Martin Loss

Right Portal Vein Ligation Combined With In Situ Splitting Induces Rapid Left Lateral Liver Lobe Hypertrophy Enabling 2-Staged Extended Right Hepatic Resection in Small-for-Size Settings

Objective:To evaluate a new 2-step technique for obtaining adequate but short-term parenchymal hypertrophy in oncologic patients requiring extended right hepatic resection with limited functional reserve. Background:Patients presenting with primary or metastatic liver tumors often face the dilemma that the remaining liver tissue may not be sufficient. Preoperative portal vein embolization has thus far been established as the standard procedure for achieving resectability. Methods:Two-staged hepatectomy was performed in patients who preoperatively appeared to be marginally resectable but had a tumor-free left lateral lobe. Marginal respectability was defined as a left lateral lobe to body weight ratio of less than 0.5. In the first step, surgical exploration, right portal vein ligation (PVL), and in situ splitting (ISS) of the liver parenchyma along the falciform ligament were performed. Computed tomographic volumetry was performed before ISS and before completion surgery. Results:The study included 25 patients with primary liver tumors (hepatocellular carcinoma: n = 3, intrahepatic cholangiocarcinoma: n = 2, extrahepatic cholangiocarcinoma: n = 2, malignant epithelioid hemangioendothelioma: n = 1, gallbladder cancer: n = 1 or metastatic disease [colorectal liver metastasis]: n = 14, ovarian cancer: n = 1, gastric cancer: n = 1). Preoperative CT volumetry of the left lateral lobe showed 310 mL in median (range = 197–444 mL). After a median waiting period of 9 days (range = 5–28 days), the volume of the left lateral lobe had increased to 536 mL (range = 273–881 mL), representing a median volume increase of 74% (range = 21%–192%) (P < 0.001). The median left lateral liver lobe to body weight ratio was increased from 0.38% (range = 0.25%–0.49%) to 0.61% (range = 0.35–0.95). Ten of 25 patients (40%) required biliary reconstruction with hepaticojejunostomy. Rapid perioperative recovery was reflected by normalization of International normalized ratio (INR) (80% of patients), creatinine (84% of patients), nearly normal bilirubin (56% of patients), and albumin (64% of patients) values by day 14 after completion surgery. Perioperative morbidity was classified according to the Dindo-Clavien classification of surgical complications: grade I (12 events), grade II (13 events), grade III (14 events, III a: 6 events, III b: 8 events), grade IV (8 events, IV a: 3 events, IV b: 5 events), and grade V (3 events). Sixteen patients (68%) experienced perioperative complications. Follow-up was 180 days in median (range: 60–776 days) with an estimated overall survival of 86% at 6 months after resection. Conclusions:Two-step hepatic resection performing surgical exploration, PVL, and ISS results in a marked and rapid hypertrophy of functional liver tissue and enables curative resection of marginally resectable liver tumors or metastases in patients that might otherwise be regarded as palliative.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer

BackgroundIn selected patients with peritoneal carcinomatosis from ovarian cancer prognosis can be improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsBetween September 1995 and February 1999, 19 patients (mean age 52 years, range 30–72 years) with peritoneal carcinomatosis from primary or recurrent epithelial ovarian carcinoma were operated with the aim of complete macroscopical cytoreduction. Surgery was followed by intraoperative HIPEC. The data was analyzed retrospectively.ResultsEleven patients had recurrent and 8 primary ovarian cancer. The median progression free interval was 18 months (range 6–36 months). Macroscopically complete cytoreduction was achieved in 9 patients. Cisplatin (n = 16) or mitoxantrone (n = 3) were used for the intraoperative chemotherapy. The median intraabdominal inflow temperature was 41.5°C. Complications occurred in seven patients. Most frequent complications were anastomotic leakage (2/19) and intraabdominal abscess formation (2/19). One patient died postoperatively. The mean (± SD) overall survival time was 33(± 6) months with a 5-year survival rate of 15%. The survival was found to be influenced by the completeness of cytoreduction (44 ± 11 vs. 25 ± 6 months, p = 0.40), tumor volume (54 ± 10 versus 16 ± 4, p = 0.002) and presence of lymph node (38 ± 8 vs. 20 ± 8 months, p= 0.2) or liver metastases (51 ± 9 vs. 21 ± 6 months, p = 0.06).ConclusionsCytoreductive surgery combined with HIPEC is feasible and is associated with a reasonable morbidity and mortality. Complete cytoreduction may improve survival in select group of patients with low tumor volume and no organ metastases.

New real-time image fusion technique for characterization of tumor vascularisation and tumor perfusion of liver tumors with contrast-enhanced ultrasound, spiral CT or MRI: First results

AIM Evaluation and characterization of the vascularisation and perfusion of liver tumors by means of image fusion of dynamic contrast-enhanced ultrasound (CEUS), multidetector-CT (MD-CT) or magnetic resonance imaging (MRI) with the ultrasound navigation technique. MATERIAL For interventional planning a real-time image fusion involving CEUS (LOGIQ E9, GE) was performed in 20 patients (12 men, 8 women, age 43-69 years, median 54) with histologically confirmed malignant liver tumors (9 x hepatocellular carcinoma (HCC), 5 x metastases, 2 x hemangiomas, 1 x cholangiocellular carcinoma (CCC), 1 x lymphoma, 1 x neuroendocrine tumor, 1 x focal nodular hypoplasia (FNH)). In 17 patients the real-time CEUS was fused with contrast-enhanced MD-CT and in three patients with contrast-enhanced MRI (Gd-DTPA and liver-specific contrast medium Resovist. All of the ultrasound examinations were performed by an experienced examiner with a multi-frequency probe (2-5 MHz, LOGIQ E9, GE); dynamic image sequences up to 3 minutes in true agent detection mode of contrast harmonic imaging (CHI) were documented. An evaluation of the tumor was performed by the characterization of the dynamics of the contrast medium and microperfusion with CEUS, fused with MD-CT or MRI. RESULTS In 18/20 cases there was an accurate agreement with respect to the segmental localization of the tumor lesion. In 2/20 cases the localization was comparable with the image fusion of CEUS and reference imaging (a total of at least 65 lesions: 3 x 1 lesion, 5 x 2 lesions, 8 x 3 lesions, 2 x 5 lesions, 1 x 8 lesions, 1 x at least 10 lesions (multifocal)). With image fusion a certain characterization was attained in 17/20 cases. In 3/20 cases (lymphoma after liver transplantation, multifocal CCC, metastases of a neuroendocrine tumor) the diagnosis was at first doubtful and had to be confirmed histologically. In patients with HCC an evaluation of the tumor perfusion was feasible in all 9 cases (8/9 after local trans-arterial chemoembolization (TACE), 1/9 after radio frequency ablation (RFA)). A tendency toward the identification of more lesions with image fusion of CEUS and CT than with contrast-enhanced CT alone could be recognized (p=0.059). CONCLUSION Applying a new real-time fusion technique of MD-CT or MRI with CEUS new possibilities for the evaluation, intervention and monitoring of the therapy of liver lesions were made possible, since the method also comprised the dynamic microperfusion.

Acute vascular rejection is associated with systemic complement activation ina pig-to-primate kidney xenograft model

Abstract: The introduction of h‐DAF transgenic porcine organs into pre‐clinical pig‐to‐primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life‐supporting model of pig‐to‐primate kidney transplantation, unmodified (n = 8) or h‐DAF‐transgenic (n = 9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low‐dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h‐DAF transgenic group. Stable initial graft function with recipient survival > 4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two‐fold increase in C3a levels and a four‐fold increase in sC5b‐9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b‐9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti‐porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short‐term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig‐to‐primate combination.

Bile duct damage after cold storage of deceased donor livers predicts biliary complications after liver transplantation

BACKGROUND & AIMS The aim of this study was to examine the development of biliary epithelial damage between organ retrieval and transplantation and its clinical relevance for patients. METHODS Common bile duct samples during donor hepatectomy, after cold storage, and after reperfusion were compared to healthy controls by hematoxylin and eosin (H&E) staining and immunofluorescence for tight junction protein 1 and Claudin-1. A bile duct damage score to quantify biliary epithelial injury was developed and correlated with recipient and donor data and patient outcome. RESULTS Control (N=16) and donor hepatectomy bile ducts (N=10) showed regular epithelial morphology and tight junction architecture. After cold storage (N=37; p=0.0119), and even more after reperfusion (N=62; p=0.0002), epithelial damage, as quantified by the bile duct damage score, was markedly increased, and both tight junction proteins were detected with inappropriate morphology. Patients with major bile duct damage after cold storage had a significantly increased risk of biliary complications (relative risk 18.75; p<0.0001) and graft loss (p=0.0004). CONCLUSIONS In many cases, the common bile duct epithelium shows considerable damage after cold ischemia with further damage occurring after reperfusion. The extent of epithelial damage can be quantified by our newly developed bile duct damage score and is a prognostic parameter for biliary complications and graft loss. Possibly, in an intraoperative histological examination, this bile duct damage score may influence decision-making in transplantation surgery.

Staged surgery with neoadjuvant 90Y-DOTATOC therapy for down-sizing synchronous bilobular hepatic metastases from a neuroendocrine pancreatic tumor

PurposeTreatment with DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), labeled with beta-emitting radioisotope yttrium-90 (90Y-DOTATOC), has successfully been used for the palliative treatment of patients with advanced somatostatin receptor-expressing neuroendocrine tumors (NETs). However, controversy persists as to whether patients with metastatic NETs of the pancreas should undergo radical (salvage) surgery or receive palliative therapy. We proposed that 90Y-DOTATOC could be used in a neoadjuvant intention for improving therapy of hepatic NET metastases.Materials and methodsWe investigated a novel therapy concept in a 49-year-old patient presenting with a neuroendocrine tumor of the pancreatic tail and synchronous multiple bilobular hepatic metastases. After surgical removal of the large primary tumor by extended left en bloc resection of the pancreatic tail, the patient received neoadjuvant 90Y-DOTATOC for therapy of primarily non-resectable bilobular hepatic metastases.ResultsThe 90Y-DOTATOC therapy resulted in an impressive regression of hepatic lesions, thus facilitating surgical removal of all remaining liver metastases in a second operation (staged surgery). In addition, one lesion was ablated using radiofrequency ablation (RFA). At 1-year of follow-up after hepatic R0 resection/RFA, there was no evidence of tumor recurrence or extrahepatic metastasis.ConclusionsThe neoadjuvant use of 90Y-DOTATOC therapy could prove valuable for treatment of advanced pancreatic NETs metastatic to the liver in terms of facilitating R0 resection by applying staged surgery concepts.

Everolimus and Early Calcineurin Inhibitor Withdrawal: 3-Year Results From a Randomized Trial in Liver Transplantation

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open‐label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI‐based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft‐Gault) at month 11 postrandomization. A 24‐month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] −1.3, 21.5 mL/min, p = 0.082) in favor of CNI‐free versus CNI using Cockcroft‐Gault, 9.4 mL/min/1.73 m2 (95% CI −0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four‐variable) and 9.5 mL/min/1.73 m2 (95% CI −1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI‐free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy‐proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI‐free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus‐based CNI‐free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Analysis of potential porcine endogenous retrovirus (PERV) transmission in a whole‐organ xenotransplantation model without interfering microchimerism

Abstract The question whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for the evaluation of the safety of pig-to-man xenotransplantation. Unfortunately, polymerase chain reaction (PCR)-based analysis of potential PERV infections in nonhuman-primate whole-organ xenotransplantation models is hampered by false positive results due to chimeric porcine cells. To avoid the inherent analytical problem of xenomicrochimerism, we developed a non-life-supporting pig-to-primate kidney xenotransplantation model: porcine kidneys were transplanted, whereas the functioning recipient kidneys remained in situ. Subsequent to rejection (after 2 hours to 15 days), xenografts were removed, and recipients remained alive for up to 287 days. Immunosuppressive therapy based on cyclophosphamide, cyclosporine, and steroids was maintained for 28 days after transplantation. Using appropriate PCR assays, xenochimerism was found in tissue samples and partly even in peripheral blood leukocytes (PBLs) while the porcine kidneys were in situ. After graft removal, xenochimerism was no longer detectable, thus allowing analysis for possible PERV transmission.

C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys

Abstract: At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life‐supporting pig to primate kidney xenotransplantation setting using h‐DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three‐day course of C1‐Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1‐Inhibitor was added to the standard anti‐rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti‐rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti‐rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h‐DAF transgenic porcine kidneys can be successfully treated by additional short‐term fluid phase complement inhibition.

Characterization of microvascularization of liver tumor lesions with high resolution linear ultrasound and contrast enhanced ultrasound (CEUS) during surgery: First results.

AIM Evaluation of high resolution linear ultrasound and intra-operative linear contrast enhanced ultrasound (CEUS) and its benefit for the detection and characterization of tumor lesions. MATERIAL AND METHODS Twenty patients were investigated preoperatively regarding tumor detection using CT (n = 8) or MRI (n = 12) and image fusion (VNav) (n = 3). All patients had surgery for their hepatic tumor (hepatocellular carcinoma (HCC), cholangiocellular carcinoma (CCC), metastasis, and adenoma). Ultrasound was performed intra-operatively first with B-scan using a convex probe. Than multifrequency linear transmitters (6-9 MHz, 6-15 MHz, LOGIQ E9, GE) were applied for B-scan, coulor coded Doppler sonography (CCDS) and Power Doppler followed by dynamic CEUS with Contrast Harmonic Imaging (CHI) after bolus injection of a maximum of 15 mL SonoVue®. RESULTS In 9 cases with the use of intra-operative CEUS additional tumor lesions (diameter 4-15 mm) could be detected and were histologically confirmed after surgical resection (7 cases) or intra-operative biopsy (2 cases). Using intraoperative CEUS 64 tumor lesions could be detected compared to 51 tumor lesions detected by preoperative CT or MRI (p < 0.05). Using the 6-15 MHz multifrequency linear transducer with CHI, arterial perfusion of adenomas, neuroendocrine metastases and HCC lesions was detectable. In 3 cases a resection was not achievable. Two of these cases were treated with radio frequency ablation (RFA). The other case had no curable option due to multifocal tumor manifestation. CONCLUSION The intra-operative use of high-resolution linear transducer techniques with CEUS offers new diagnostic perspectives for an effective liver surgery.