Liver Transplantation for Hepatocellular Carcinoma beyond the Milan Criteria: A Specific Role for Living Donor Liver Transplantation after Neoadjuvant Therapy.

PURPOSE: This study was designed to elucidate the various new classifications and the use of LDLT and bridging therapy for HCC in this context beyond the Milan criteria (MC). METHODS: The clinical data of patients with HCC outside the MC who underwent LT at Jena University between January 2007 and August 2023 were retrospectively analysed. Eligible patients were classified according to various classification systems. Clinicopathological features, overall and disease-free survival rates were compared between LT and LDLT within the context of bridging therapy. THE RESULTS: Among the 245 patients analysed, 120 patients did not meet the MC, and 125 patients met the MC. Moreover, there were comparable overall survival rates between patients outside the MC for LT versus LDLT (OS 44.3 months vs. 28.3 months; 5-year survival, 56.4% vs. 40%; p = 0.84). G3 tumour differentiation, the presence of angioinvasion and lack of bridging were statistically significant risk factors for tumour recurrence according to univariate and multivariate analyses (HR 6.34; p = 0.0002; HR 8.21; p < 0.0001; HR 7.50; p = 0.0001). Bridging therapy before transplantation provided a significant survival advantage regardless of the transplant procedure (OS: p = 0.008; DFS: p < 0.001). CONCLUSIONS: Patients with HCC outside the MC who underwent LT or LDLT had worse outcomes compared to those of patients who met the MC but still had a survival advantage compared to patients without transplantation. Nevertheless, such patients remain disadvantaged on the waiting list, which is why LDLT represents a safe alternative to LT and should be considered in bridged HCC patients because of differences in tumour differentiation, size and tumour marker dynamics.

[Anastomotic techniques in minimally invasive hepatobiliopancreatic surgery]. / Anastomosentechniken in der minimal-invasiven hepatobiliopankreatischen Chirurgie.

The established anastomotic techniques conventionally used in open surgery are increasingly being implemented in a minimally invasive approach and further developed. The aim of all innovations is to carry out a safe anastomosis with a feasible minimally invasive technique; however, there is currently no broad consensus about the role of laparoscopic and robotic surgery in performing pancreatic anastomotic techniques. Pancreatic fistulas determine the morbidity following a minimally invasive resection. The simultaneous minimally invasive resection and reconstruction of pancreatic processes and vascular structures is currently exclusively performed in specialized centers.

Impact of metabolic indices of 18F-fluorodeoxyglucose positron emission tomography/computed tomography on post transplantation recurrence of hepatocellular carcinoma.

BACKGROUND: Tumor recurrence is the leading cause of death after liver transplantation in patients with hepatocellular carcinoma. There is an ongoing debate as to whether metabolic indices such as tumor to liver standardized uptake value ratio in 18F-fluorodeoxyglucose positron emission tomography/computed tomography of the primary tumor can identify patients outside the Milan criteria with as low recurrence rates as patients inside Milan and thus should be added to the established prognostic factors. METHODS: This retrospective study analyzes 103 consecutive patients who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before liver transplantation for hepatocellular carcinoma using data of clinical tumor registry. Primary endpoints were overall survival and 10-year cumulative recurrence rates. RESULTS: Tumor to liver standardized uptake value ratio of the primary tumor was statistically significant higher in Milan out tumors, "up-to-seven" out tumors, grade 3 tumors, α- fetoprotein level >400 ng/ml and lesions > 5cm in diameter. Factors with statistically significant influence on the 10- year overall survival in the univariate analysis were Milan, up-to-seven" criteria, number of lesions and pT-category. COX regression analysis did not show independently statistically significant factors for 10-year overall survival. Milan, "up-to-seven" criteria, grade, pV, number of lesions, size of lesion, pT-category, tumor to liver standardized uptake value ratio influenced 10-year cumulative recurrence rates statistically significant. Tumor to liver standardized uptake value ratio, grade and pT-category proved to be independently statistically significant factors for 10-year cumulative recurrence rates. CONCLUSIONS: Our study suggests that tumor to liver standardized uptake value standardized uptake value ratio in 18F-fluorodeoxyglucose positron emission tomography/computed tomography is an independent prognostic factor in transplanted patients with hepatocellular carcinoma. If we focus on preoperative findings, such as tumor size, tumor number and AFP value adding the information given by TLR of 18F-FDG PET/CT allows to estimate the risk of tumor recurrence more accurate than the established classifications Milan and UTS. Therefore, it may add valuable information to other preoperative findings, such as tumor size, tumor number and AFP level.

Feasibility and Efficacy of Adjuvant Chemotherapy With Gemcitabine After Liver Transplantation for Perihilar Cholangiocarcinoma - A Multi-Center, Randomized, Controlled Trial (pro-duct001).

Background: Liver transplantation (LT) is considered a therapeutic option for unresectable perihilar cholangiocarcinoma (PHC) within defined criteria. It remains uncertain whether patients can safely receive adjuvant chemotherapy after LT. Methods: We performed a prospective, multi-center, randomized, non-blinded two-arm trial (pro-duct001). Patients after LT for unresectable PHC within defined criteria were randomized to adjuvant gemcitabine (LT-Gem group) and LT alone (LT alone group). The primary objective was to investigate if adjuvant chemotherapy is feasible in ≥ 85% of patients after LT. The primary endpoint was the percentage of patients completing the 24 weeks course of adjuvant chemotherapy. Secondary endpoints included overall survival (OS) and disease-free (DFS), and complication rates. Results: Twelve patients underwent LT for PHC, of which six (50%) were eligible for randomization (LT-Gem: three patients, LT alone: three patients). Two out of three patients discontinued adjuvant chemotherapy after LT due to intolerance. The study was prematurely terminated due to slow enrollment. One patient with PHC had underlying primary sclerosing cholangitis (PSC). Tumor-free margins could be achieved in all patients. In both the LT-Gem and the LT alone group, the cumulative 1-, 3-, and 5-year OS and DFS rates were 100%, 100%, 67%, and 100%, 67% and 67%, respectively. Conclusions: This prospective, multi-center study was prematurely terminated due to slow enrollment and a statement on the defined endpoints cannot be made. Nevertheless, long-term survival data are consistent with available retrospective data and confirm defined criteria for LT. Since more evidence of LT per se in unresectable PHC is urgently needed, a prospective, non-randomized follow-up study (pro-duct002) has since been launched.

Surgical treatment of liver metastases from non-colorectal non-neuroendocrine carcinomas.

INTRODUCTION: In the literature, results after surgical treatment of non-colorectal non-neuroendocrine liver metastases (NCNNLM) are reported that are often inferior to those from colorectal liver metastases. The selection of patients with favorable tumor biology is currently still a matter of discussion. MATERIALS/METHODS: The retrospective data analysis was based on data that were collected for the multicenter study "Role of surgical treatment for non-colorectal liver metastases" in county Thuringia. RESULTS: For the study, 637 patients were included from 1995 to 2018. 5 and 10-year survival of R0 resected patients were 33% and 19%, respectively. In the multi-variate analysis of the entire group, sex, timing, disease-free interval, number of metastases, R-classification as well as lymph node status of the primary lesion showed an independent statistical influence on the 5-year survival. In the group of R0 resected patients, disease-free interval, number of metastases and lymph node status of the primary lesion influenced the 5-year survival in the multi-variate analysis. In kidney malignancies, R-classification, timing and number of liver metastases were statistically significant in the multi-variate analysis of the 5-year survival, in mamma carcinomas only the R-classification. CONCLUSION: The Adam score identifies some risk factors which influence prognosis in most but not in all tumor entities. For kidney cancer and breast cancer it can be simplified.

[Minimally invasive liver surgery]. / Minimal-invasive Leberchirurgie.

Minimally invasive liver surgery is safe and can be performed with results practically equal to those in open surgery. There are different techniques of parenchyma dissection and hemostasis available for the safe performance of minor and major resections, both laparoscopically and robotics based. Due to its technical options robotics-based surgery is a further development of laparoscopy. Expertise in minimally invasive and in liver surgery are essential prerequisites.

[Surgical treatment of hepato-pancreatic metastases from renal cell carcinoma]. / Chirurgische Therapie von Leber- und Pankreasmetastasen von Nierenzellkarzinomen.

BACKGROUND: The role of surgical treatment of hepato-pancreatic metastases from renal cell carcinoma is still under discussion. MATERIAL AND METHODS: We report about 52 patients of whom 33 underwent surgery for liver metastases and 19 for pancreatic metastases from 1995 to 2018. RESULTS: The 5­year survival rate of all patients with partial liver resection was statistically significantly lower (38%, median survival time 34 months) than with pancreas resection (69%, median survival time 69 months, p = 0.017). Of the patients 21 survived the resection of metastases longer than 5 years and 4 patients longer than 10 years. In R0 resected patients, recurrences were observed in 13 cases after liver resection and in 9 cases after pancreas resection. The cumulative recurrence rate after 5 years was 38% for the liver and 57% for the pancreas. In R0 partial liver resections, an interval <24 months between nephrectomy and liver resection as well as multiple metastases were negative prognostic factors. CONCLUSION: In spite of high recurrence rates, surgical treatment for hepato-pancreatic metastases from renal cell carcinoma yielded very good long-term results, in particular with complete resection of solitary metachronous metastases. Repeated surgery for completely resectable metastases, resulted in long tumor-free intervals and thus contributed to good long-term results.

Impact of successful local ablative bridging therapy prior to liver transplantation on long-term survival in patients with hepatocellular carcinoma in cirrhosis.

BACKGROUND: It has been shown that local ablative procedures enable downsizing, reduce drop-out from the waiting list and improve prognosis after liver transplantation. It is still unclear whether a response to the local ablative therapy is due to a favorable tumor biology or if a real benefit in tumor stabilization exists, particularly in complete pathological response. METHOD: Data of 163 HCC patients who underwent liver transplantation were extracted from our prospectively maintained registry. We analyzed the tumor load, pre-transplant α-fetoprotein levels, child stage aside the application and success of local ablative therapies as bridging procedures before transplantation. RESULTS: 87 patients received multiple and/or combined local therapies. In 20 cases, this resulted in a complete remission of the tumor as observed in the explant histology. The other 76 patients underwent no bridging procedure. The observed 5- and 10-year survival rates for patients with bridging were 67% and 47% and without bridging 56% and 46%, respectively. Tumor-related 10-year survival showed a statistically significant difference between both groups (81% versus 59%). In the multivariate analyses bridging, number of lesions and α-fetoprotein level showed an independent statistically significant influence on tumor-related survival in these patients. CONCLUSIONS: Successful local ablative therapy before liver transplantation is an independent statistically significant factor in long-term tumor-related survival for patients with HCC in cirrhosis and reduces tumor recurrences.

Robotic hepatic surgery in malignancy: review of the current literature.

The use of minimally invasive liver surgery, such as laparoscopic and robotic surgery, is increasing worldwide. Robot-assisted laparoscopy is a new surgical technique that improves surgical handling. The advantage of this technique is improved dexterity, which leads to increased surgical precision and no tremor or fatigue. Comparable oncological results were documented for laparoscopic and open surgery. Currently, "conventional" laparoscopic liver surgery has limitations with respect to the treatment of lesions in the posterior-superior segments, and there are limited technical features for the reconstruction steps. These limitations might be overcome with the use of robotic surgery. The use of robotic surgery for hepatic procedures originated because of the technical potential to overcome several of the major technical limitations known from conventional laparoscopy and the possibility of performing more extended liver resections. Additionally, there is increasing evidence indicating that robotic hepatic surgery is feasible and safe in resections of the posterior segments. Studies showed that using the robotic technique is associated with a decreased or at least equal amount of intraoperative blood loss compared to that of the conventional laparoscopic or open technique. There is increasing evidence that robotic liver surgery might be as safe as conventional laparoscopic procedures in cancer cases in terms of resection margins, disease-free and overall survival. Furthermore, robotic surgery might be more favorable with respect to postoperative patient recovery. Despite promising results, still large, multicenter, randomized and prospective studies are needed to analyze the exact value of robotic liver surgery in patients with malignant liver tumors.

Morphologically 'invisible' proinsulin - secreting adenoma detected by Ga-68 Exendin-4 (GLP-1 Receptor) positron emission tomography/CT.

This case report of a young man suffering from recurring hypoglycaemia illustrates a rare condition of a neuroendocrine tumour, predominantly secreting proinsulin and invisible to conventional imaging approaches. Only a GLP-1 receptor PET/CT using Exendin-4 visualized the pancreatic lesion and enabled curative therapy, confirming the diagnostic value of this tracer for detection of neuroendocrine tumours. As only few publications on this topic are available, an overview of the available data is also given. The known cut-off value of 60% for proinsulin level indicating malignancy is critically discussed.

Analysis of prognostic factors after resection of solitary liver metastasis in colorectal cancer: a 22-year bicentre study.

PURPOSE: The investigation of the predictors of outcome after hepatic resection for solitary colorectal liver metastasis. METHODS: We recruited 350 patients with solitary colorectal liver metastasis at the University Hospitals of Jena and Magdeburg, who underwent curative liver resection between 1993 and 2014. All patients had follow-up until death or till summer 2016. RESULTS: The follow-up data concern 96.6% of observed patients. The 5- and 10-year overall survival rates were 47 and 28%, respectively. The 5- and 10-year disease-free survival rates were 30 and 20%, respectively. The analysis of the prognostic factors revealed that the pT category of primary tumour, size and grade of the metastasis and extension of the liver resection had no statistically significant impact on survival and recurrence rates. In multivariate analysis, age, status of lymph node metastasis at the primary tumour, location of primary tumour, time of appearance of the metastasis, the use of preoperative chemotherapy and the presence of extrahepatic tumour proved to be independent statistically significant predictors for the prognosis. Moreover, patients with rectal cancer had a lower intrahepatic recurrence rate, but a higher extrahepatic recurrence rate. CONCLUSION: The long-term follow-up of patients with R0-resected liver metastasis is multifactorially influenced. Age and comorbidity have a role only in the overall survival. More than three lymph node metastasis reduced both the overall and disease-free survival. Extrahepatic tumour had a negative influence on the extrahepatic recurrence and on the overall survival. Neither overall survival nor recurrence rates was improved using neoadjuvant chemotherapy.

Surgery for colorectal cancer in elderly patients: how can we improve outcome?

PURPOSE: Patients over 70 years of age are characterised by diminished long-term survival rates following resection of colorectal cancer (CRC) compared to younger patients. The aim of this study was to clarify whether reduced survival is a result of malignancy, comorbidities or the treatment received. METHODS: All patients with CRC, who were admitted to our institution over a period of 10 years, were selected from a prospectively maintained database. Disease-specific, disease-free and overall survival rates were calculated dependent on variables considered potentially relevant for the patients' prognosis. RESULTS: 915 patients were included in the study. Observed 5- and 10-year survival rates for the whole group were 48 ± 2% and 40 ± 2%, respectively, but 10-year survival rates dropped to 14 ± 4% for patients aged 80 and older. Resection of the primary tumour was attempted in all cases independent of age. Emergency admission, Charlson index ≥2, ECOG ≥2, old age, second malignancies, distant metastases, high grading and non-resective surgery were identified as independent prognostic parameters associated with decreased overall survival. In contrast, disease-specific and disease-free survival rates for patients after elective radical resection in UICC-stage I-III did not show significant differences related to age. Tumour site, UICC-stage and resection status were independent statistically significant predictors of disease-specific survival. CONCLUSIONS: Similar disease-specific survival rates in all age groups speak in favour of tumour resection in curative intent even in old patients. Better outcome may be achieved, if regular screening for colorectal cancer is considered even in the elderly to avoid late presentation requiring emergency surgery.

ABO-Incompatible Living Donor Liver Transplantation in Focus of Antibody Rebound.

BACKGROUND: Living donor liver transplantation (LDLT) is an option to expand the donor organ pool for patients with life-threatening diseases who cannot be supplied with a cadaver organ. Next to the donor risks, complications after ABO-incompatible LDLT (ABOi LDLT) in the recipient are subject to controversial discussion. Improvement in ABOi graft survival rates have been achieved with plasma treatment procedures (PTP) and immunosuppression but antibody-mediated rejection (AMR) and graft loss still occur. METHODS: Since 2008, we have prepared 10 patients for ABOi LDLT. Seven of the 10 patients for transplantation had hepatocellular carcinoma (HCC). RESULTS: All patients underwent PTP before and after ABOi LDLT as well as immunosuppression according to the treatment schedule. We did not use anti-CD20 monoclonal antibodies in the transplant setting. We transplanted 6 of 10 preconditioned patients. After 3 years, 5 of the 6 transplanted patients were still alive. CONCLUSION: Even if B-cell depletion with anti-CD 20 treatment in the setting of ABOi LDLT is commonly accepted, our center successfully administered only quadruple drug immunosuppression combined with PTP. Especially patients with HCC had a high titer increment also pre-transplantation and were at high risk for arterial thrombosis and graft loss.

IgG4-related systemic disease--a rare indication for multi-visceral transplantation.

Multivisceral transplantations (MVT) are rarely performed procedures. In this case report, we present a 37-year-old male patient with a large retroperitoneal tumor. After exclusion of malignancy, we performed MVT (distal stomach, liver, pancreas, and small bowel). After a follow-up of 1 year, the patient is in good clinical condition. Histologic examination revealed a chronic sclerosing IgG4-associated disease. Our case shows that MVT can be successfully performed in this rare disease.