration after Hepatectomy among Colorectal Cancer Patients.

An ongoing debate surrounds the impact of chemotherapy on post-hepatectomy liver regeneration in patients with colorectal cancer liver metastases (CRLM), with unclear regulatory mechanisms. This study sought to delve into liver regeneration post-resection in CRLM patients, specifically examining the roles of hepatocyte growth factor (HGF) and transforming growth factor ß1 (TGF-ß1). In this longitudinal observational study, 17 patients undergoing major liver resection for CRLM and 17 with benign indications as controls were enrolled. Liver regeneration within 30 postoperative days was assessed via CT, considering clinicopathological characteristics, liver enzymes, liver stiffness by elastography, and the impact of HGF and TGF-ß1 on liver regeneration. The results revealed that the control group exhibited significantly higher mean liver regeneration volume (200 ± 180 mL) within 30 days postoperatively compared to the CRLM group (72 ± 154 mL); p = 0.03. Baseline alkaline phosphatase (AP) and TGF-ß1 blood levels were notably higher in the CRLM group. Immunohistochemical analysis indicated a higher proportion of CRLM patients with high TGF-ß1 expression in liver tissues compared to the control group (p = 0.034). Correlation analysis showed that resected liver volume, baseline plasma HGF, AP, and albumin levels significantly correlated with liver regeneration volume. However, in multivariable analysis, only resected liver volume (ß: 0.31; 95% CI: 0.14-0.47, p = 0.01) remained significant. In conclusion, this study highlights compromised liver regeneration in CRLM patients post-chemotherapy. Additionally, these patients exhibited lower serum TGF-ß1 levels and reduced TGF-ß1 expression in liver tissue, suggesting TGF-ß1 involvement in mechanisms hindering liver regeneration capacity following major resection after chemotherapy.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in combination with FOLFOX chemotherapy as a first-line treatment for gastric cancer patients with peritoneal metastases: single-arm phase II study.

BACKGROUND: Gastric cancer (GC) remains among the most common and most lethal cancers worldwide. Peritoneum is the most common site for distant dissemination. Standard treatment for GC peritoneal metastases (PM) is a systemic therapy, but treatment outcomes remain very poor, with median overall survival ranging between 3-9 months. Thus, novel treatment methods are necessary. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the most novel technique for intraperitoneal chemotherapy. Some preliminary data suggest PIPAC can achieve improved long-term outcomes in patients with GC PM, especially when used in combination with systemic chemotherapy. However, there is a lack of data from well-design prospective studies that would confirm the efficacy of PIPAC and systemic therapy combination for first-line treatment. METHODS: This study is an investigator-initiated single-arm, phase II trial to investigate the efficacy of PIPAC combined with systemic FOLFOX (5-fluorouracil, oxaliplatin, leucovorin) as a first-line treatment for GC PM. The study is conducted in 2 specialized GC treatment centers in Lithuania. It enrolls GC patients with histologically confirmed PM without prior treatment. The treatment protocol consists of PIPAC with cisplatin (10.5 mg/m2 body surface in 150 mL NaCl 0.9%) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9%) followed by 2 cycles of FOLFOX every 6-7 weeks. In total 3 PIPACs and 6 cycles of FOLFOX will be utilized. The primary outcome of the study is the objective response rate (ORR) according to RECIST v. 1.1 criteria (Eisenhauer et al., Eur J Cancer 45:228-47) in a CT scan performed 7 days after the 4th cycle of FOLFOX. Secondary outcomes include ORR after all experimental treatment, PIPAC characteristics, postoperative morbidity, histological and biochemical response, ascites volume, quality of life, overall survival, and toxicity. DISCUSSION: This study aims to assess PIPAC and FOLFOX combination efficacy for previously untreated GC patients with PM. TRIAL REGISTRATION: NCT05644249. Registered on December 9, 2022.

Initial Experience of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Baltic Country Center.

Background: Peritoneal surface malignancies (PSMs) are a heterogenous group of primary and metastatic cancers affecting the peritoneum. They are associated with poor long-term outcomes. Many centers around the world adopt cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in routine clinical practice for these otherwise condemned patients despite a lack of high-level evidence from randomized control trials. This study aimed to investigate and present our 10-year experience with this controversial method, CRS and HIPEC, for PSM in a single tertiary center in a Baltic country. Methods: Patients who underwent CRS and HIPEC at Vilnius University Hospital Santaros Klinikos between 2011 and 2021 were included in this retrospective study. Overall survival was the primary study outcome. Secondary outcomes included postoperative morbidity and mortality, and local or systemic recurrence rates. Results: Sixty-nine patients who underwent CRS and HIPEC were included in the study. Most patients underwent treatment for peritoneal metastases from colorectal, ovarian, and appendiceal cancers. Six (8.7%) patients received CRS and HIPEC for primary peritoneal neoplasm-pseudomyxoma peritonei. The mean peritoneal carcinomatosis index score was 12 ± 7. Complete cytoreduction was achieved in 62 (89.9%) patients. The mean OS was 39 ± 29 months. The mean survival of patients with PSMs of different origin was as follows: 39 ± 25 (95% CI: 28-50) months for colorectal cancer, 44 ± 31 (95% CI: 30-58) months for ovarian cancer, 32 ± 21 (95% CI: 21-43) months for appendiceal cancer, 422 ± 1 (95% CI: 12-97) months for pseudomyxoma peritonei, and 7 months for gastric cancer. Conclusions: The current study demonstrated the results of the CRS and HIPEC program in a single Baltic country tertiary center. Patients who underwent CRS and HIPEC for PSMs achieved moderate survival rates with acceptable postoperative morbidity and mortality risk.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal malignancy: initial experience of the first program in the Baltic countries.

BACKGROUND: Peritoneal malignancies include primary and metastatic cancer of the peritoneal cavity. The most common origin for peritoneal metastasis is ovarian, gastric, and colorectal cancers. Irrespective of the origin, peritoneal metastases represent the advanced disease and are associated with poor long-term outcomes. The minimally invasive approach of pressurized intraperitoneal aerosol chemotherapy (PIPAC) allows repeated applications and objective assessment of tumor response by comparing histological samples. This study aimed to investigate the initial experience with PIPAC in the Baltic region. METHODS: All patients who underwent PIPAC at Vilnius University Hospital Santaros Klinikos between 2015 and 2020 were included in this retrospective study. The primary outcome of the study was overall survival (OS) in patients with peritoneal carcinomatosis treated by PIPAC. The secondary outcomes included postoperative morbidity; peritoneal carcinomatosis index (PCI) and ascites reduction after treatment by PIPAC. RESULTS: In total, 15 patients underwent 34 PIPAC procedures. PIPAC-related intraoperative and postoperative morbidity occurred in 3 (8.8%) of 34 procedures. Following PIPAC, the median PCI decreased from 8 (4; 15) to 5 (1; 16) in GC patients, although, the difference failed for significance, p = 0.581. In OC patients, PCI after PIPAC remained stable. Median overall survival after PIPAC procedure was 25 (95% CI 5-44) months. Ovarian cancer patients (22; 95% CI 12-44 months) had significantly higher OS, compared to gastric cancer patients (8; 95% CI 4-16 months), p = 0.018. CONCLUSIONS: PIPAC is safe and feasible for patients with gastric and ovarian cancers peritoneal metastases.

Short- and long-term outcomes of surgery for colorectal and non-colorectal liver metastasis: a report from a single center in the Baltic country.

BACKGROUND: The liver is a major target organ for metastases of various types of cancers. Surgery is a well-established option for colorectal liver metastases (CRLM). Regarding the improved surgical and anesthetic techniques, the safety of liver resection has increased. Consequently, the interest in the surgical management of non-colorectal liver metastases (non-CRLM) has gained significant attention. Therefore, this study was designed to investigate the surgical treatment outcomes for non-CRLM and to compare it with an outcome of CRLM in a tertiary care center in the Baltic country-Lithuania. METHODS: We retrospectively analyzed data from all patients who underwent liver resection for CRLM or non-CRLM between 2010 and 2017 in a tertiary care center-Vilnius University hospital Santaros Clinics. Demographic and metastasis characteristics, as well as disease-free and overall survival, were compared between the study groups. RESULTS: In total, 149 patients were included in the study. Patients in the CRLM group were older (63.2 ± 1.01 vs 54.1 ± 1.8 years, p < 0.001) and mainly predominant by males. Overall postoperative morbidity rate (16.3% vs 9.8%, p = 0.402) and major complications rate (10% vs 7.8%, p = 0.704) after liver resection for CRLM and non-CRLM was similar. Kaplan-Meier analysis showed higher disease-free survival in the CRLM group with 89.4% vs 76.5% and 64.9% vs 31.4% survival rates at 1 and 3 years, respectively (p = 0.042), although overall survival was not different between the CRLM and non-CRLM groups with 89.4% vs 78.4% and 72.0% vs 46.1% survival rates at 1 and 3 years, respectively (p = 0.300). CONCLUSIONS: In this study, we confirmed comparable short- and long-term outcomes after liver resection for CRLM and non-CRLM. Surgical resection should be encouraged as an option in well-selected patients with non-CRLM.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitonealy disseminated gastric cancer: A retrospective cooperative Central-Eastern European study.

BACKGROUND AND OBJECTIVES: Clinical experience in Western Europe suggests that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are promising methods in the management of gastric cancer (GC) with peritoneal metastases. However, there are almost no data on such treatment results in patient from Central-Eastern European population. METHODS: A retrospective cooperative study was performed at 6 Central-Eastern European HIPEC centers. HIPEC was used in 117 patients for the following indications: treatment of GC with limited overt peritoneal metastases (n = 70), adjuvant setting after radical gastrectomy (n = 37) and palliative approach for elimination of severe ascites without gastrectomy (n = 10). RESULTS: Postoperative morbidity and mortality rates were 29.1% and 5.1%, respectively. Median overall survival in the groups with therapeutic, adjuvant, and palliative indications was 12.6, 34, and 3.5 months. The only long-term survivors occurred in the group with peritoneal cancer index (PCI) of 0-6 points without survival difference in groups with PCI 7-12 vs PCI 13 or more points. CONCLUSIONS: GC patients with limited peritoneal metastases can benefit from CRS + HIPEC. Hyperthermic intraperitoneal chemotherapy could be an effective method of adjuvant treatment of GC with a high risk of intraperitoneal progression. No long-term survival may be expected after palliative approach to HIPEC.

Orthotopic liver transplantation: the first experience and results of the Vilnius University Hospital Santariskiu Klinikos.

BACKGROUND: Liver transplantation has become the treatment of choice for chronic and acute end-stage liver failure as well as for selected cases of malignancies and metabolic disorders. We report our first experience of the orthotopic liver transplantation. MATERIAL/METHODS: Between 2005 and 2008 16 cadaveric orthotopic liver transplantations in 16 adults (12 males, 4 females, mean age 44 years) were performed. Main indications for orthotopic liver transplantation were cholestatic liver disease (31%), viral-induced cirrhosis (25%), alcoholic liver disease (19%), hepatocellular carcinoma associated with hepatitis virus infection (13%), autoimmune cirrhosis (6%), cryptogenic acute liver failure (6%). Mean follow-up was 15 month (range: 4 days - 43 month). RESULTS: Intraabdominal haemorrhage was observed in 6 patients (37.5%). Vascular complications were observed in 3 patients (18.75%). Biliary complication were observed in 3 patients (18.75%). Overall 1 year patient survival was 87,5%. Four (25%) patients died during follow-up. All patients died because of sepsis and multiorgan system failure. CONCLUSIONS: Our first results showed that secret of successful liver transplantation is perfect interdisciplinary team approach, including selection of the recipient and timing of transplantation, the operative procedure itself, prevention and treatment of complications, the perioperative anaesthesiological and intensive-care management, and careful follow up after transplantation.

The comparison of 2-dimensional with 3-dimensional hepatic visualization in the clinical hepatic anatomy education.

OBJECTIVE: To determine whether 2-dimensional or 3-dimensional hepatic visualization is better for the medical students to be used while studying the clinical hepatic anatomy. MATERIAL AND METHODS: Twenty-nine patients who underwent surgical intervention due to focal hepatic pathology at the Department of General Surgery, University of Heidelberg, and at Clinics of Santariskes, Vilnius University Hospital were included in the retrospective cohort study. Before the surgical intervention, the computed tomography (CT) liver scan and 3-dimensional (3D) hepatic visualization were performed. A total of 58 2-dimensional and 3-dimensional digital liver images, mixed up in random sequence not to follow each other with a specially designed questionnaire, were presented to the students of Faculty of Medicine, Vilnius University. Their aim was to determine tumor-affected liver segments, to plan which liver segments should be resected, and to predict anatomical difficulties for liver resection. Results were compared with the data of real operation. RESULTS: The students achieved better results for tumor localization analyzing 3D liver images vs. CT scans. This was especially evident determining the localization of tumor in segments 5, 6, 7, and 8 (P<0.05). Furthermore, the results of proposed extent of liver resection have been found to be better with 3D visualization (mean+/-SD - 0.794+/-0.175) in comparison with CT scans (mean+/-SD - 0.670+/-0.200), (P<0.001). CONCLUSIONS: Computer-generated 3D visualizations of the liver images helped the medical students to determine the tumor localization and to plan the prospective liver resection operations more precisely comparing with 2D visualizations. Computer-generated 3D visualization should be used as a means of studying liver anatomy.

Controlled-surgical education in clinical liver transplantation is not associated with increased patient risks.

INTRODUCTION: A qualified surgical team is required to perform liver transplantation (LTX). Growing numbers of transplants at transplant centers and large variations of transplant frequencies make a continuous education to train young surgeons on this complex field of hepato-biliary surgery mandatory, both from the organizational and motivational point of view (job enrichment and professional growth). On the contrary, perioperative patient risk management is of major importance in surgical practice and given growing organizational concern in hospitals. A retrospective clinical study was performed to describe and evaluate the process of surgical training for orthotopic LTX. Patient risks associated with or caused by the education process in clinical LTX were analyzed. METHODS: Perioperative patient data and details of surgical strategies were collected for 155 consecutive LTX carried out at a single center. Operative and follow-up data were correlated with the degree of surgical experience of the first operating surgeon. Two groups were defined. In group A, transplant surgeons with >30 personally performed LTXs (n = 3) and in group B, transplant fellows with >30 assistance in LTx (n = 3) performed the operations. All LTX operations were standardized based on modified piggyback technique described by Belghiti. Group B operations were performed under close supervision/assistance of the ''transplant surgeon.'' Selection of patients for exposure to surgical training was based on the pre-operative estimation of surgical difficulty. Operative time, blood loss, liver function, post-operative morbidity, and survival rate data were compared in both groups. RESULTS: A total of 155 LTX were performed in 131 patients and were analyzed, and 106 operations (68.3%) were performed by group A and 49 operations (31.6%) were performed by transplant fellows under supervision (group B). No significant differences concerning mean patient age, distribution of type of disease, operating time, the Model for Endstage Liver Disease (MELD) score and frequency of category Child A, B and C were detected between groups. Overall post-operative complication rate was 21.9% (n = 34). Transplant surgeons and transplant fellows had 19.8% (n = 21) and 26.5% (n = 13) of complication rate, respectively (p > 0.05). Overall patients survival rate was 94% and 89% at 45 days for the patients operated in groups A and B, respectively (p > 0.05). Survival rate, blood loss, intraoperative transfusion requirements and operating time did not differ significantly between groups. CONCLUSIONS: Liver transplantation requires team performance to minimize patient risks. Incidence of complications was associated with the severity of disease but not with the education process. It could be demonstrated that with careful patient selection and supervision of the transplant fellow with a more experienced surgeon, the results are equal to those obtained when the experienced transplant surgeon is the prime operator.

Surgical strategies for liver transplantation in the case of portal vein thrombosis--current role of cavoportal hemitransposition and renoportal anastomosis.

Portal vein thrombosis (PVT), a common complication of end stage liver disease, is no longer considered a definite contraindication for liver transplantation (LTx). The clinical decision to perform an LTx in the case of PVT depends on the degree of PVT and the experience of the surgeon. Eversion thromboendovenectomy was suggested by most authors as the surgical technique of choice for PVT grade 1, 2, and 3. If PVT obstructs more extended parts of the porto-mesenteric venous circulation, surgical options would include different types of venous jump graft reconstructions or arterialization of the portal vein. Combined liver and small bowel transplantation is another possible alternative. Cavoportal hemitransposition (CPHT) and renoportal anastomosis (RPA) were recently particularly advocated as creative surgical strategies in case of diffuse PVT. In this work, we focus on CPHT and RPA surgical techniques during LTx, which attempts to secure the portal flow to the liver graft in case of pre-existent diffuse PVT. We provide a review of all reported clinical experience at international clinical centers using these techniques. According to our meta-analysis a total of 15 studies were published on this topic between 1996 and 2005. In summary, a total of 56 orthotopic LTx have been performed in 53 patients (28 men, 25 women) combined with either CPHT or RPA, for the purpose of providing the donor graft with adequate inflow. Mean age was 44 yr including two patients who were infants, with the youngest recipient being two yr old. Main indications for LTx were liver cirrhosis caused by viral hepatitis, alcoholic cirrhosis and cryptogenic cirrhosis. CPHT was performed in 46 cases, and RPA in 10 cases. Thirty-five of 53 patients (66%) had surgery previous to LTx. Of these, 13 patients (37%) [corrected] presented with a history of other previous surgical procedures for decompression of portal hypertension or treatment of associated complications (portocaval shunts, splenectomy, etc). Ascites, renal dysfunction, lower extremity and torso edema and variceal bleeding were dominant post-operative complications after CPHT or RPA noted in 22 cases (41.5%), 18 cases (34%), 17 cases (32%) and 13 cases (24.5%) respectively. Patients' follow-up ranged from two to 48 months. Thirty nine of 53 patients [corrected] (74%) survived [corrected] and 14 patients died (26%) [corrected] during the course of observation. Based on the literature, we conclude that the ideal technique to overcome PVT during LTx is still controversial. Short-term follow-up results of both methods are promising, however, long-term results are unknown at present. Furthermore, clinical follow-up and basic experimental work is required to evaluate the influence of systemic venous inflow to the liver graft with respect to long-term liver function and liver regeneration.