[Impact of preoperative drug therapy on the expression of angiogenesis markers in colorectal liver metastases]. / Vliyanie predoperatsionnoi lekarstvennoi terapii na ekspressiyu markerov angiogeneza v metastazakh kolorektal'nogo raka v pecheni.

AIM: to study changes in the expression of angio- and vasculogenesis markers in colorectal adenocarcinoma metastases to the liver during combined cytotoxic and targeted anti-VEGF therapy versus cytotoxic monotherapy. SUBJECTS AND METHODS: Intraoperative samples from 96 patients with colorectal adenocarcinomas metastases to the liver were immunohistochemically examined. The investigation enrolled patients who had preoperatively received either combined FOLFOX6 cytotoxic therapy and targeted anti-VEGF therapy with bevacizumab or only FOLFOX6 therapy, as well as patients who had not received preoperative anti-tumor drug treatment. The expression of SDF1α, CXCR4, CXCR7, and VEGF-A was compared in these groups. Statistical significance was accepted at p<0.05. RESULTS: The expression of CXCR4 in the vessel endothelial cells was significantly less frequently detected in the patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy as compared to those had not drug therapy. Comparing the patients treated with cytotoxic drugs with those who had not received anti-tumor therapy revealed similar results in the women. CXCR7 expression in the tumor cells and stromal cells from the metastatic foci was significantly more common in the group of male patients treated with cytotoxic drugs according to the FOLFOX6 regimen. The expression of SDF1α in the tumor cells was significantly more often observed in the male patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy than in those who had not drug therapy. VEGF expression in the stromal cells was significantly less frequently seen in the patients who had received the combined therapy. CONCLUSION: Combined cytotoxic therapy and targeted anti-VEGF therapy for colorectal adenocarcinoma metastases to the liver leads to some suppression of the alternative pathway in the formation of new vessels, by reducing the expression of CXCR4 in the vessel endothelial cells and that of VEGF in the stromal cells from the metastatic foci. In men, this therapy simultaneously causes an increase in the expression of SDF1α in the tumor cells and in that of CXCR4 in the stroma. Preoperative FOLFOX6 therapy significantly increases the expression of CXCR7 in the tumor cells and stromal cells in the male patients, which may suggest that this pathway in vessel formation can be activated.

[Impact of preoperative drug therapy on the expression of apoptosis markers in colorectal liver metastases].

AIM: to estimate the expression of p53 protein, effector caspases-3 and -7, and the antiapoptotic protein survivin in colorectal adenocarcinoma metastases to the liver in patients who have received preoperative cytotoxic and combined cytotoxic and target anti-VEGF therapies. SUBJECTS AND METHODS: Intraoperative samples from 122 patients with colorectal carcinoma metastases to the liver were immunohistologically examined. The investigation included patients who had received preoperative treatment with cytotoxic drugs, combined cytotoxic and targeted anti-VEGF therapy. A control group consisted of patients who had not received preoperative anti-tumor drug treatment. RESULTS: Expression of Caspase 3, including that of survivin, was significantly more frequently detected in the patients who had received combined cytotoxic and anti-VEGF therapy as compared to both those treated with only cytotoxic agents (p=0.00004) and the control group (p=0.0008) As compared to the latter, the women who had received cytotoxic therapy were found to have no survivin expression (p=0.015). Investigation of the expression of caspase-7 and p53 revealed no statistically significant differences between the three groups. CONCLUSION: Addition of bevacizumab to preoperative standard therapy regimens for colorectal adenocarcinoma metastases to the liver leads to activated apoptosis in tumor cells, by enhancing the expression of effector caspase 3. At the same time, standard cytotoxic chemotherapy regimens in women results in activated apoptosis, by decreasing the expression of the antiapoptotic protein survivin.

[Radiofrequency ablation in combined treatment of metastatic colorectal liver cancer]. / Radiochastotnaya ablyatsiya v kombinirovannom lechenii metastaticheskogo kolorektal'nogo raka pecheni.

AIM: To study surgical and oncological outcomes in patients with metastatic colorectal liver cancer who underwent radiofrequency ablation in the structure of combined approach. MATERIAL AND METHODS: It is a prospective analysis of treatment of 76 patients with metastatic colorectal liver cancer who underwent RFA for the period 2004-2013. Overall survival was analyzed using univariate and multivariate analysis. RESULTS: According to univariate analysis overall 5-year survival is negatively determined by following factors: primary localization of the tumor in rectum (36.2% and 7.2%; p=0.021); bilobed metastatic liver disease (35.9% and 15.4%; p=0.068); metastases dimensions over 5 cm (27.4% and 0%, p=0.091); augmentation of CAE levels over 4 norms (26.7% and 11.4%, p=0.09); RFA as a component of two-stage liver surgery (23.3% and 26.0%, p=0.09). CONCLUSION: RFA is an effective method of local antineoplastic effect for metastatic colorectal cancer. Dimensions of coagulated metastases, volume of metastatic lesion, carcinoembryonic antigen level, ablation as a component of two-stage surgery affect long-term survival after RFA.

[Impact of preoperative drug therapy on adhesion molecule expression in colorectal cancer liver metastases].

OBJECTIVE: To study E-cadherin and ß-catenin expression in colorectal cancer (CRC) liver metastases in order to assess the impact of different drug therapy regimens on the adhesive properties of tumor cells. MATERIAL AND METHODS: Intraoperative metastatic CRC samples from patients who had received preoperative cytotoxic chemotherapy or combined cytotoxic and targeted anti-VEGF (vascular endothelial growth factor) therapy were immunohistochemically examined using antibodies to E-cadherin and ß-catenin. A comparison group consisted of patients who had not received drug therapy. RESULTS: Combined therapy with cytotoxic and anti-VEGF agents was shown to result in a significant increase in the number of cases of normal membrane localization of E-cadherin as compared with control (p = 0.00043) and cytotoxic therapy-alone (p = 0.01) groups. A comparison of ß-catenin levels in three patient groups revealed no significant differences, but addition of an anti-VEGF agent caused some decrease in the number of cases of abnormal nuclear localization of the protein as compared to both the control group and the cytotoxic therapy groups. The comparison of E-cadherin and ß-catenin localization in tumor cells showed that a combination of normal E-cadherin membrane localization and ß-catenin membrane-cytoplasmic expression prevailed in the combined therapy group compared to the control (p = 0.009) and cytotoxic therapy (p = 0.04) groups. CONCLUSION: The addition of a targeted anti-VEGF agent to the drug therapy of metastatic CRC has a positive impact on the cadherin-catenin complex, leading to increased intercellular contacts and suppressed ß-catenin functioning as a transcription factor that enhances tumor cell proliferation.

[Prevention of gastrostasis after pancreaticoduodenal resection: new technique of gastroenterostomy].

It was performed a retrospective comparative analysis of treatment results of 113 patients with pancreatic head and periampular cancer. The main group consisted of 58 patients in whom pancreaticoduodenal resection was performed according to an original technique of Russian Scientific Center of Surgery. Control group included 55 patients who underwent end-to-side gastrojejunostomy reconstruction. We have analyzed immediate postoperative complications in 2 groups without taking into consideration nosological forms of the disease. Pancreaticojejunostomy failure was diagnosed postoperatively in 5 (8.6%) patients in main group and in 10 (18.2%) patients in control group. There was no hepaticoentero- and gastroenterostomy failure in patients who underwent new technique of gastrojejunostomy while these events were observed in 8 (14.5%) and 3 (5.5%) patients respectively in control group. Mortality was 1.7% (n=1) in main group and 5.5% (n=3) in control group (p=0.29). Mild degree of gastrostasis (A class) was observed in 54 (93.7%) patients of main group and in 34 (61.8%) patients of control group (p=0.0004). There was B class of gastrostasis in 4 (6.9%) patients of main group. Severe gastrostasis (C class) was not revealed in any observation. In control group B class of gastrostasis was diagnosed in 14 (25.5%) patients, severe degree - in 7 (12.7%) patients. Univariant analysis showed hemotransfusion (p=0.037), pancreatic fistula (p=0.001), enteric fistula (p=0.005) and reconstruction technique (p=0.00004) as predictors of gastrostasis. Multivariant analysis defined pancreatic fistula (p=0.01), enteric fistula (p=0.04) and reconstruction technique (p=0.001) as significant predictors of gastrostasis. Thus, our study revealed significant decreasing gastrostasis incidence in case of original technique in comparison with conventional anastomosis, as well as demonstrated effect of anastomoses failure on augmentation of gastrostasis frequency after pancreaticoduodenal resection. Further randomized investigations are necessary to confirm our results.

Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases.

BACKGROUND: The management of patients with colorectal cancer and simultaneously diagnosed liver and lung metastases (SLLM) remains controversial. METHODS: The LiverMetSurvey registry was interrogated for patients treated between 2000 and 2012 to assess outcomes after resection of SLLM, and the factors associated with survival. SLLM was defined as liver and lung metastases diagnosed 3 months or less apart. Survival was compared between patients with resected isolated liver metastases (group 1, control), those with resected liver and lung metastases (group 2), and patients with resected liver metastases and unresected (or unresectable) lung metastases (group 3). An Akaike test was used to select variables for assessment of survival adjusted for confounding variables. RESULTS: Group 1 (isolated liver metastases, hepatic resection alone) included 9185 patients, group 2 (resection of liver and lung metastases) 149 patients, and group 3 (resection of liver metastases, no resection of lung metastases) 285 patients. Ten variables differed significantly between groups and seven were included in the model for adjusted survival (age, number of liver metastases, synchronicity of liver metastases with primary tumour, carcinoembryonic antigen level, node status of the primary tumour, initial resectability of liver metastases and inclusion in group 3). Adjusted overall 5-year survival was similar for groups 1 and 2 (51·5 and 44·5 per cent respectively), but worse for group 3 (14·3 per cent) (P = 0·001). CONCLUSION: Patients who had resection of liver and lung metastases had similar overall survival to those who had undergone removal of isolated liver metastases.

The role of prognostic models in metastatic colorectal liver cancer surgery.

INTRODUCTION: Patients with metastatic colorectal liver cancer differ from each other by some characteristics which affect on the prognosis of disease. Long-term results and, consequently, the prognosis depend on not one but group of factors which may be incorporated into mathematical models allowing to classify patients according to their risk of recurrence or prognosis of survival. AIM: To calculate survival in patients with metastatic colorectal liver cancer and to evaluate the most popular models of 3- and 5-year survival rate prognosis after liver resection. MATERIAL AND METHODS: We analyzed the results of treatment of 342 patients with metastatic colorectal cancer who underwent different resections since 1991 to 2014. The effectiveness of prognostic models was estimated according to the most popular scales that were developed based on groups of more than 200 patients. RESULTS: Long-term results were followed in 312 (91.2%) patients. Median life in the total group of patients was 24 months in 3-, 5- and 10-year survival of 56.3%, 36.1% and 18.1% respectively. The most accurate stratification of patients into groups was obtained using preoperative Rees scale for 5-year and 3-year survival (C-statistics - 0.73 and 0.69, respectively). Analysis of Iwatsuki and Fong scales for 5-year survival prediction (C-statistics - 0.68 and 0.62) and postoperative Rees scale for 3-year survival (C-statistics - 0.63) also showed relatively good results. None of models showed C-statistics level over 0.8. CONCLUSION: Stratification of patients according to prognostic scales should not affect on monitoring of patients with high risk of recurrence and poor prognosis of survival.

[Transarterial therapy for hepatocellular cancer].

AIM: To estimate treatment of patients with hepatocellular cancer after transarterial chemoembolization as independent curative method, "bridge" to liver transplantation and in the context of combined therapy. MATERIAL AND METHODS: We presented an experience of transarterial chemoembolization in treatment of 29 patients with hepatocellular cancer. Curative procedures were performed in the context of independent therapy, "bridge" to liver transplantation and combined treatment. It was performed 48 procedures in all. 44.9% of patients underwent one and two procedures, 10.2%--three performances. Mean interval between procedures was 76.2±116.2 days (range 8-139 days). RESULTS: Post-embolization syndrome including fervescence, nausea and pain was observed in 24.1% after 1st stage, in 50% and 33.3% after 2nd and 3rd stages respectively. Mean time of expectation of liver transplantation in bridge therapy group was 8.5±6.8 months (range 1-20 months). Median survival after transarterial chemoembolization in monotherapy group was 9 months.

[Impact of preoperative chemotherapy on the expression of apoptosis factors in colorectal cancer liver metastases].

OBJECTIVE: To study the effects of cytotoxic and targeted anti-VEGF drugs on some mechanisms of apoptosis. MATERIAL AND METHODS: The effects of cytotoxic and targeted anti-VEGF drugs on the expression of the apoptosis activators Bax and PML and the apoptosis inhibitor Bcl-2 were studied in the colorectal cancer (CRC) liver metastases; a comparison group comprised patients receiving no chemotherapy. RESULTS: Immunohistochemical examination revealed lower Bax and PML expressions and higher Bcl-2 expression in the majority of untreated patients, suggesting the suppressed mechanisms triggering tumor cell apoptosis. Cytotoxic therapy resulted in a statistically significant rise in the expression of the apoptosis activator Bax (p = 0.01), a reduction in the level of the apoptosis inhibitor Bcl-2 (p = 0.04) and a slight increase in PML that controlled the induction of apoptosis. Adding an anti-VEGF agent to cytotoxic therapy exerted no statistically significant impact on Bax and Bcl-2, but caused more frequent positive PML expression than in the control and cytotoxic chemotherapy groups. CONCLUSION: Our study showed that cytotoxic and targeted anti-VEGF agents activate the apoptosis of tumor cells in the CRC liver metastases.

[Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) - new opportunity in two-stage liver resection in patients with colorectal cancer metastases].

Major hepatic resection is often necessary for cure in patients with multiple colorectal cancer metastases but low future liver remnant (FLR) volume makes surgery risky because of the posthepatectomy liver failure (PHLF). Right portal vein ligation/embolization and two-stage hepatectomy were proposed previously to overcome this problem. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel approach aimed for FLR volume hypertrophy. During the first stage right portal vein is ligated followed by liver parenchyma in situ splitting. Right liver lobe removal is performed during the second stage when FLR hypertrophy becomes sufficient. Three patients with colorectal cancer liver metastases were scheduled for major hepatic resection. ALPPS was applied because of insufficient FLR volume. We observed FLR hypertrophy of 77, 90 and 70% after 7, 7 and 14 days waiting period. FLR/Total Liver Volume ratio increased from 22, 23 and 15% to 33, 35 and 32% respectively. The second stage was performed successfully in all patients. All patients are alive and they have not disease relapse after 17, 15 and 15 months after surgery. ALPPS is promising technique that allows rapid FLR hypertrophy and enables curative liver resections in initially unresectable patients. But it is necessary more data concerning ALPPS safety and long-term results.

[The training concept of laparoscopic surgery in post-graduate education of doctors].

The active use of virtual devices and laparoscopic boxes for the control of the achieved skills level are the general idea of the suggested concept of the laparoscopic surgical training. The in vivo training make sense only after finishing the "virtual" course. The complete realization of these new concept of laparoscopic surgery training is possible only in frames of the endoscopic surgery department of the mighty hospital center. The organization of such center promise to rise the level of doctors' training.

[Novel approach to two-stage hepatic surgery (in situ splitting)].

Two-stage liver surgery with preliminary right portal vein occlusion procedure (ligation or embolisation) became standard in clinical practice and allows liver resections in 60-82% of initially inoperable patients. Right portal vein ligation with concomitant liver partition in situ (in situ splitting, ISS) is innovatory and promising approach. Right portal vein ligation and in situ splitting was performed in 40 years old male with two metachronous rectal metastases in right liver lobe and insufficient volume of future liver remnant (22%). MRI on 7th postoperative day showed left liver lobe hypertrophy rate of 77% and left liver lobe volume increase from 22 to 33.5%. Right hemihepatectomy was performed on day 8 after the first stage. There were no signs of postoperative liver failure. Conclusion. New two-stage surgery approach (ISS) can decrease number of patients who were inoperable because of insufficient volume of future liver remnant and high risk of postoperative liver failure.

[The surgical hepatology in SCS: from the beginning to development].

The article highlights survey stakes of surgical hepatology in world and Russia, and the 20 years experience of the Russian Scientific Center of Surgery named after B.V. Petrovskiy. 472 liver resections were performed during the period. Main indications for surgery were malignant liver tumors, predominantly metastatic (75.8%). Technical and tactical questions, as well as treatment results were discussed. The issue compares own data with world's experience.

[Recent advances of monitoring and glycaemia control during early postoperative period in patients after pancreas surgery].

Recently new technologies of diagnostics and correction of carbohydrates metabolism disturbances are introduced in the ICU to improve the safety for patients during intensive care. 33 patients after pancreas surgery were included into the study 13 patients (39%) had underlying diabetes mellitus. Glucose level changes in the interstitial liquid of the subcutaneous fat during postoperative period were monitored by system of CGM Medtronic MiniMed Guardian RT, MiniMed Paradigm Real-time. Valid values of glucose were from 4.1 to 10.1 mmol/L. Episodes of glucose level increasing occurred in 94% of patients in postoperative period after pancreas surgery. Average level of glucose was within the limits of valid values. However in 64% of cases patients needed insulin therapy Used systems of continuous glucose monitoring in the ICU allow improving the safety for patients receiving artificial nutrition and intravenous insulin therapy.

[Alveococcosis of liver: retrospective analysis of treatment of 51 patients].

51 patients with liver alveococcosis were operated on: radical operations with the whole hydatid tumor removal, cytoreductive operations with 50-80% of the tumor removal and alveococcal nodes' preserving on vital organs; and palliative manipulations, aimed the relief of complications were performed. According to the treatment results, the radical liver resection proved to be the most effective. When the complete tumor removal is impossible, cytoreductive operations are possible. Combination with antiparasitic therapy is required.

[The liver hemangioms: operation or observation].

The treatment results of 178 patients with liver hemangioms were analyzed. 322 liver hemangioms of the average size of 36,5 (4-350) mm were diagnosed in 178 patients. 50 (28%) patients were operated on. The largest operated lesion was 100mm. Basic indications to the surgical treatment were: symptomatic course of the disease (42%), unclear diagnosis (24%) and fast growth of the lesion (16%). The lethality rate was 2% (1 of 50), postoperative complications were registered in 24% (12 of 50). Tumor enucleation was performed in 12 (24%) cases, the liver resection - in 38 (76%). The long-term follow-up (average of 55 months) was achieved in 50%(89 of 178) patients. The were no symptoms of the disease in 88,5% of the operated patients and they disappeared in 84% of the non-operated patients. The majority of the patients with the nonsympomatic course of the disease showed anuy negative dynamics of the process. Thus, in 85,2% there were no hemangiom growth registered, 11,1% demonstrated the enlargement of the lesion on 13-38 mm, and 3,7% showed the smaller diameter of the tumour. The study highlights the seldom necessity of the operative treatment of liver hemangioms: by severe symptoms, unclear diagnosis and the fast tumour growth. The enucleation of the tumor is preferable to the liver resection. The exact diagnosis permits the long observance with the ultrasound control as often as once a year.