Liver resection, or hepatectomy, is a major abdominal surgery performed most often for the removal of malignant tumors of the liver, either primary or metastatic. It is often associated with significant blood loss and therefore, with blood transfusions. While transfusions are common, there is incomplete knowledge of their effects on clinical outcomes. Furthermore, both current practices and best practices in perioperative blood management, including blood product administration, are not well defined. This manuscript-based thesis will examine the clinical impact, current practices, and appropriate use of perioperative red blood cell transfusions for patients undergoing liver resection.

Ideally, tumors that might cause morbidity and mortality should be treated, preferably early, with proven, convincing, and effective therapy to prevent tumor progression or recurrence, while maintaining a favorable risk-benefit profile for the individual patient. For patients with colorectal cancer (CRC), this diagnostic, prognostic, and therapeutic precision is currently impossible. Despite significant improvements in diagnostic procedures, a sizable number of patients with CRC have liver metastases either at presentation or will subsequently develop it. And in many parts of the world, most cancer-related deaths are still due to metastases that are resistant to conventional therapy. Metastases to the liver occur in more than 50% of patients with CRC and represent the major determinant of outcome following curative treatment of the primary tumor. Liver resection offers the best chance of cure for metastases confined to the liver. However, due to a paucity of randomized controlled trials, its timing is controversial and a hotly debated topic. This article reviews some of the main controversies surrounding the surgical management of colorectal cancer liver metastases (CRLM).

Ideally, tumors that might cause morbidity and mortality should be treated, preferably early, with proven, convincing, and effective therapy to prevent tumor progression or recurrence, while maintaining a favorable risk-benefit profile for the individual patient. For patients with colorectal cancer (CRC), this diagnostic, prognostic, and therapeutic precision is currently impossible. Despite significant improvements in diagnostic procedures, a sizable number of patients with CRC have liver metastases either at presentation or will subsequently develop it. And in many parts of the world, most cancer-related deaths are still due to metastases that are resistant to conventional therapy. Metastases to the liver occur in more than 50% of patients with CRC and represent the major determinant of outcome following curative treatment of the primary tumor. Liver resection offers the best chance of cure for metastases confined to the liver. However, due to a paucity of randomized controlled trials, its timing is controversial and a hotly debated topic. This article reviews some of the main controversies surrounding the surgical management of colorectal cancer liver metastases (CRLM).

In recent years laparoscopic liver surgery established itself into today’s standard of care regarding surgical liver treatment. It was a long way for minimally invasive liver resection to develop and popularize as it was accompanied by initial reservations and concerns. Some of these already had been clarified while other questions still remain and require further investigation in the complex field of laparoscopic liver surgery. Initial concerns with respect to oncological inferiority and technical inapplicability in contrast to open surgery treatment could have been disproved within the framework of retrospective studies. In contribution to that, the aim of the study was to compare the surgical results and postoperative outcomes of consecutive laparoscopic liver resections (LLR) and open liver resections (OLR) at the high-volume liver tumor center of Leipzig university hospital. Since common classification systems for open liver surgery cannot be applied for LLR, the introduction of specific difficulty scoring systems for LLR helps to assess and classify the complexity of minimal invasive liver resection. With an increase in experience, modification of hybrid surgery and the application of novel visualization techniques such as indocyanine green (ICG) staining or hyperspectral imaging (HSI), more challenging procedures were accomplished, that initially would have been contraindicated for the laparoscopic approach (e.g. perihilar cholangiocarcinoma (pCCA) requiring biliary reconstruction). During the years 2018 and 2019 42% of all liver resections were approached laparoscopically at the Leipzig University hospital. A retrospective data analysis of n=231 patients undergoing LLR or OLR for the years 2018 and 2019 was performed and previously determined variables were collected. As a primary outcome measure, the short-term surgical and postoperative outcome of patients receiving LLR (=LLR group) compared to the patient cohort being treated by open resection (=OLR group) was evaluated. All liver resections were executed or assisted by the same two surgeons. Prior to surgery, every case was reviewed in a multidisciplinary tumor-board meeting and primarily assessed for possible minimal invasive approach. Analysis for patient demographics, pathologic diagnosis, radiologic findings and peri- and intraoperative surgical data was carried out. For LLRs intraoperatively, ICG counter perfusion staining was used in anatomic liver resection and direct ICG tumor staining was employed for tumor demarcation. With respect to classification, the extent of OLR was graded according to the Brisbane 2000 terminology in minor and major resections, whereas LLRs were categorized by means of difficulty (in accordance with Ban et al. and Di Fabio et al.). For measurement of surgical complication and assessment of morbidity, the Clavien-Dindo classification was applied. OLR was performed in n=124 (57%) and LLR in n=93 (43%). From all minimally invasive treated patients, 79% were operated totally laparoscopic and 16% were laparoscopic-hand-assisted due to infeasible lesions in the posterosuperior segments 7, 8 and 4a. In 5 cases a conversion to open surgery was necessary because of inaccessibility, tumor infiltration or morbid obesity. 28% of patients had previous upper abdominal surgery, whereof 36% in the OLR group and 19% in the LLR group. Regarding patient demographics, the mean age was significantly higher in OLR and the sex ratio was in favor of men for both groups. Malignant tumor lesions comprised 77%, while 24% were benign lesions. In both groups this larger number of malignant oncologic operation remained valid. The most common benign indications comprised focal nodular hyperplasia (FNH) and liver adenomas. It was shown that patients with CCA and Colorectal liver metastases (CRLM) were predominantly treated by open surgery, while patients with HCC diagnosis received LLR to a greater extent. Concerning the type of liver resection, non-anatomical resections were the most frequent in the cohort with 47%, thereof 55% LLR and 40% OLR. Followed second most by anatomic right and left hemihepatectomies and third most by left lateral resections, which were predominantly performed in laparoscopic technique. On the other hand, extended resections and trisectionectomies were predominantly operated by OLR. Radical lymphadenectomy was performed to a greater extent during OLR. Results showed that the mean operative time was longer for OLR (341 minutes in median) compared to LLR (273 minutes in median). Also the mean length of hospital stay was shorter for LLR patients, as well as abdominal drains were placed to lesser extent in LLR compared to OLR. In regard to R0-resection, R0-rates were higher in LLR with 98% vs. 86% in OLR. Thereby being highest for CRLM resections, followed by HCC and CCA. Putting all liver resections into classification systems, it was found that of all open procedures, 52% had major and 48% underwent minor resection according to Brisbane 2000. From the LLR group, in accordance with Di Fabio et al. 39% were classified as laparoscopic major hepatectomies, comprising 44% laparoscopic traditional major hepatectomies (LTMH) and 56% laparoscopic posterosuperior major hepatectomies (LPMH), which were technically challenging. The difficulty index stated by Ban et al. was classified as low for 8% of all performed LLRs, intermediate for 45% and of high difficulty in even 47%. Relating to morbidity (=Clavien-Dindo 3b or greater), patients with LLR had significantly lower morbidity compared to OLR. The same applies for in-hospital mortality. Our data show that despite the high number of complex and high-difficulty-classified liver resections that were performed, morbidity and mortality rates were low. As mentioned before, R0 resection rate in the LLR group was better than in the OLR group, however, this was not a case matched study, so a direct comparison is not valid. But still the study could demonstrate that the high number of LLRs being performed at the Leipzig University hospital, did not impair R0-resection rates. With an overall hospital mortality rate of 5.9% in the cohort, good results were achieved. Particularly the low rate of 1% in the LLR group speaks for itself and confirms that the development of a minimal invasive liver resection program should be on the right track. The majority of patients in the LLR and OLR group received an oncologic resection, what also resembles the global attitude that minimally invasive techniques are not reserved for selected tumor entities. Still it should be emphasized, the indication for a liver resection should not be loosened just due to minimal invasive accessibility, especially in benign liver lesions. Nevertheless, in the study the majority of benign lesions was operated by LLR. A few patients diagnosed with CCA received LLR. Thereof predominantly iCCA cases were indicated for a minimal invasive approach without biliary duct reconstruction and satisfying short-term outcomes over OLR could be obtained. However, only one case of pCCA which required Roux-Y bile duct reconstruction was treated with LLR in the study group, so if laparoscopic surgery is capable to replace the open approach in terms of treatment strategies for pCCA remains questionable. Patients with CRLM represent the centerpiece of our study population, still only 13% received LLR. The main reason of applying OLR was the high tumor load requiring future liver remnant augmentation strategies. As liver resection is confirmed to be the approach of choice for patients with HCC in cirrhosis, it is not surprising that HCC diagnosis accounted for the major part of LLRS in our collective.:Vorbemerkung und Bibliographie, 3 Abkürzungsverzeichnis, 4 Einführung, 5 - 1. Development of minimal invasive liver surgery, 5 - 2. Prior concerns of LLR, 6 - 3. Benefits of laparoscopic surgery, 6 3.1 General advantages of minimal invasive surgery, 6 3.2 Specific benefits of applying LLR, 7 - 4. Indications for LLR, 7 4.1 Benign liver lesions, 8 4.2 Malignant liver lesions, 8 4.3 Liver transplantation, 9 - 5. Technical supplement, 9 5.1 Hybrid and hand-assisted techniques, 10 - 6. Classification systems, 11 6.1 Difficulty scoring, 11 6.2 Clavien-Dindo Classification ,12 - 7. Limitations of LLR, 12 - 8. Aim of the study, 13 Publikation, 14 Zusammenfassung, 26 Literaturverzeichnis, 30 Darstellung des eignen Beitrags, 34 Selbstständigkeitserklärung, 35

Background: The value of liver-directed therapy (LDT) in patients with metastasic renal cell carcinoma (MRCC) is still an active field of research, particularly in the era of tyrosinkinase inhibitor (TKI) therapy. Methods: The records of 35 patients with MRCC undergoing LDT of metastasic liver lesions between 1992 and 2015 were retrospectively analyzed. Immediate postoperative TKI was given in a subgroup of patients after LDT for metastasic lesions. Uni- and multivariate models were applied to assess overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS). Results: Following primary tumor (renal cell cancer) resection and LDT, respectively, median OS was better for a total of 16 patients (41 %) receiving immediate postoperative TKI with 151 and 98 months, when compared to patients without TKI therapy with 61 (p = 0.003) and 40 months (p = 0.032). Immediate postoperative TKI was associated with better median PFS (47 months versus 19 months; p = 0.023), whereas in DFS only a trend was observed (51 months versus 19 months; p = 0.110). Conclusions: LDT should be considered as a suitable additive tool in the era of TKI therapy of MRCC to the liver. In this context, postoperative TKI therapy seems to be associated with better OS and PFS, but not DFS.

Racional: O carcinoma hepatocelular é uma neoplasia maligna agressiva com elevada morbidade e mortalidade. Objetivo: Revisão da literatura sobre o diagnóstico e o manejo do carcinoma hepatocelular nos vários estágios da doença. Método: Revisão da literatura utilizando a base Medline/PubMed e literatura adicional. Resultados: O carcinoma hepatocelular é geralmente complicação da cirrose hepática. As hepatites virais crônicas B e C também são fatores de risco para o surgimento do carcinoma hepatocelular. Quando associado à cirrose hepática, o carcinoma hepatocelular geralmente surge a partir da evolução de um nódulo regenerativo hepatocitário que sofre degeneração maligna. O diagnóstico é efetuado através de tomografia computadorizada de abdome com contraste endovenoso (efeito wash in e wash out), e a ressonância magnética pode auxiliar nos casos que não possam ser definidos pela tomografia computadorizada. O único tratamento potencialmente curativo para o carcinoma hepatocelular é a ressecção do tumor, seja ela realizada através de hepatectomia parcial ou de transplante. Infelizmente, apenas cerca de 15% dos carcinomas hepatocelulares são passíveis de tratamento cirúrgico. Pacientes portadores de cirrose hepática estágio Child B e C não devem ser submetidos à ressecção hepática parcial. Para esses pacientes, as opções terapêuticas curativas restringem-se ao transplante de fígado, desde que selecionáveis para esse procedimento, o que na maioria dos países dá-se através dos Critérios de Milão (lesão única com até 5 cm de diâmetro ou até três lesões de até 3 cm de diâmetro). A sobrevida em 5 anos para pacientes transplantados para o carcinoma hepatocelular pode alcançar 70% Conclusão: Quando diagnosticado em seus estágios iniciais, o carcinoma hepatocelular é potencialmente curável. O conhecimento das estratégias de 17 diagnóstico e tratamento do carcinoma hepatocelular a fim propiciam sua identificação precoce e a indicação de tratamento apropriado. / Introduction: Hepatocellular carcinoma is an aggressive malignant tumor with high lethality. Aim: A literature review on diagnosis and management of hepatocellular carcinoma was performed. Methods: Literature review utilizing databases Medline/PubMed. Results: Hepatocellular carcinoma is a common complication of hepatic cirrhosis. Chronic viral hepatitis B and C also constitute as risk factors for development of hepatocellular carcinoma. In patients with cirrhosis, hepatocelular carcinoma usually develops from a malignant transformation of a dysplastic regenerative nodule. Diagnosis is confirmed through computed tomography scan with intravenous contrast (wash in and wash out effect), and magnetic resonance may be helpful in some instances. Curative treatment for hepatocellular carcinoma may be performed through partial liver resection or liver transplantation. Only 15% of all hepatocellular carcinomas are localized and amenable to operative treatment. Patients with Child C liver cirrhosis are not amenable to partial liver resections. The only curative treatment for hepatocellular carcinomas in patients with Child B or C cirrhosis is liver transplantation. In most countries, only patients with hepatocellular carcinoma under Milan Criteria (single tumor with up to 5 cm diameter or up to three nodules with a maximum diameter of 3 cm) are considered candidates for liver transplant. Five-year survival following liver transplantation for hepatocellular carcinoma may reach 70%. Conclusion: Hepatocellular carcinoma is a potentially curable neoplasm if discovered in its initial stages. Clinicians and surgeons should be familiar with strategies for early diagnosis and treatment of hepatocellular carcinoma as a way to decrease mortality associated with this malignant neoplasm.

Various techniques are used to transect the liver. With increase in laparoscopic liver resections (LLR), it is of even more interest to develop surgical techniques to minimize bleeding and the risk for gas embolism during transection. Instrument like argon enhanced coagulator provides good hemostasis but increases the danger of gas embolism. The CO2 pneumoperitoneum that is routinely used in most types of laparoscopic surgery can be modified by the use of different gas pressure. It can be assumed that different pressure influences bleeding but also the risk for gas embolism. In presented porcine studies, three instrumental combinations have been studied. In study I sixteen piglets were randomized to LLR with either the cavitron ultrasonic aspirator (CUSA™) in combination with vessels sealing system (Ligasure™) or with CUSA™ and ultrascision scissors (Autosonix™), with the endpoints of intra-operative bleeding and gas embolism.  In study IV sixteen piglets were randomized to LLR either with staple device (Endo-GIA™) or the Ligasure™ - CUSA™ combination with same primary endpoints and additionally secondary endpoints of effect on gas-exchange, systemic- and pulmonary hemodynamic. Focusing on intra-abdominal pressure (IAP) in study II, sixteen piglets were randomized to LLR with an IAP of either 8 or 16 mmHg.  Primary endpoints were bleeding and gas embolism and secondary endpoints, effect on gas-exchange, systemic- and pulmonary hemodynamic. In study III effect of argon gas was tested during LLR. Sixteen piglets were randomized to either argon pneumoperitoneum or CO2 pneumoperitoneum. Primary endpoints were effect on gas-exchange, systemic- and pulmonary hemodynamic. In presented studies, we tested efficacy and safety of different techniques for LLR. CUSA™ can be used in combination with either Ligasure™ or Autosonix™. However, Ligasure™ reduces the amount of bleeding. The recent introduction of staplers seems promising with a further reduction in bleeding, gas embolism, and operating time. The IAP influences both the amount of bleeding as well as gas embolism. It seems reasonable to use a higher IAP to decrease bleeding with caution and with close monitoring for gas embolism. Argon gas embolism gives more extensive effect on gas-exchange and hemodynamic and should probably be avoided in this type of surgery.

This is a prospective, non-randomized pilot study comparing the cost-utility of hepatic resection, radiofrequency ablation (RFA), systemic chemotherapy, and symptom control only for the treatment of colorectal liver metastases. Seven patients underwent hepatic resection, 7 underwent RFA, 20 received chemotherapy, and 6 received symptom control alone. Liver resection provided an average of 2.51 QALY’s compared to 1.99 QALY’s for RFA, and 1.18 QALY’s for chemotherapy, and 0.82 QALY’s for symptom control alone. The costs were $20,122, $ 15,845, $15,069, and $3,899, respectively. The cost-utilities of liver resection and RFA were similar at $8,027 and $7,965 per QALY, respectively, although patients receiving RFA generally had more advanced disease. The cost-utility of chemotherapy was $12,751/QALY and the cost-utility of symptom control alone was $4,788/QALY. RFA is still a relatively new. However, if long-term survival proves promising, it may prove to be a viable alternative to liver resection. / May 2006

This is a prospective, non-randomized pilot study comparing the cost-utility of hepatic resection, radiofrequency ablation (RFA), systemic chemotherapy, and symptom control only for the treatment of colorectal liver metastases. Seven patients underwent hepatic resection, 7 underwent RFA, 20 received chemotherapy, and 6 received symptom control alone. Liver resection provided an average of 2.51 QALY’s compared to 1.99 QALY’s for RFA, and 1.18 QALY’s for chemotherapy, and 0.82 QALY’s for symptom control alone. The costs were $20,122, $ 15,845, $15,069, and $3,899, respectively. The cost-utilities of liver resection and RFA were similar at $8,027 and $7,965 per QALY, respectively, although patients receiving RFA generally had more advanced disease. The cost-utility of chemotherapy was $12,751/QALY and the cost-utility of symptom control alone was $4,788/QALY. RFA is still a relatively new. However, if long-term survival proves promising, it may prove to be a viable alternative to liver resection.

This is a prospective, non-randomized pilot study comparing the cost-utility of hepatic resection, radiofrequency ablation (RFA), systemic chemotherapy, and symptom control only for the treatment of colorectal liver metastases. Seven patients underwent hepatic resection, 7 underwent RFA, 20 received chemotherapy, and 6 received symptom control alone. Liver resection provided an average of 2.51 QALY’s compared to 1.99 QALY’s for RFA, and 1.18 QALY’s for chemotherapy, and 0.82 QALY’s for symptom control alone. The costs were $20,122, $ 15,845, $15,069, and $3,899, respectively. The cost-utilities of liver resection and RFA were similar at $8,027 and $7,965 per QALY, respectively, although patients receiving RFA generally had more advanced disease. The cost-utility of chemotherapy was $12,751/QALY and the cost-utility of symptom control alone was $4,788/QALY. RFA is still a relatively new. However, if long-term survival proves promising, it may prove to be a viable alternative to liver resection.