Non-colorectal liver metastases: surgical treatment options.

BACKGROUND/AIMS: Due to different biological characteristics of non-colorectal liver metastasizes (NCLM), surgical treatment, especially it´s long term results, is a topic of discussion. The aim of the study was to evaluate the single center experience with surgical treatment of NCLM. METHODOLOGY: Seventy two patients were prospectively included. The average length of time after the primary surgery was 3.9 years (0-8.5 years). RFA prevailed -50 patients (69.4%), resection presenting 30.6%. Preoperative chemotherapeutical downstaging or portal vein embolization was performed on 12 patients (16.7%). Resectable or radiofrequency ablation (RFA) treatable extrahepatic metastasizes were removed in 26 patients (36.1%). RESULTS: One, three and five years patient survival after the liver resection or RFA was 88.6, 72.5 and 36.9%. The best survival rate was in patients with carcinoid (5 years-100%), breast cancer (5 years-33.8%), renal carcinoma (3 years-44.4% ) and gynecological tumors metastasizes (2 years-72.9%). With regards to long-term survival of patients, we did not find any statistically significant difference between RFA and resection. Patients with extrahepatic metastasizes had worse prognosis (p<0.01). CONCLUSIONS: Liver resection and RFA in NCLM have an unambiguous place in multi-modal curative strategy. The decision for surgical treatment of patients suffering from NCLM, is strictly individual with the aim of achieving qualitative long-term survival.

Effects of liver tumor and post-ablation necrosis volume on the result of radiofrequency ablation.

BACKGROUND/AIMS: To find out whether the total tumor mass and post-ablation necrosis volume influence the disease-free survival of patients following radiofrequency ablation (RFA). METHODOLOGY: Fifty nine patients with RFA of primary and secondary tumors were evaluated retrospectively in a four year period. Total liver mass, post-ablation necrosis volume and their ratio were evaluated using computed tomography examination in the relationship with the risk of insufficient tumor ablation and the disease-free patients survival. RESULTS: A complete ablation was performed in 51 patients, non-ablation in 8 (13.6%) patients. Tumor, necrosis volume were 19.2±19.5, 58.7±44.7mL, respectively. The tumor and necrosis mass ratio was 0.39±0.45. The tumor or necroses mass volume or the tumor/necroses mass ratio had no effect on the patients progression-free survival. Patients with a necrosis volume <25mL had a 10-times higher risk of insufficient ablation (OR=9.9; 95% CI=1.9-51.5; p<0.002) and patients with the tumor/necrosis mass ratio >0.4 had a 8-times higher risk of insufficient ablation (OR=7.9; 95% CI=1.4-44.6; p<0.01). CONCLUSIONS: Necrosis volume after RFA and tumor/necrosis mass ratio are the important factors for insufficient ablation but do not have any influence on the patients progression-free survival.

Prognostic value of the number and volume of liver tumours on portal vein embolization outcomes.

BACKGROUND/AIMS: Portal vein embolization (PVE) extends the resecability of liver tumours.The issue of PVE is an insufficient growth of the liver parenchyma or a tumour progression in some patients. We evaluated the effect of the volume and the number of liver tumours on the effect of PVE. METHODOLOGY: PVE was performed in 40 patients with liver tumours due to an insufficient future remnant liver volume. The number and the volume of the tumours were evaluated and compared with the final PVE effect. RESULTS: In patients without any increase of the liver volume after PVE (n=3) the number and the volume of the tumours before PVE were 2.7±2.1 and 2205.1±2432.7mm3, respectively. In patients with sufficient growth of the liver (n=22) it was 3.8±2.2 (NS) and 1164.9±1392.1mm3 (NS), respectively. In patients with tumour progression (n=11) it was 5.6±2.2 and 6971.4±5189.5mm3, respectively (p<0.04 and p<0.005, respectively). Four patients were treated by radiofrequency ablation only due to worsening of their health state. Patients with >4 foci (OR 4.7) and a tumour volume >400mm3 (OR=13.0) had a higher probability of cancer progression or insufficient growth of the liver tissue. Patients with <6 foci and a tumour volume <3100mm3 had an 87.5% probability of a successful liver hypertrophy after PVE. CONCLUSIONS: The tumour number and volume were crucial for progression of a malignant disease and growth of the liver parenchyma after PVE.

Tumour necrosis factor-alpha stimulates liver regeneration in porcine model of partial portal vein ligation.

BACKGROUND/AIMS: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Tumor necrosis factor- alpha (TNF-α) is a pleiotropic cytokine that is connected with initial phase of liver regeneration. The aim of this basic pilot study was to accelerate regeneration of liver parenchyma after PVL. The experimental porcine model was developed to be as much compatible as possible with portal vein embolization (PVE) in human medicine. METHODOLOGY: After ligation of portal branches of caudate and right lateral and right medial liver lobes recombinant porcine TNF-α (TNF-α group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed. RESULTS: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05); nevertheless this stimulating effect was lost at the end of experiment. The important differences in biochemical or histological studied parametres between study groups were not proved. CONCLUSIONS: The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-α confirms the role of studied cytokine in priming of liver regeneration.

Inhibition of transforming growth factor beta-1 augments liver regeneration after partial portal vein ligation in a porcine experimental model.

BACKGROUND/AIMS: TGF-ß1 is a pleiotropic cytokine that is over expressed in terminal phase of liver regeneration. METHODOLOGY: Twenty-four hours after partial portal vein ligation monoclonal antibody against TGF-ß1 (TGF-ß1 group, 7 piglets) or physiological solution (control group, 9 piglets) were applied into the central venous catheter. The biochemical parameters (bilirubin, urea, creatinine, alkaline phosphatase, gamma- glutamyl transferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase and albumin) were assessed. The compensatory hypertrophy of the non-occluded liver lobes was evaluated by periodic ultrasonography during the next fourteen days and by histological examination. RESULTS: The acceleration of growth of the hypertrophic liver lobes was maximal between 3rd and 7th postoperative days in comparison with the control group (p<0.05). No important differences in the biochemical or studied histological parameters were proved. CONCLUSIONS: The present study describes a new usage of monoclonal antibody against TGF-ß1 in large animal experimental model of partial portal vein ligation.

Interleukin-6 augments activation of liver regeneration in porcine model of partial portal vein ligation.

BACKGROUND: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Interuleukin-6 (IL-6) is a pleiotropic cytokine that is associated with an initial phase of liver regeneration. The aim of this study was to accelerate the regeneration of liver parenchyma after PVL by intraportal cytokine application. MATERIALS AND METHODS: After ligation of portal branches of caudate and right lateral and right medial liver lobes, recombinant porcine IL-6 (IL-6 group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed. RESULTS: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05), nevertheless, this stimulating effect was lost at the end of the experiment. Important differences in biochemical or histological studied parametres were not proved. CONCLUSION: The presented study describes the use of IL-6 for stimulation of the first phase of liver regeneration. The achieved acceleration of growth of hypertrophic liver lobes after application of IL-6 confirmed the key role of the studied cytokine in priming regenerating liver parenchyma after portal vein ligation.

Recurrence of colorectal liver metastases after surgical treatment: multifactorial study.

BACKGROUND/AIMS: The authors evaluated the significance of various factors regarding the recurrence of colorectal liver metastases (CLM) after liver resection or radiofrequency ablation. METHODOLOGY: 82 patients were operated on for CLM at our department between 1998 and 2003. Radical surgery was performed in 58 patients (74.4%), an palliative surgery in 20 (25.6%). Recurrence of the disease was recorded in 53 patients (71.6%), 21 (28.4%) were without any sign of recurrence. The factors examined in the multifactorial analysis were: age and sex, localization of the primary carcinoma, Dukes classification, grading, histology, microscopically free resection line, chemotherapy and radiotherapy after colorectal or liver surgery, different types of liver resection, radical versus palliative liver surgery, complication after liver surgery, laterality of metastatic process, number of metastases, blood transfusion, staging, repeated liver surgery. Long-rank and Wilcoxon test were used for the statistical evaluation. RESULTS: The factors statistically significant for disease-free interval after liver surgery were: unilaterality of metastatic process, microscopically free resection line, radical versus palliative surgical treatment. The survival rates after liver surgery and after the primary operation were dependent on grading, age, radical versus palliative resection, Dukes classification and staging. CONCLUSIONS: These factors could play an important role as predictors of colorectal cancer recurrence in patients' follow-up period after liver surgery for CLM.

Prognostic importance of some clinical and therapeutic factors for the effect of portal vein embolization in patients with primarily inoperable colorectal liver metastases.

INTRODUCTION: Portal vein embolization (PVE) may increase the resectability of liver metastases. However, the problem of PVE is insufficient growth of the liver or tumor progression in some patients. The aim of this study was to evaluate the significance of commonly available clinical factors for the result of PVE. MATERIAL AND METHODS: Portal vein embolization was performed in 38 patients with colorectal liver metastases. Effects of age, gender, time between PVE and liver resection, oncological therapy after PVE, indocyanine green retention rate test, synchronous, metachronous and extrahepatic metastases, liver volume before and after PVE, increase of liver volume after PVE and the quality of liver parenchyma before PVE on the result of PVE were evaluated. RESULTS: Liver resection was performed in 23 (62.2%) patients within 1.3 ±0.4 months after PVE. Tumor progression occurred in 9 (23.7%) patients and 6 (15.8%) patients had insufficient liver hypertrophy. Significant clinical factors of PVE failure were number of liver metastases (cut-off - 4; odds ratio - 4.7; p < 0.03), liver volume after PVE (cut-off 1000 cm(3); odds ratio - 5.1; p < 0.02), growth of liver volume after PVE (cut-off 150 cm(3); odds ratio - 18.7; p < 0.002), oncological therapy administered concomitantly with PVE (p < 0.003). CONCLUSIONS: Negative clinical factors of resectability of colorectal cancer liver metastases after PVE included more than four liver metastases, liver volume after PVE < 1000 cm(3), growth of the contralateral lobe by less than 150 cm(3) and concurrent oncological therapy.

Plasma TIMP1 level is a prognostic factor in patients with liver metastases.

UNLABELLED: TIMP1 (tissue inhibitor of metalloproteinases 1) regulates extracellular matrix turnover and also promotes cell growth and has anti-apoptotic activity, which promotes malignant processes in tumor tissue. The aim of our study was to evaluate the relation of plasma TIMP1 protein levels with prognosis in patients with liver metastases, with particular regard to possible early-prediction of recurrence of the disease. PATIENTS AND METHODS: We studied a group of 87 patients with metastatic liver disease (mostly from colorectal cancer) who underwent surgery for liver metastases, and assessed their preoperative plasma TIMP1 levels. These levels were evaluated according to prognosis. Furthermore, we measured plasma TIMP1 in the post-operative period and tried to relate the changes with the diagnosis of relapse. RESULTS: We found preoperative plasma TIMP1 levels to be related to overall survival in the group of all patients with metastatic liver disease (p=0.0047), with a higher level being associated with an adverse outcome; the cut-off value was set at 165 ng/ml. This applied to all patients, regardless of the type of surgery. Assessment of the post-operative dynamics of TIMP1 was not found to be statistically significant to indicate disease recurrence. CONCLUSION: We found there to be a relationship between higher plasma levels of TIMP1 and an adverse prognosis in patients with liver metastases. The assessment of plasma TIMP1 levels could help the detection of patients with worse outcome.

Predictive value of serum biomarkers in patients after portal vein embolization (PVE): a pilot study.

BACKGROUND/AIM: Insufficient growth of the liver or tumor progression is an important issue of portal vein embolization (PVE) in some patients. This study evaluated the predictive value of serum biomarkers for liver hypertrophy and tumor progression after PVE. PATIENTS AND METHODS: Serum levels of tumor markers, growth factors and cytokines were determined in 40 patients with malignant liver tumors in the pre- and post-PVE period. The values were compared with contralateral liver hypertrophy and tumor progression. RESULTS: Liver tissue hypertrophy occurred in 26 (65%), tumor progression in 11 (27.5%) and insufficient liver hypertrophy in 3 (7.5%) of the patients. The significant predictive biomarkers of PVE included serum TPA levels, monototal, IGF-BP3, IGF1, TGF-α, EGF, HGF, VEGF, TNFa and IL-10 before PVE; and TK, TPA, monototal, IGF-BP3, TGFa and IL-8 over the course of 28 days after PVE. CONCLUSION: Certain serum biomarkers have an important predictive value for the result of PVE.

Evaluation of tumour markers as differential diagnostic tool in patients with suspicion of liver metastases from breast cancer.

AIM: The liver is the site of breast cancer metastasis in 50% of patients with advanced disease. Tumour markers have been demonstrated as being useful in follow-up of patients with breast cancer, in early detection of recurrence of breast cancer after radical surgical treatments, and in assessing oncologic therapy effect, but no study has been carried out on their usefullness in distinguishing benign liver lesions from breast cancer metastases. The aim of this study was therefore to evaluate the importance of tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen CA19-9 (CA19-9), thymidine kinase (TK), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS) and cytokeratin 19 fragment (CYFRA 21-1) in differential diagnosis between benign liver lesions and liver metastases of breast cancer. PATIENTS AND METHODS: The study includes 3 groups: 22 patients with liver metastases of breast cancer; 39 patients with benign liver lesions (hemangioma, focal nodular hyperplasia, liver cyst, hepatocellular adenoma); and 21 patients without any liver disease or lesion that were operated on for benign extrahepatic diseases (groin hernia, varices of lower limbs) as a control group. The serum levels of tumour markers were assessed by means of immunoanalytical methods. RESULTS: Preoperative serum levels of CYFRA 21-1, TPA, TPS and CEA were significantly higher in patients with liver metastases of breast cancer in contrast to healthy controls and patients with benign liver lesions (p-value<0.05). Serum levels of CA19-9 and TK were higher in patients with malignancy in comparison with benign liver disease and healthy controls but these differences were not statistically significant. CONCLUSION: Tumour markers CEA, CYFRA 21-1, TPA and TPS can be recommended as a good tool for differential diagnosis between liver metastases of breast cancer and benign liver lesions.

Relevance of miR-21 and miR-143 expression in tissue samples of colorectal carcinoma and its liver metastases.

MicroRNAs, which are endogenously expressed regulatory noncoding RNAs, have an altered expression in colorectal cancer. The aim of our study was to assess the relationship of miR-21 and miR-143 expression to the prognostic/clinicopathological features of colorectal carcinoma (CRC) and colorectal liver metastases (CLM). The estimation was performed in 46 paired (tumor and control) tissue samples of CRC. Further, we studied 30 tissue samples of CLM. MiR-21 and miR-143 expressions were quantified by using the quantitative reverse transcription polymerase chain reaction method. Relation of miR-21 and miR-143 expression to disease-free interval (DFI) (Wilcoxon; P = 0.0026 and P = 0.0191, respectively) was recorded. There was shorter DFI in patients with a higher expression of miR-21 and, surprisingly, also in patients with a higher expression of miR-143, which is a putative tumor suppressor. There was a higher expression of miR-21 and lower expression of miR-143 in CRC tissue in comparison with adjacent normal colon tissue (P < 0.0001; P < 0.0001, respectively). Similarly, we observed a higher expression of miR-21 and a lower expression of miR-143 in CLM in comparison with normal colon tissue (P < 0.0001; P < 0.0001, respectively). Our results support the hypothesis about oncogenic function of miR-21 and show its relation to DFI. The role of miR-143 in carcinogenesis seems to be more complex.