Variation in complications and mortality following ALPPS at early-adopting centers.

BACKGROUND: Various, often conflicting, estimates for post-operative morbidity and mortality following ALPPS have been reported in the literature, suggesting that considerable center-level variation exists. Some of this variation may be related to center volume and experience. METHODS: Using data from seventeen centers who were early adopters of the ALPPS technique, we estimated the variation, by center, in standardized 90-day mortality and comprehensive complication index (CCI) for patients treated between 2012 and 2018. RESULTS: We estimated that center-specific 90-day mortality following treatment with ALPPS varied from 4.2% (95% CI: 0.8, 9.9) to 29.1% (95% CI: 13.9, 50.9), and that center-specific CCI following treatment with ALPPS varied from 17.0 (95% CI: 7.5, 26.5) to 49.8 (95% CI: 38.1, 61.8). Declines in estimated 90-day mortality and CCI were observed over time, and almost all individual centers followed this trend. Patients treated at centers with a higher number of ALPPS cases performed over the prior year had a lower risk of post-operative mortality. CONCLUSION: Despite considerable center-level variation in ALPPS outcomes, perioperative outcomes following ALPPS have improved over time and treatment at higher volume centers results in a lower risk of 90-day mortality. Morbidity and mortality remain concerningly high at some centers.

ALPPS for Locally Advanced Intrahepatic Cholangiocarcinoma: Did Aggressive Surgery Lead to the Oncological Benefit? An International Multi-center Study.

BACKGROUND: ALPPS is found to increase the resectability of primary and secondary liver malignancy at the advanced stage. The aim of the study was to verify the surgical and oncological outcome of ALPPS for intrahepatic cholangiocarcinoma (ICC). METHODS: The study cohort was based on the ALPPS registry with patients from 31 international centers between August 2009 and January 2018. Propensity score matched patients receiving chemotherapy only were selected from the SEER database as controls for the survival analysis. RESULTS: One hundred and two patients undergoing ALPPS were recruited, 99 completed the second stage with median inter-stage duration of 11 days. The median kinetic growth rate was 23 ml/day. R0 resection was achieved in 87 (85%). Initially high rates of morbidity and mortality decreased steadily to a 29% severe complication rate and 7% 90-day morbidity in the last 2 years. Post-hepatectomy liver failure remained the main cause of 90-day mortality. Multivariate analysis revealed insufficient future liver remnant at the stage-2 operation (FLR2) to be the only risk factor for severe complications (OR 2.91, p = 0.02). The propensity score matching analysis showed a superior overall survival in the ALPPS group compared to palliative chemotherapy (median overall survival: 26.4 months vs 14 months; 1-, 2-, and 3-year survival rates: 82.4%, 70.5% and 39.6% vs 51.2%, 21.4% and 11.3%, respectively, p < 0.01). The survival benefit, however, was not confirmed in the subgroup analysis for patients with insufficient FLR2 or multifocal ICC. CONCLUSION: ALPPS showed high efficacy in achieving R0 resections in locally advanced ICC. To get the most oncological benefit from this aggressive surgery, ALPPS would be restricted to patients with single lesions and sufficient FLR2.

Animal Models for Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Achievements and Future Perspectives.

BACKGROUND: Since 2012, Associated Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been standing in the limelight of modern liver surgery and numerous questions have been raised regarding this novel approach. On the one hand, ALPPS has proved to be a valuable method in the treatment of hepatic tumors, while on the other hand, there are many controversies, such as high mortality and morbidity rates. Further surgical research is essential for a better understanding of underlying mechanisms and for enhancing patient safety. SUMMARY: Until recently, only 8 animal models have been created with the purpose to mimic ALPPS-induced liver regeneration. From these 7 are rodent (6 rat and 1 mouse) models, while only 1 is a large animal model, which uses pigs. In case of rodent models, portal flow deprivation of 75-90% is achieved via portal vein ligation leaving only the right (20-25%) or left median (10-15%) lobes portally perfused, while liver splitting in general is carried out positioned according to the falciform ligament. As for the swine model, the left lateral and medial lobes (70-75% of total liver volume) are portally ligated, and the right lateral lobe (accounting for 20-24% of the parenchyma) is partially resected in order to reach critical liver volume. Each model is capable of reproducing the accelerated liver regeneration seen in human cases. However, all species have significantly different liver anatomy compared with the human anatomic situation, making clinical translation somewhat difficult. Key Messages: Unfortunately, there are no perfect animal models available for ALPPS research. Small animal models are inexpensive and well suited for basic research, but may only provide limited translational potential to humans. Clinically large animal models may provide more relevant data, but currently no suitable one exists.

[The importance of postoperative circulatory alterations in hepatic surgery]. / A posztoperatív keringésváltozások jelentosége a májsebészetben.

There are two afferent (hepatic artery, portal vein) and one efferent (hepatic veins) systems responsible for the unique circulation of the liver. Given this special form of vasculature, acute, isolated (i.e. involving selectively one particular vessel) vascular occlusions may lead to different, however still life threatening conditions. Hence, it is essential to recognize these anomalies in order to preserve the healthy state of both the liver and the patient's lives. Acute circulatory failures are dominantly associated with liver surgery. Adequate therapy can only be provided promptly, if the clinician is well aware of the peculiarities of these conditions. The aim of this study is to overview the etiology and symptoms of these clinical conditions; furthermore to offer technical proposals for the required diagnostic and therapeutical steps via case reports. Furthermore, hepatic injury, caused by ischemia-reperfusion secondary to total vascular occlusion (Pringle maneuver) used in hepatic surgery is outlined.

[Laparoscopic surgery of benign liver tumours]. / Benignus májdaganatok laparoszkópos resectiója.

273 patients underwent elective surgical treatment for benign liver lesions at the 1st Surgical Department of Semmelweis University, Budapest, Hungary between 2004 and 2014. Laparoscopic (LAP) interventions were performed in 83 cases. Cyst fenestration in 52, and hepatic resection in 31 cases. LAP liver resections were set against to open surgery of paired group of patients with comparable demographic and clinical parameters. Data revealed that the operative time in LAP group (113.7 min) was significantly longer than that in the open surgery group (89.5 min). The average postoperative length of hospital stay was shorter after LAP surgery (5.8 vs 9.1 days). There was no postoperative complication in the LAP group, two wound infections and one biliary collection were treated by ultrasonic drainage in the open group. Three patients were given blood transfusion in the LAP, four in the open group. Operative mortality was zero, and no reoperation required. The surgical technique which is described in detail in the text enables safe resection of segments 7-8 which are difficult to approach. Our data support the safety and feasibility of laparoscopic liver resection after adequate preoperative investigations.

Long-term outcomes after breast cancer liver metastasis surgery: A European, retrospective, snapshot study (LIBREAST STUDY).

INTRODUCTION: Breast cancer (BC) is the most common malignant tumor in women. Between 20 % and 30 % of patients develop metastases from BC, 50 % of them in the liver. The mean survival rate reported in patients with liver metastases from BC (LMBC) ranges from 3 to 29 months. The role of surgery in LMBC is not clearly defined. The objective of the present study was to determine the long-term survival and disease-free survival of patients undergoing surgery for LMBC and to identify the patients who most likely benefit from surgery. MATERIAL AND METHODS: This retrospective multicenter cohort study included all consecutive patients undergoing LMBC surgery at the participating European centers from January 1, 2010, to December 31, 2015. The ClinicalTrials.gov ID is NCT04817813. RESULTS: A hundred women (mean age 52.6 years) undergoing LMBC surgery were included. Five-year disease-free survival was 29 %, and 5-year overall survival was 60 %. Median survival after BC surgery was 12.4 years, and after LMBC surgery, 7 years. Patients with ECOG 1, ASA score I-II, metachronous LMBC, positive hormone receptors, and who had received neoadjuvant and adjuvant hormone treatment obtained the best overall and disease-free survival results. CONCLUSIONS: In cases of correct patient selection and as part of a comprehensive onco-surgical strategy, surgery for LMBC improves overall long-term survival. In our series, certain factors were linked to better disease-free and overall survival; consideration of these factors could improve the selection of the best candidates for LMBC surgery. GOV ID: NCT04817813.

[ALPPS (Associated Liver Partition and Portal vein ligation for Staged hepatectomy) -- faster and greater growth of liver]. / ALPPS (Associated Liver Partition and Portal vein ligation for staged hepatectomy) -- gyorsabb, nagyobb májhypertrophia.

CASE REPORT: 75 years old female patient was referred with large, multifocal colorectal liver metastasis. Prior to this consultation she received chemotherapies of various protocols and series. Liver metastasis, however, increased at about 3 times of the original size during the 5 months of the oncological treatment. A right extended hepatectomy was planned to remove the tumor, but the residual liver (FLR) was found to be too small. Portal occlusion technique was necessary to induce the hypertrophy of the FLR. Due to rapid tumor progression we decided to perform the first ALPPS (PVL + in situ split) procedure in Hungary. After a very fast (9 days) and significant (94%) hypertrophy of the FLR the planned liver resection was successfully performed.

Microvascular flow imaging to differentiate focal hepatic lesions: the spoke-wheel pattern as a specific sign of focal nodular hyperplasia.

Microvascular flow imaging (MVFI) is an advanced Doppler ultrasound technique designed to detect slow-velocity blood flow in small-caliber microvessels. This technique is capable of realtime, highly detailed visualization of tumor vessels without using a contrast agent. MVFI has been recently applied for the characterization of focal liver lesions and has revealed typical vascularity distributions in multiple types thereof. Focal nodular hyperplasia (FNH) constitutes an important differential diagnosis of malignant liver tumors. In this essay, we provide iconographic documentation of the MVFI appearance of FNH and other common solid liver lesions. Identifying the typical patterns of vascularity, including the spoke-wheel pattern with MVFI, can expedite the diagnosis, spare patients from unnecessary procedures, and save costs.

Multimodality management of focal nodular hyperplasia / A focalis nodularis hyperplasia multimodális kezelése

Focal nodular hyperplasia (FNH) is the second most common benign mass of the liver. According to the current recommendations, removal makes relative indication. Several different treatment methods are known. The purpose of the paper is to provide a summary of FNH care and to present alternative treatment options in two cases. A 40-year old woman was investigated for abdominal complaints; CT scan confirmed FNH of the liver. Given the localization of the lesion, we chose transarterial embolization (TAE) due to the high risk of surgical resection. After multiple treatments, regression was achieved, and the patient became asymptomatic. Painful FNH in a 25-year-old female was confirmed by MRI. The lesion was dominantly seen in segment 1, causing vena cava compression and collaptiform episodes. As a definitive solution, liver resection was performed, after which her complaints ceased. Long-term follow-up of patients may be sufficient when asymptomatic FNH is detected. In the case of symptoms or high risk of surgery, TAE can be used effectively by FNH either alone or in combination with surgical treatment. For lower-risk patients, primary laparoscopic resection is the most appropriate choice.

The effect of ischemic preconditioning on redox status during liver resections--randomized controlled trial.

BACKGROUND AND OBJECTIVES: Portal clamping during liver resection decreases intraoperative blood loss, but causes ischemic-reperfusion (I-R) injury. Intermittent portal clamping (IPC) and ischemic preconditioning (IP) decreased I-R injury in animal models. Most of the human studies about IP excluded cirrhotic patients, whose liver is more vulnerable to I-R injury. The effect of IP and IPC during extended liver resection was investigated in this randomized controlled trial, with special respect to cirrhotic patients. METHODS: One hundred sixty patients (100 normal liver, 60 cirrhotic) undergoing major liver resection were randomized to receive IPC (15 min ischemia, 5 min reperfusion), or IP (10 min ischemia, 10 min reperfusion). Serum oxygen-derived free radicals (ODFR) and antioxidant concentrations (preoperative, after reperfusion and 7th postoperative day), such as "conventional" liver tests (preoperative, 1st, 3rd, and 7th postoperative day) were measured. RESULTS: IP resulted in significantly lower peak ODFR, AST, ALT, and bilirubin levels after liver resection than IPC (P < 0.05). The level of serum antioxidants after reperfusion was significantly higher in IP than in IPC groups (P < 0.05). In cirrhotic patients without IP none of these values normalized until the 7th postoperative day. CONCLUSIONS: Ischemic preconditioning--especially in patients with liver cirrhosis--is a suitable method to decrease the I-R injury of the liver.

Single-port cholecystectomy through the lateral ring of the left inguinal hernia.

BACKGROUND: Single-port surgery was developed by the evolution of the laparoscopy. The advantage of this new method is mainly cosmetic, but the risk of the hernia-owing to the larger port-increased. CASE REPORT: A 71-year-old man was admitted with a left lateral inguinal hernia and gallbladder stones. After preparation of the sac of the hernia, a single-port was inserted into the lateral ring and a cholecystectomy was performed. The operation was completed by the reconstruction of the abdominal wall using a polypropylene mesh. The total operating time was 85 minutes. CONCLUSION: In the case of the combined operation, the defect of the abdominal wall could be used as a location of the single port, and the trauma of the abdominal wall could be avoided. This is the first publication about single-port cholecystectomy where the ring of the inguinal hernia was used as a placement site of the single port.

Polymyositis and rhabdomyolysis caused by hepatocellular carcinoma - Case report and literature review.

INTRODUCTION: Rhabdomyolysis is a syndrome characterized by a rapid necrosis of muscle fibers and the release of muscle-derived metabolic products into the circulatory system. A rare cause of rhabdomyolysis is paraneoplastic polymyositis. CASE PRESENTATION: A 67-year-old man was diagnosed with paraneoplastic polymyositis and rhabdomyolysis caused by hepatocellular carcinoma (HCC). Intravenous steroid was used as a symptomatic therapy for rhabdomyolysis, and the tumour was removed by left hemihepatectomy to treat the underlying cause. After muscle strength gradually improved, steroid therapy was discontinued. The patient was reoperated multiple times due to bleeding and bile leakage. Following the operations, his overall state and muscle strength further improved. Despite that, the patient's condition worsened again, and eventually, he died of candida albicans pneumonia and sepsis. DISCUSSION: HCC is an extremely rare cause of paraneoplastic polymyositis and rhabdomyolysis. Treatment is challenging, as none of the few available case reports record long term survival and less than half of the reports record muscle strength improvement. In our case, the patient was treated with systemic steroid therapy and resection of the tumour. The patient's muscle strength temporarily improved, but subsequently, the patient died. CONCLUSION: Our case confirms the importance of a definitive treatment of HCC, as we achieved a significant improvement in muscle strength by removing the tumour. On the other hand, our paper highlights the dangers of double-sided steroid therapy, which, combined with the essential, effective treatment of rhabdomyolysis, may have contributed to the development of postoperative complications and candida sepsis leading to death.

[Decreasing morbidity after Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) with technical modification and patient selection]. / Speciális májmutét (Associating Liver Partition and Portal vein ligation for Staged hepatectomy, ALPPS) morbiditásának csökkentése átértékelt betegkiválasztási elvek és mutéttechnikai módosítás révén.

Introduction: Resecability of liver tumors is exclusively depending on the future liver remnant (FLR). The remnant can be hypertrophised using portal vein occlusion techniques. The latest hypertrophising method is Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS), which provides the most significant induced hypertrophy in the shortest time. Morbidity and mortality of this procedure were initially unacceptably high. Aim: Reducing complications by better patient selection and modified surgical technique. Method: The First Department of Surgery, Semmelweis University, Budapest, prefers the 'no touch' technique, instead of 'complete mobilization'. For optimizing patient selection, an international registry (including our patients' data) was established. In addition to the surgical, we collected demographic, disease, liver function, histology, morbidity (Clavien-Dindo) and mortality parameters. Volume and function measurements were performed by using CT-volumetry and 99mtechnecium-mebrofenin SPECT/CT. Data were analyzed by multivariate analysis (significance: p<0.05). Results: We performed 20 ALPPS procedures from 2012 to 2018. The relative volume increment and resectability in our department and among the 320 registry patients were 96% vs. 86% and 95% vs. 98%. Using 'no touch' technique, the Clavien-Dindo III-IV morbidity and mortality rates were significantly lower (22%-0%) than with 'complete mobilization' (63%-36%) (p<0.05). Based on the multivariate analysis of the registry patients, age over 60 years, liver macrosteatosis, non-colorectal liver tumor, >300 minutes operation time, >2 units of red blood cell transfusion, or insufficient FLR function before stage 2 were identified as independent factors influencing mortality (p<0.05). Conclusion: Mortality and morbidity of ALPPS can be reduced by proper patient selection and 'no touch' surgical technique. Orv Hetil. 2019; 160(32): 1260-1269.

Oxidative stress with altered element content and decreased ATP level of erythrocytes in hepatocellular carcinoma and colorectal liver metastases.

Our aim was to study the possible alterations of redox status (enzymatic and nonenzymatic parameters and metal elements) in erythrocytes of patients with hepatocellular carcinoma (HCC), colorectal liver metastases (CRLM) and benign liver neoplasms. The function of redox homeostasis is closely connected to the energy level of erythrocytes, therefore, the ATP level was also determined. Antioxidant parameters, enzyme activities of superoxide dismutase and glutathione peroxidase were estimated in the erythrocytes of 11 patients with benign tumour, 23 patients with primary malignant and 37 metastatic liver tumour patients and 30 age-matched and sex-matched healthy controls. Element content with inductively coupled plasma optical emission spectrometer and ATP level by the chemiluminometric method were also determined from the samples. Free radical intensity was significantly increased, whereas erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the HCC and CRLM groups versus benign groups and controls. Se, Mn and Zn levels were lowered in HCC and CRLM groups versus benign and control groups. The content of Cu, Mg, Se and Zn changed significantly between HCC and CRLM groups. Similarly, ATP concentration decreased in HCC and CRLM versus controls and benign groups. The lowest levels of ATP and antioxidant enzyme activities were found in the case of CRLM patients. These results reveal an alteration in the ATP level of erythrocytes with concomitant changes in the antioxidant defence system in hepatic cancer patients. Altered redox homeostasis (oxidative damage) may lead to decreased ATP level and consequently may play an important role in primary carcinogenesis and generation of metastases, as well.

Short-term alanyl-glutamine dipeptide pretreatment in liver ischemia-reperfusion model: effects on microcirculation and antioxidant status in rats.

BACKGROUND & AIMS: Ischemia-reperfusion (I-R) injury is responsible for the morbidity associated with liver surgery. Production of toxic free radicals influences the microcirculation. The aim of our study was to examine the effect of glutamine (Gln) supplementation--adminstered in alanyl-glutamine dipeptide form--on liver function, immuno/histopathology and the oxidative state of the liver after injury. METHODS: Two-hundred and fifty grams male Wistar rats underwent normothermic, 60 min, segmental liver ischemia followed by 6 h of reperfusion. The animals (n = 45) were divided into three groups: sham operated, I-R and parenteral Gln pretreatment. Hepatic microcirculation was monitored by laser Doppler flowmetry. At the 6 h of reperfusion, histological alterations, TUNEL reaction, active caspase-3 reaction, serum and liver tissue antioxidant levels, serum ALAT, ASAT and TNF-alpha levels were measured. RESULTS: Upon reperfusion, the Gln group had significantly (p<0.05) higher flow rates than the I-R group and, at the end of the 6h of reperfusion, significantly (p<0.05) lower serum ALAT and ASAT levels. The liver chemiluminescent intensity was lower, free SH-groups were elevated, while the reducing power was decreased in the Gln-pretreated group. Positive staining for caspase-3 after Gln pretreatment was significantly increased in contrast to the control tissues. CONCLUSION: Glutamine pretreatment is beneficial in supporting hepatic microcirculation and can prevent hepatocellular necrosis in liver reperfusion injury.

In depth evaluation of the prognostic and predictive utility of PTEN immunohistochemistry in colorectal carcinomas: performance of three antibodies with emphasis on intracellular and intratumoral heterogeneity.

BACKGROUND: Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer. Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy. Unfortunately, while immunohistochemical assessment of PTEN expression is widespread, it lacks standardization and the results are hardly comparable across the available publications. METHODS: Retrospectively collected, formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray (TMA) blocks. We used three different PTEN antibodies to determine the frequency, intensity and intracellular pattern of PTEN immunohistochemical labeling: Neomarkers, Dako and CellSignaling. We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity (H1-H3-score). We also evaluated intracellular localization. RESULTS: The Dako and CellSignaling antibodies stained predominantly cytoplasms, while the Neomarkers antibody specifically stained cell nuclei. PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies. Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies. Neither Dako, neither CellSignaling, nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT, Dukes/MAC and clinical stage. KRAS status, histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody. PTEN H-scores did not correlate with MMR status. PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody. CONCLUSIONS: While PTEN expression decreased in colorectal cancer according to two antibodies, neither of the three applied PTEN antibodies could justify significant correlation with clinicopathological data, nor had prognostic value. Thus, we might conclude that immunohistochemical PTEN investigation remains a challenge requiring more standardized evaluation on larger number of cases to clarify its utility as a prognostic and predictive tool in CRC. The standardization of immunohistochemical method is key in the evaluation process, which is further discussed.