Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Analysis of the hemostatic potential of modern topical sealants on arterial and venous anastomoses: an experimental porcine study.

One of the widely accepted adjunctive agents in the variety of surgical modalities are sealants. Our study aim was to compare four commonly used modern sealants in a standardized experimental setting to assess their feasibility, and hemostatic efficacy in vascular anastomosis. Forty landrace pigs (weight: 24.7 ± 3.8 kg) were randomized into the control (n = 8) and four sealant groups; TachoSil® (n = 8), Tissucol Duo® (n = 8), Coseal® (n = 8), and FloSeal® (n = 8). After doing a portal vein end-to-end anastomosis as well as stitches of aortic incision, the sealants were applied on anastomotic site. The control group was left intact. In portal vein anastomosis, the sealants led to a complete hemostasis significantly better than control group. The mean of blood loss was also significantly reduced. In successful subgroups, there was a difference in the mean-time to reach complete hemostasis ranging from 15 s in Coseal® to 76 s in FloSeal® group (p < 0.05). In aortotomy experiments, except Tissucol Due®, which had insufficient hemostasis, other sealants led to a complete hemostasis. The mean blood loss was significantly reduced in sealants groups as well. The four sealants are effective in reducing the suture-hole bleeding in portal vein anastomosis. However, the hemostatic potential is heterogeneous among sealants. This means that "one-size-fits-all" approach is not appropriate for application of sealants in diversity of vascular surgery and it should be based on the type and the severity of injury and the structure of tissue. Comparison of hemostasis efficacy of four modern sealants (TachoSil®, Tissucol Duo®, Coseal®, and FloSeal®) in vascular anastomosis in porcine model. The figures below show the total blood loss (g) in the control and sealant groups after aortotomy (left) and portal vein anastomosis (right). The mean of blood loss decreased significantly by the usage of sealants in both experiment groups as compared to control group (*: p < 0.05; sealant groups vs. control group). 1. The right column shows the mean of blood loss (g) in all experiments in each group. 2. The middle column presents the subgroup with unsuccessful hemostasis at the end of observation time (Tmax = 20 sec. for aortotmy and 300 sec. for portal vein anastomosis). 3. The left column shows mean of total blood loss in subgroups with successful hemostasis during observation time (20 sec for aortotomy and 300 sec for portal vein).

Risk Factor Identification for Delayed Gastric Emptying after Distal Pancreatectomy-An Evaluation of 1688 Patients Based on the German StuDoQ|Pancreas Registry.

Delayed gastric emptying (DGE) ranks as one of the most frequent complications in pancreatic surgery. It leads to increased costs for healthcare systems, lengthened hospital stays and reduced quality of life. Data about DGE after distal pancreatectomy (DP) are scarce. The StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery provided data of patients who underwent distal pancreatectomy from 1 January 2014 to 31 December 2018. The retrospective evaluation included comprehensive data: 1688 patients were enrolled; DGE occurred 160 times (9.5%); grade "A" was reported for 98 (61.3%), grade "B" for 41 (25.6%) and grade "C" for 21 (13.1%) patients. In univariate analysis pancreatic fistulas were associated with higher frequencies of intraabdominal abscesses (9.1% vs. 2%, p > 0.001), postpancreatectomy haemorrhage (8.1% vs. 3.7%, >0.001) and DGE (14.5% vs. 6%, p < 0.001). According to multivariate analysis, "abscesses with invasive therapy" (p < 0.001), "other surgical complications" (p < 0.001), prolonged "stays in ICU" (p < 0.001), lengthened duration of surgery (p < 0.001) and conventional surgery (p = 0.007) were identified as independent risk factors for DGE. Perioperative and postoperative factors were identified as risk factors for DGE. Following research should examine this highly relevant topic in a prospective, register-based manner. As there is no causal therapy for DGE, its avoidance is of major importance.

Incarcerated hiatal hernia - A rare postoperative complication following gastrectomy for stomach cancer. A case report and literature review.

INTRODUCTION: Diaphragmatic complications following gastrostomies for gastric malignancies are extremely rare. The incidence of hiatal hernias after total gastrectomy for carcinoma is not well documented because of the poor prognosis associated with gastric cancer and the short life expectancy. PRESENTATION OF CASE: This case report presents a 66-year-old male patient who developed an acute incarcerated hiatal hernia 8 month after total gastrectomy for gastric adenocarcinoma. The patient was found to have a herniated alimentary limb and dilated, incarcerated loops of the bowel through the 3.5-cm hiatal defect. The hernia was gently reduced. Posterior cruroplasty without mesh augmentation was performed with nonabsorbable sutures. The patient was discharged in good general condition. His history highlights an important and potentially morbid complication following gastrectomy. DISCUSSION: To our knowledge, only 5 cases have been reported in the literature. The incidence of symptomatic hiatal hernias following esophageal and gastric resection for carcinoma is 2.8%, and the median time between primary surgery and the diagnosis of hiatal hernias is 15 months. CONCLUSION: During primary surgery, it is recommended, in the cases of pre-existing hiatal hernias or a crural dissection, to perform cruroplasty after adequate mobilization of the lower thoracic esophagus and a tension-free subdiaphragmatic anastomosis.

Modified laparoscopic toupet fundoplication with fundo-phrenico-pexy.

This article presents an alternative technique to the common Toupet fundoplication. It is a modern combination of the standard Toupet procedure and an additional fundophrenicopexie of the gastric wrap. In 1963 Toupet first described his technique of a fundoplication for reflux surgery. Over the past years this procedure has been modified and expanded many times. We have learned that the short gastric vessels need to be divided to get the wrap closer and easier around the esophagus. Furthermore, it is likely necessary to perform a balanced hiatoplasty to avoid slippage of the wrap. Our procedure is a modification of the standard Toupet fundoplication, but is extended by fixing the wrap to the anterior wall of the diaphragm. We consider our modification successful and safe in treating gastroesophageal reflux disease in patients with type I/II hiatal hernia and prevent postoperative complications such as dysphagia or slippage of the wrap.

Mechanical strength of biliary defect closure after topical sealing: Comparison of four sealants in a porcine model.

BACKGROUND/OBJECTIVE: Biliary leakage is a potential complication of liver resection and is still a concern. The aim of the present study was to evaluate the effectiveness of four routinely used sealants in preventing bile leakage under pressure from an induced perforation of the gallbladder in a porcine model. METHODS: Forty Landrace pigs were randomly assigned to one of five groups. These included a control group (n = 8) and one group each for the sealants TachoSil®, TissuCol Duo®, Coseal®, and FloSeal® (n = 8 per group). In the control group, the perforation was left unsealed. To evaluate the biliostatic potential of the sealants, we measured the pressure that was needed to induce leakage (mmHg) and the gallbladder volume (cc) at the time of leakage in each group. RESULTS: A significantly higher mean pressure was required to induce leakage in the sealant groups compared with the control group. However, the biliostatic effects were heterogeneous among the sealant groups. Sealants with the highest to lowest effectiveness were TachoSil, Coseal, TissuCol, and FloSeal. The mean gallbladder volume at the time of leakage also varied between sealant groups. CONCLUSION: Biliostatic properties are markedly improved by the use of modern sealants compared with using no sealant. However, the advantages and disadvantages of using sealants should be carefully considered in each clinical situation. The effectiveness of the sealants should be evaluated in chronic and clinical studies.

The comparison of 2-dimensional with 3-dimensional hepatic visualization in the clinical hepatic anatomy education.

OBJECTIVE: To determine whether 2-dimensional or 3-dimensional hepatic visualization is better for the medical students to be used while studying the clinical hepatic anatomy. MATERIAL AND METHODS: Twenty-nine patients who underwent surgical intervention due to focal hepatic pathology at the Department of General Surgery, University of Heidelberg, and at Clinics of Santariskes, Vilnius University Hospital were included in the retrospective cohort study. Before the surgical intervention, the computed tomography (CT) liver scan and 3-dimensional (3D) hepatic visualization were performed. A total of 58 2-dimensional and 3-dimensional digital liver images, mixed up in random sequence not to follow each other with a specially designed questionnaire, were presented to the students of Faculty of Medicine, Vilnius University. Their aim was to determine tumor-affected liver segments, to plan which liver segments should be resected, and to predict anatomical difficulties for liver resection. Results were compared with the data of real operation. RESULTS: The students achieved better results for tumor localization analyzing 3D liver images vs. CT scans. This was especially evident determining the localization of tumor in segments 5, 6, 7, and 8 (P<0.05). Furthermore, the results of proposed extent of liver resection have been found to be better with 3D visualization (mean+/-SD - 0.794+/-0.175) in comparison with CT scans (mean+/-SD - 0.670+/-0.200), (P<0.001). CONCLUSIONS: Computer-generated 3D visualizations of the liver images helped the medical students to determine the tumor localization and to plan the prospective liver resection operations more precisely comparing with 2D visualizations. Computer-generated 3D visualization should be used as a means of studying liver anatomy.

Hemostatic efficiency of modern topical sealants: Comparative evaluation after liver resection and splenic laceration in a swine model.

Parenchymal transection during hepatobiliary surgery can disrupt small vasculature or bile ducts, which could be managed difficultly. Sealants are helpful tools to achieve better hemostasis. The aim of this study is to analyze the hemostatic efficiency of four modern sealants in a porcine model. In this study, 40 landrace pigs were assigned equally to the control (without sealant) and four sealant groups. Standardized liver resection and splenic lesions were performed and left without using sealant (control) or treated with one of the following sealants: TachoSil® , Tissucol Duo® , Coseal® , and FloSeal® . We measured relative and absolute bleeding times (seconds) as well as total blood loss (g) in a maximum observation time of 300 s. Sealants could show a significantly improved hemostasis comparing to the control group. However, hemostasis was heterogeneous among the sealant groups (liver resection: 60%-100%, spleen injury: 70%-100%). The mean blood loss decreased significantly using sealants comparing to control group (liver resection: 6-120 fold, spleen injury: 2.5-36 fold). The hemostatic time in groups that achieved complete hemostasis was different in each sealant group (liver resection: 30-166 s, spleen injury: 60-180 s). We conclude that the hemostatic efficacy of modern sealants is impressive but heterogeneous in liver resection or splenic lesion. To maximize the effectiveness of these tools, the indication of each sealant should be carefully considered in individual settings by the surgeons. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1307-1316, 2018.

Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial.

IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients. CONCLUSIONS AND RELEVANCE: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00849615.

Liver transplantation for hepatocellular carcinoma: is there evidence for expanding the selection criteria?

A consequent application of the Milan criteria in patients undergoing liver transplantation for hepatocellular carcinoma (HCC) may lead to excellent long-term survival and a low incidence of recurrence. Expanding the selection criteria will result in more patients with hepatocellular carcinoma being potentially curative treated, but this approach is associated with at least a higher incidence of recurrence. Kaplan-Meier analysis of 110 patients, who underwent liver transplantation for HCC in our institution between 1987 and 2004, showed a significant improvement in patient survival with time. A change in criteria for patient selection may have contributed to the improved outcome. In 28 of 110 patients a recurrence of HCC was observed. In 82% of patients, who developed recurrence of carcinoma, the Milan criteria were not met. Dropout from the waiting list is common and several methods, including percutaneous ethanol injection, radiofrequency ablation, and chemoembolization, are used to prevent tumor progression and thus prevent dropout. As no randomized trials are available some uncertainty remains, whether these neoadjuvant procedures improve outcome. At present, there is no evidence that this approach enables expansion of the selection criteria. Hepatocellular carcinoma is a major indication for living related liver transplantation because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of living related liver transplantation may offer more patients a potentially curative treatment, without reducing the donor pool of organs for other patients on the waiting list with nonmalignant liver disease.

Living related liver transplantation: the ultimate technique to expand the donor pool?

Today, living donor liver transplantation (LDLT) is well established in many centers as a therapeutic method for end-stage liver disease. LDLT is an option for selected cases and is still under development. From the beginning of LDLT until now, many innovations have been presented and as a consequence both the surgical and medical complications in both donors and recipients reduced greatly. As a benefit, this procedure enriches the donor organ pool and reduces the imbalance between the scarcity of organ resource and organ demand; however, LDLT will not solve the problem of organ shortage. Because the modality of LDLT is still associated with morbidity and mortality of the donors, recipient's graft-size match problems and substantial surgical complications, ethical issues of live organ donation must be discussed. Nevertheless, estimates of patient survival and complications in both donors and recipients should incorporate waiting time mortality. With this background, the extended indications for LDLT compared with cadaveric liver transplantation would have to be discussed in many cases. In this brief review, we focus on potential complications for both donors and recipients after adult-to-adult LDLT, discuss ethical problems and controversies with special interest on the perspective and potentials of this surgical method.

Surgical treatment of primary hepatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma is a very rare tumor of vascular origin. It can develop in different tissues such as soft tissue, lung, or liver. Hepatic epithelioid hemangioendothelioma (HEH) mostly affects females. The malignant potential of HEH often remains unclear in the individual patient. It can range from benign hemangioma to malignant hemangioendotheliosarcoma. Here we present our experience with five patients with primary HEH, who were treated with curative intention in our department. All patients in our series with confirmed histological HEH did not show extrahepatic extension and consequently underwent surgical treatment. In three patients, liver transplantation (LTx) was performed (two cadaveric and one living related). In one patient, a right-sided hemihepatectomy with partial resection of the diaphragm was performed. One patient died while she was on the waiting list for LTx due to rapid tumor progression. Postoperative follow-up ranged from 1 to 13 years. No adjuvant chemotherapy was applied. Until now, no recurrence of local tumor or distant metastases could be observed during follow-up in our series. Early detection and surgical intervention in case of HEH can potentially offer curative treatment. The treatment of first choice appears to be radical liver resection. In our view, LTx represents a potentially important option for patients with a nonresectable tumor. Despite the long waiting time, its often unclear dignity, and a proven progressive growth pattern, living related LTx also plays a potentially important role. The 5-year overall survival rate of patients with HEH in the literature varies from 43% to 55%. Long-term survival of patients with HEH is significantly higher compared to other hepatic malignancies. The role of adjuvant therapy currently remains unclear.

Evolution of liver transplantation at the University of Heidelberg: interventions influencing patient referral.

In Heidelberg, liver transplantation was first performed in 1987. In this article, we report our experience with an interdisciplinary approach (intervention) to improve the internal and external acceptance of the liver transplantation program. Formation of a transplant team and interdisciplinary standard setting of pre-, peri-, and postoperative protocols significantly stimulated this process. Involvement of the referring doctors in patient's treatment by transferring competencies enhanced patients referral to our center and increased the numbers of patients on the waiting list, an indispensable factor for organ allocation by Eurotransplant and transplantation. Involvement of patient organizations increased patient acceptance in the program.

Cost distribution of orthotopic liver transplantation: single-center analysis under DRG-based reimbursement.

Costs of orthotopic liver transplantation (OLT) are influenced by multiple factors. Surgeons must be interested in determining the probability of meeting the projected cost averages. Costs of procedures, labor, drugs and pharmaceuticals, materials, and overhead costs of infrastructure were calculated during the primary stay in 38 consecutive patients undergoing OLT at a single center. Endpoint of cost aggregation was discharge from acute care. Costs per patient were grouped to plot the cost density distribution function. Mean cost of OLT was 49,000. Costs showed a large variation, ranging from 18,000 to 189,000 per case. Most patients were grouped in the G-DRG-A01C split (n=31), which characterizes the least resource consumptive split. Costs of OLT were not normally distributed. There was a left-skewed beta-distribution of costs. Labor-related costs were responsible for the largest cost fraction (mean 42.9%), whereas drugs and medication accounted for 24.9% on average. Most patients could be transplanted within cost groups below 50,000. The marked cost heterogeneity after OLT suggests that primarily medical comorbidities are of relevance for extraordinary resource consumption. A minimum number of transplants should be performed in single institutions to improve chances to financially counterbalance higher costs of individual cases under DRG-based reimbursement. Small programs have to bear increased risks of financial distortion. The asymmetry of cost distribution after OLT should be taken into account in future reimbursement regulations.

Indications for liver transplantation in patients with amyloidosis: a single-center experience with 11 cases.

Familial amyloidotic polyneuropathy (FAP) is an inherited disorder with the systemic deposition of amyloid fibrils containing mutant transthyretin variants. The mutant form of transthyretin amyloidosis is produced mainly in the liver. Successful liver transplantation (LTx) could eliminate the source of the variant transthyretin molecule, and is now the only known curative treatment. The aim of this study is to evaluate the results of LTx for FAP at the University of Heidelberg. Eleven patients who underwent LTx between 1985 and 2004 with the diagnosis of FAP were evaluated. Of 11 patients, seven (64%) were male and four (36%) were female. The mean age was 49.5 years (range 27-70). Met 30 (n=5) was the most common type of amyloidosis followed by Arg 50 (n=3), Val 107 (n=2), and Phe 33 (n=1). All of the patients were selected for LTx and Domino LTx was performed in six patients. The majority (80%) of the patients with type Met 30 amyloidosis are alive, whereas in other types of amyloidosis only 33% are living. This finding emphasizes better prognosis of Met 30 variant of FAP in comparison to other variants such as Arg 50, Val 107, and Phe 33. After LTx, improvement of clinical symptoms (completely or partially) was observed in six patients (55%). In conclusion, LTx is considered as the only therapeutic alternative in patients with amyloidosis accompanied by hepatic synthesis of the amyloid protein. The most important risk factors for LTx can be predicted by assessing the nutritional condition of the patient, the duration of the disease, and the amyloid variant. Therefore, precise diagnostic measures are required before listing a patient for LTx. Domino LTx is an acceptable form of LTx that can preserve the pool of organ donors. In order to stop the progression of FAP, LTx would be justified in a subgroup of patients with amyloidosis. Based on our results, we support the idea that the effectiveness of extended preoperative period before LTx or the transplantation of other transthyretin variants other than Met 30 is questionable.

HEGPOL: randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312].

BACKGROUND: Kupffer cell-dependent ischemia/reperfusion (I/R) injury after liver transplantation is still of high clinical relevance, as it is strongly associated with primary dysfunction and primary nonfunction of the graft. Glycine, a non-toxic, non-essential amino acid has been conclusively shown in various experiments to prevent both activation of Kupffer cells and reperfusion injury. Based on both experimental and preliminary clinical data this study protocol was designed to further evaluate the early effect of glycine after liver transplantation. METHODS/DESIGN: A prospective double-blinded randomized placebo-controlled multicenter study with two parallel groups in a total of 130 liver transplant recipients was designed to assess the effect of multiple intravenous doses of glycine after transplantation. Primary endpoints in hierarchical order are: peak levels of both aspartat-amino-transaminase (AST) and alanine-amino-transaminase (ALT) as surrogates for the progression of liver related injury, as well as both graft and patient survival up to 2 years after transplantation. Furthermore, the effect of glycine on cyclosporine A-induced nephrotoxicity is evaluated. DISCUSSION: The ongoing clinical trial represents an advanced element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a randomized, prospective, controlled double-blinded clinical trial. If the data of this ongoing research project confirm prior findings, glycine would improve the general outcome after liver transplantation.