Open abdomen in liver transplantation.

INTRODUCTION: Damage control laparotomy with vacuum assisted closure (VAC) is used for selective cases in trauma. In liver transplantation, VAC has also been applied for management of intra-operative hemorrhage. The primary objective was to evaluate peri-operative blood loss and blood product utilization in VAC compared to primary abdominal closure (PAC) at the index transplant operation. METHODS: Retrospective review of all adults undergoing deceased donor liver transplantation (2007-2011) at a single center tertiary care institution. RESULTS: 201 deceased donor liver transplantations were performed, with 167 PAC and 34 VAC cases. Intra-operative blood loss (4.4L vs 10.7L), cell saver return (1399 ml vs 3998 ml), FFP (7.6U vs 15.9U) and PLT requirements (8.5U vs 18.3U), were all significantly elevated in VAC compared to PAC. VAC patients had significantly increased RBC, FFP, PLT, and total volume requirements during initial ICU admission. 30 PAC cases required on demand laparotomy and most commonly for post-operative bleeding. CONCLUSION: In liver transplantation, application of VAC secondary to massive intra-operative exsanguination was safely utilized. Further evaluation is required to identify long-term morbidity and mortality.

Hepatic embolotherapy in interventional oncology: technology, techniques, and applications.

Embolotherapy continues to play a growing role in the management of primary and secondary hepatic malignancies. In this review article, we examine the basis of therapy with a focus on neovascularization, which makes treatments via the hepatic artery possible. An overview of the three generations of embolic and therapeutic agents follows. The techniques, technologies, and complications of bland embolization, transarterial chemoembolization, drug-eluting beads, and selective internal radiotherapy are covered to give the reader an overview of this exciting field in interventional radiology.

Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.

BACKGROUND: The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects. METHODS: Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients. RESULTS: Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, K(trans) values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1alpha, IL-8, ICAM-1, and VCAM-1. CONCLUSION: Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.

Hepatic abscesses after liver transplantation secondary to traumatic intrahepatic bile duct injuries in a cadaveric allograft donor.

We report the case of an ultimately successful liver transplant recipient whose post-transplant course was complicated by the early development of multiple abscesses in the graft. Post-transplant cholangiography identified multiple shear injuries to the second and third order intrahepatic bile ducts, originating from blunt trauma to the donor liver. Treatment was non-operative following recent reports of the successful management of intrahepatic bile duct injury in the stable trauma patient. This discussion adds to the limited literature available on the transplantation of injured donor livers, despite this being a relatively common practice. Further experience is needed in determining the appropriate criteria for the use of traumatized donor livers. Cholangiography carried out on the back table may help to determine if such injured livers are suitable for transplantation.

A cross-sectional study of SEN virus in liver transplant recipients.

A new DNA virus, referred to as SEN virus (SEN V), has been isolated and is associated with blood-product transfusion and possibly Non A to Non E hepatitis. We performed a cross-sectional analysis of SEN V in liver transplant recipients at our center. Polymerase chain reaction was used to test for 2 genotypes of SEN V (SEN V:C/H and SEN V:D) in 58 unselected patients. Comparisons were made between SEN V--positive and SEN V--negative groups in terms of age, time posttransplantation, indications for transplantation, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and cytomegalovirus and Epstein-Barr virus status. Thirty of 58 transplant recipients (51.7%) were SEN V positive; 15.5% were positive for SEN V:C/H, 24.1% for SEN:D, and 12.1% for both strains. No significant differences were found based on primary indication for transplantation, including hepatitis C virus (HCV). Of the 14 of 21 patients with HCV seropositivity and HCV reinfection, 79% were positive for SEN V (P =.02). There was no difference in the proportion of patients with abnormal serum ALT and/or AST levels. A trend for the SEN V--positive group to have a greater mean ALT level (82 v 41 U/L; P =.067) was attributable to the subgroup with HCV recurrence because there was no difference in mean ALT levels (34.9 v 34.5 U/L; P =.968) in non--HCV-infected transplant recipients. Even in the subgroup (n = 14) with recurrent HCV, there was no statistically significant difference in mean ALT levels (140 v 105 U/L; P =.665). Age and cytomegalovirus or Epstein-Barr virus status were not significantly different between the 2 groups, but a significant difference in posttransplantation time was noted (16.8 v 32 months; P =.021). We conclude that SEN V is common among liver transplant recipients but does not appear to cause graft dysfunction as an isolated agent. There is a suggestion that SEN V may be associated with HCV recurrence, but we did not detect biochemical differences attributable to SEN V.

Indications for liver transplantation in British Columbia's Aboriginal population: a 10-year retrospective analysis.

OBJECTIVES: To study the indications for liver transplantation among British Columbia's First Nation population. MATERIALS AND METHODS: A retrospective analysis of the British Columbia Transplant Society's database of Aboriginal and non-Aboriginal liver transplant recipients from 1989 to 1998 was undertaken. For primary biliary cirrhosis (PBC), the transplant assessment database (patients with and without transplants) was analyzed using a binomial distribution and compared with published census data regarding British Columbia's proportion of Aboriginal people. RESULTS: Between 1989 and 1998, 203 transplantations were performed in 189 recipients. Fifteen recipients were Aboriginal (n=15; 7.9%). Among all recipients, the four most frequent indications for liver transplantation were hepatitis C virus (HCV) infection (n=57; 30.2%), PBC (n=34; 18.0%), alcohol (n=22; 11.6%) and autoimmune hepatitis (n=14; 7.4%). Indications for liver transplantation among Aboriginal people were PBC (n=8; 53.3%; P<0.001 compared with non-Aboriginal people), autoimmune hepatitis (n=4; 26.67%; P=0.017), acute failure (n=2; 13.3%) and HCV (n=1). Among all patients referred for liver transplantation with PBC (n=43), 29 (67.44%) were white and 11 (25.6%) were Aboriginal. A significant difference was found between the proportion of Aboriginal people referred for liver transplantation and the proportion of Aboriginal people in British Columbia (139,655 of 3,698,755 [3.8%]; 1996 Census, Statistics Canada) (P<0.001). CONCLUSIONS: Aboriginal people in British Columbia are more likely to be referred for liver transplantation with a diagnosis of PBC but are less likely to receive a liver transplant because of HCV or alcohol than are non-Aboriginal people.

Mesohepatectomy.

BACKGROUND: Formal anatomic (lobar) or extended hepatectomies are recommended for liver malignancies located centrally within the liver (Couinaud's segments IVA, IVB, V, and VIII). Mesohepatectomy, resection of central hepatic segments and leaving the right and left segments in situ, removes large central tumors preserving more functioning liver tissue than either extended left or right hepatectomy. Mesohepatectomy is a seldom used, technically demanding procedure, and its application is yet to be defined. METHODS: Medical charts of 244 consecutive liver resection patients were reviewed retrospectively. Eighteen patients were treated with mesohepatectomy. Six patients had metastatic liver tumor (MLT), 11 had hepatocellular carcinoma (HCC), and 1 had gallbladder adenocarcinoma. The operative results were compared with groups of patients treated by lobar hepatectomy (n = 71) and extended left or right hepatectomy (n = 43). RESULTS: The mean mesohepatectomy operative time was 238 versus 304 minutes in the extended group. Inflow occlusion mean time was longer in the mesohepatectomy group than in extended procedures, 45 versus 39 minutes (P = not significant). Comparing the extended hepatectomy group, the mesohepatectomy group had a mean operative estimated blood loss 914 cc versus 1628 cc (P <0.01), postoperative hospital stay 9 versus 16 days (P = 0.054) and volume of resected liver 560cc versus 1500cc (P <0.01) respectively. The late complication rate was lower in the mesohepatectomy group than in the extended group and was comparable to the lobar hepatectomy group (P = 0.05). CONCLUSIONS: Despite its technical demands, mesohepatectomy should be considered as an alternative to extended hepatectomy for selected patients with primary and secondary hepatic tumors localized in middle liver segments, as its complication rate, postoperative recovery, and preserved liver tissue compare favorably with extended hepatic resection.

Post-transplant diabetic ketoacidosis--a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series.

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.

Assessment of immunologic status of liver transplant recipients by peripheral blood mononuclear cells in response to stimulation by donor alloantigen.

OBJECTIVE: To determine whether there is a role for assessing peripheral blood mononuclear cell (PBMC) cytokine patterns as a means of measuring the immunologic and clinical status of liver transplant recipients. SUMMARY BACKGROUND DATA: The role of assessing cytokine patterns in the prediction of clinical graft rejection or acceptance remains unclear. The purpose of this study was to examine the cytokine profiles of PBMC stimulated in vitro with donor alloantigen and to correlate prospectively the data with clinical assessment of graft status in orthotopic liver transplant (OLT) recipients. METHODS: PBMCs from OLT recipients were examined for proliferation and cytokine mRNA expression after stimulation by donor alloantigen, third-party alloantigen, or phytohemagglutinin (PHA). mRNA extracted from PBMC was amplified by reverse transcriptase-polymerase chain reaction with oligospecific primer pairs for interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN) gamma, tumor necrosis factor (TNF) alpha and transforming growth factor (TGF) beta. Results were prospectively correlated with each patient's allograft status. RESULTS: Increased IL-4 and TGF-beta and decreased IL-2, IFNgamma, and TNF-alpha mRNA expression by PBMCs in response to donor alloantigen stimulation predicted immunologic graft stability over a minimum 60-day interval compared with mRNA expression of PBMCs from patients with established rejection or those who experienced a rejection episode within a 30-day period (p < 0.05). Stimulation of recipient PBMCs with third-party alloantigens or PHA yielded similar but less specific results. PBMC proliferation to varying antigenic stimulation did not correlate with clinical graft status, nor did cytokine production by unstimulated PBMC. CONCLUSIONS: Prospective assessment of cytokine expression by PBMC from OLT recipients in response to stimulation by donor alloantigen is helpful for predicting the clinical status of the allograft and may be useful in the development of more precise immunologic monitoring protocols.

Radiofrequency ablation followed by resection of malignant liver tumors.

BACKGROUND: Radiofrequency ablation (RFA) has recently been used to treat liver tumors, but few clinical reports have described the pathological characteristics of radiofrequency ablation in human specimens. This study delineates the gross pathologic and histochemical changes induced by RFA in benign and malignant human liver tissue and confirms the tumor necrosis described in early clinical reports. METHODS: Ten patients with metastatic tumors of the liver received a single treatment of ultrasound-guided percutaneous RFA to 12 tumors. Hepatic resection was carried out within 6 weeks of RFA. Specimens were stained with standard hematoxylin and eosin stain followed by oxidative stain to determine if there was evidence of viable tumor within the zone of ablation. RESULTS: Nine of the 12 ablations were resected. Microscopic examination within the zone of ablation showed successful ablation in 8 of the 9 resected ablations. CONCLUSIONS: Percutaneous RFA creates well-circumscribed areas of tumor necrosis with apparent cell death using an oxidative stain. Further investigation is encouraged to determine the clinical effectiveness of radiofrequency ablation in the complete destruction of liver tumors for palliative or curative intent.

Post-surgical shunt hepatopulmonary syndrome in a case of non-cirrhotic portal hypertension: lack of efficacy of shunt reversal.

Hepatopulmonary syndrome, a consequence of significant liver disease and portal hypertension, is thought to be secondary to the effects of vasoactive substances, normally inactivated in the liver, on the pulmonary vasculature. We report a patient with preserved hepatic function who underwent a decompressive surgical porto-systemic shunt for non-cirrhotic portal hypertension. This patient developed hepatopulmonary syndrome with dyspnoea and oxygen desaturation 2 years post-surgical shunt. Over the next 7 years, the patient's respiratory function became increasingly impaired although hepatic function remained preserved. Because of the hypothesized role of porto-systemic shunting in the aetiology of this syndrome, the surgical shunt was successfully reversed angiographically. No improvement in dyspnoea or oxygen saturation occurred and liver transplantation was undertaken. Six months post-transplant, the patient has decreased his oxygen requirements and is free of dyspnoea. Our experience supports the causal role of porto-systemic shunting in the pathogenesis of hepatopulmonary syndrome but suggests that merely decreasing the extent of porto-systemic shunting is not beneficial. Liver transplantation remains the only reliable therapeutic modality available to these patients.

Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size.

OBJECTIVE: To determine, in vivo, the effect of radiofrequency ablation (RFA) treatment time and tissue blood flow on the size and shape of the resulting necrotic lesion in porcine liver. SUMMARY BACKGROUND DATA: Radiofrequency ablation is an electrosurgical technique that uses a high frequency alternating current to heat tissues to the point of desiccation (thermal coagulation). Radiofrequency ablation is well established as the treatment of choice for many symptomatic cardiac arrhythmias because of its ability to create localized necrotic lesions in the cardiac conducting system. Until recently, a major limitation of RFA was the small lesion size created by this technique. Development of bipolar and multiple-electrode RFA probes has enabled the creation of larger lesions and therefore has expanded the potential clinical applications of RFA, which includes the treatment of liver tumors. A basic understanding of factors that influence RFA lesion size in vivo is critical to the success of this treatment modality. The optimal RFA technique, which maximizes liver lesion size, has yet to be determined. Theoretically, lesion size varies directly with time of application of the RF current, and inversely with blood flow, but these relationships have not been previously studied in the liver. METHODS: Six animals underwent hepatic RFA (460 kHz), for 5, 7.5, 10, 12.5, 15, and 20 minutes. Identical, predetermined anatomic areas of the liver were ablated in each animal. Two additional animals underwent 12 RFA treatments -- 6 with vascular inflow occlusion (Pringle maneuver) and 6 with uninterrupted hepatic blood flow. Animals were euthanized and the livers were removed for gross pathologic examination. All lesions were measured in three dimensions and photographed. Tissues were examined by routine histology and by histochemistry to determine viability. RESULTS: Increasing duration of RFA application from 5 through 20 minutes did not create lesions of larger diameter, but this time increase did predict deeper lesion production (beta = 0.34, p = 0.04). A range of lesion shapes were created from four separate ovals (corresponding to each electrode), to larger ovals intersecting to form a cross, to spheroid lesions. The number of blood vessels in close proximity to the probe tip (within a 1-cm radius from the center of the lesion) strongly predicted minimum lesion diameter (beta = -0.61, p = 0.0001) and lesion volume (beta = -0.56, p = 0.0004). This negative effect of blood flow on lesion size was confirmed experimentally. Radiofrequency ablation lesions created during a Pringle maneuver were significantly larger in all three dimensions than lesions created without a Pringle maneuver: minimum diameter was 3.0 cm (with Pringle) versus 1.2 cm (p = 0.002), maximum diameter was 4.5 cm (with Pringle) versus 3.1 cm (p = 0.002), depth was 4.8 cm (with Pringle) versus 3.1 cm (p < 0.001), and lesion volume was 35.0 cm3 (with Pringle) versus 6.5 cm3 (p < 0.001). CONCLUSIONS: Blood flow is a strong predictor of all RFA lesion dimensions in porcine liver in vivo, whereas a change of treatment time from 5 to 20 minutes is predictive only of lesion depth, but not diameter or volume.

Surgical staplers for vascular control of hepatic veins and portal structures in major hepatic resection.

Phenomenal progress has occurred in the art of liver resection. Only a decade ago massive blood transfusion, liver failure, bile leak, or sepsis were alI frequent attendants of major resection, and intraoperative death from torrential bleeding from hepatic veins or vena cava was not uncommon. Now, major liver resection may be accomplished routinely without blood transfusion, and operative mortality of 0% to 2% is standard in expert hands. Uncontrolled hemorrhage remains the primary cause of intraoperative death. Mortality in the early postoperative period is usually related to delayed hemorrhage, inadequate hepatic reserve, or injury to vital blood supply or biliary drainage in the liver remnant.

Veno-veno bypass of the inferior vena cava in trauma, tumor, and transplantation.

Interrupting the venous return from below the diaphragm is usually associated with sudden hypotension, hypovolemic cardiac failure, and increased bleeding secondary to acute venous hypertension and hepatic congestion. Shaw, Starzl, and Griffith developed a veno-veno bypass technique to shunt the somatic and splanchnic venous return around the retrohepatic vena cava to the superior vena cava. This permitted continuation of venous return and simultaneous blood warming, allowing surgeons to perform complex procedures in a dry operative field. These bypass techniques have evolved since their introduction in the 1980s and are now being applied for the removal of otherwise nonresectable tumors of the liver, adrenal gland, and kidney. Further, traumatic injuries to the hepatic veins and the retrohepatic cava associated with a high mortality rate can be repaired safely using vascular isolation techniques and bypass.

Liver tumor ablation techniques.

Despite advances in surgical technique, patients with primary and secondary liver tumors remain a difficult management problem, as most tumors are unresectable at presentation. Alternative therapies, involving the in situ destruction of liver tumors, have recently come under scrutiny as palliative options. Percutaneous ethanol injection and cryosurgery have been advocated, but both have associated technical difficulties and adverse effects. Novel liver tumor ablation techniques have recently been developed that work via the induction of localized hyperthermia. There is mounting evidence to support a hypothesis that cancer cells are more selectively sensitive to heat than are normal cells, due to the poor blood supply of neoplastic tissue and the decreased vasodilatation capacity of the neovascular bed. These ablative modalities induce a variable degree of tumor necrosis in unresectable tumors, and therefore may provide useful palliation. Clinical trials are needed to determine the true nature and degree of any palliative benefit. In addition, the determinants of treatment efficacy and the predictability of the necrotic zone must be better understood before these techniques can be contemplated as alternatives to liver resection for cure.

Stapler technique for extrahepatic vascular control during hepatic resection.

A technique is described for extrahepatic division of the hepatic veins and portal structures to be resected utilizing a vascular stapler. The authors have employed this technique in more than 200 consecutive cases of hepatic resection. No major hepatic venous bleeding has been identified.

Radiofrequency ablation in surgery.

Recently, hyperthermia has been employed clinically as one of a variety of multimodal therapies for cancer. Hyperthermia has been applied locally, regionally, and systemically to various tumors. Local or regional hyperthermia has the advantage that a localized tumor can be heated to temperatures higher than 420 C, the maximum for total-body hyperthermia. There is mounting evidence to support a hypothesis that cancer cells are more selectively sensitive to heat than are normal cells, due to the poor blood supply of neoplastic tissue and the decreased vasodilatation capacity of the neovascular bed.