Sorabh Kapoor

Giant Haemangioma of the Liver: Is Enucleation Better than Resection?

INTRODUCTION Haemangioma is the most common liver tumour. Treatment is indicated for symptomatic tumours, rapid increase in size, rupture or doubt in diagnosis. There is continuing debate regarding the ideal method of surgical treatment for liver haemangiomas, with some surgeons favouring enucleation over liver resection. PATIENTS AND METHODS Retrospective analysis of prospectively compiled database of patients who were surgically treated for liver haemangioma. RESULTS Between 1987 and 2003, we operated on 21 patients with liver haemangioma. Pre-operative diagnosis on imaging was made in 16 patients (13 symptomatic, 3 had progressive increase in size). In five patients, the indication of surgery was uncertain diagnosis. Enucleation was performed in 9 patients and liver resection in 12. The size of the haemangioma was similar in the enucleation and resection groups (8.9 cm versus 10 cm; P = 0.85). The mean intra-operatiive blood loss was significantly less in the enucleation group (400 ml versus 1330 ml; P = 0.004). The mean operative time was significantly less in the enucleation group as compared to the resection group (170 min versus 230 min; P = 0.035). Five patients had major postoperative morbidity in the resection group as compared to none in the enucleation group (P = 0.045). The duration of hospital stay was significantly longer in the resection group.(9.9 days versus 5.6 days; P = 0.005). CONCLUSIONS Enucleation of liver haemangiomas is safer, quicker and associated with less morbidity than liver resection. Except for some situations, such as uncertain diagnosis or total replacement of a lobe, we recommend enucleation as the surgical procedures of choice for the treatment of hepatic haemangiomas.

Bile salt–induced pro‐oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long‐Evans Cinnamon rat model

Insights into disease‐specific mechanisms for liver repopulation are needed for cell therapy. To understand the efficacy of pro‐oxidant hepatic perturbations in Wilson disease, we studied Long‐Evans Cinnamon (LEC) rats with copper toxicosis under several conditions. Hepatocytes from healthy Long‐Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of copper to below 250 μg/g liver, presence of ATPase, Cu++ transporting, beta polypeptide (atp7b) messenger RNA (mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic bile salt, cholic acid, or liver radiation before cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial hepatectomy followed by cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus cholic acid followed by cell transplantation was most effective, with cure in 75%, P < 0.001. As a group, cell therapy cures in rats preconditioned with liver radiation plus cholic acid resulted in less hepatic copper, indicating greater extent of liver repopulation. We observed increased hepatic catalase and superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that pro‐oxidant perturbations were uniquely effective for cell therapy in Wilson disease because of the nature of preexisting hepatic damage. (HEPATOLOGY 2009.)

Caudate lobectomy: tumor location, topographic classification, and technique using right- and left-sided approaches to the liver

BACKGROUND Resection of the caudate lobe (involving segments I [dorsal sector] and/or IX [right paracaval region]) often presents a technical challenge. It is difficult to perform because of its deep location and adjacency to the major hepatic vessels (ie, the left and middle hepatic veins). METHODS A literature review was performed based on a Medline search to identify articles on caudate lobectomy published from 1990 to 2005. This article describes the right and left-sided approaches to the liver for caudate resection according to caudate lobe tumor location and topographic classification. RESULTS The results of 377 lobectomies were analyzed in this review. The left-sided approach to the liver was used in 55 (14.58%), the right-sided approach in 24 (6.36%), and both approaches in 298 (79.04%) caudate lobectomies. Primary benign and malign liver tumors, as well as secondary liver tumors, were resected. CONCLUSIONS Access to and resection of the caudate lobe should be determined on the basis of tumor location and hepatic function. The left or right approach to the caudate lobe can be recommended for local resection of tumor located at Spiegels portion or process portion. Approaches to caudate lobectomy are therefore largely dependent on size and location of the lesion, type of associated resection, and presence of scarring from previous resection.

Hepatic stellate cells promote hepatocyte engraftment in rat liver after prostaglandin-endoperoxide synthase inhibition

BACKGROUND & AIMS Hepatic inflammation occurs immediately after cells are transplanted to the liver, but the mechanisms that underlie this process are not fully defined. We examined cyclooxygenase pathways that mediate hepatic inflammation through synthesis of prostaglandins, prostacyclins, thromboxanes, and other prostanoids following transplantation of hepatocytes. METHODS We transplanted F344 rat hepatocytes into syngeneic dipeptidyl peptidase IV-deficient F344 rats. Changes in cyclooxygenase pathways were analyzed, and specific pathways were blocked pharmacologically; the effects on cell engraftment and native liver cells were determined. RESULTS Transplantation of hepatocytes induced hepatic expression of prostaglandin-endoperoxide synthases 1 and 2, which catalyze production of prostaglandin H2, as well as the downstream factor thromboxane synthase, which produces thromboxane A2 (a regulator of vascular and platelet responses in inflammation). Transplanted hepatocytes were in proximity with liver cells that expressed prostaglandin-endoperoxide synthases. The number of engrafted hepatocytes increased in rats given naproxen or celecoxib before transplantation but not in rats given furegrelate (an inhibitor of thromboxane synthase) or clopodigrel (an antiplatelet drug). Naproxen and celecoxib did not prevent hepatic ischemia or activation of neutrophils, Kupffer cells, or inflammatory cytokines, but they did induce hepatic stellate cells to express cytoprotective genes, vascular endothelial growth factor and hepatocyte growth factor, and matrix-type metalloproteinases and tissue inhibitor of metalloproteinase-1, which regulate hepatic remodeling. CONCLUSIONS Activation of cyclooxygenase pathways interferes with engraftment of transplanted hepatocytes in the liver. Pharmacologic blockade of prostaglandin-endoperoxide synthases stimulated hepatic stellate cells and improved cell engraftment.

Implementation of a Surgical Safety Checklist and Postoperative Outcomes: a Prospective Randomized Controlled Study

The implementation of a surgical safety checklist is said to minimize postoperative surgical complications. However, to our knowledge, no randomized controlled study has been done on the influence of checklists on postoperative outcomes in a developing country. We conducted a prospective randomized controlled study with parallel group study design of the implementation of WHO surgical safety checklist involving 700 consecutive patients undergoing operations in our hospital between February 2012 and April 2013. In 350 patients, the checklist was implemented with modifications—the Rc arm. The control group of 350 patients was termed the Rn arm. The checklist was filled in by a surgery resident, and only the participants in the study were blinded. Postoperative wound-related (p = 0.04), abdominal (p = 0.01), and bleeding (p = 0.03) complications were significantly lower in the Rc compared to the Rn group. The number of overall and higher-grade complications (Clavien-Dindo grades 3 and 4) per patient reduced from 0.97 and 0.33 in the Rn arm to 0.80 and 0.23 in the Rc arm, respectively. A significant reduction in mortality was noted in the Rc arm as compared to the Rn arm (p = 0.04). In a subgroup analysis, the number of overall and higher-grade complications per patient with incomplete checklists was higher than that with fully completed checklist group. Implementation of WHO surgical safety checklist results in a reduction in mortality as well as improved postoperative outcomes in a tertiary care hospital in a developing country.

Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rodent liver

To optimize strategies for liver‐directed cell therapy, prevention of initial transplanted cell losses is particularly important for subsequent liver repopulation. After cell transplantation in hepatic sinusoids, perturbations in hepatic microcirculation along with changes in various liver cell types are among the earliest changes. Therefore, for advancing further concepts in cell engraftment we studied vascular and related events in the liver after transplanting syngeneic hepatocytes into dipeptidyl peptidase IV‐deficient rats. We treated rats with vascular drugs to define whether deleterious cell transplantation‐induced events could be controlled followed by improvements in transplanted cell engraftment and proliferation. We found cell transplantation altered liver gene expression related to vessel tone, inflammation, cell adhesion, thrombosis, or tissue damage/remodeling. This was due to hepatic ischemia, endothelial injury, and activation of neutrophils, Kupffer cells, and hepatic stellate cells. Treatment of rats before cell transplantation with the angiotensin converting enzyme blocker, lisinopril, or angiotensin II receptor blocker, losartan, did not improve cell engraftment. By contrast, direct‐acting nitroglycerine or prostacyclin improved cell engraftment and also kinetics of liver repopulation. These drugs lowered hepatic ischemia and inflammation, whereas pretreatment of rats with the dual endothelin‐1 receptor blocker, bosentan, improved cell engraftment independently of hepatic ischemia or inflammation, without improving liver repopulation. However, incubation of hepatocytes with bosentan protected cells from cytokine toxicity in vitro and produced superior cell engraftment and proliferation in vivo. Conclusion: Cell transplantation‐induced changes in hepatic microcirculation contributed to transplanted cell clearances from liver. Vascular drugs, such as nitroglycerine, prostacyclin, and bosentan, offer opportunities for improving cell therapy results through superior cell engraftment and liver repopulation. Ongoing clinical use of these drugs will permit rapid translation of the findings in people. (HEPATOLOGY 2013)

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

Engraftment of transplanted cells is critical for liver‐directed cell therapy, but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells (KCs). To define whether tumor necrosis factor alpha (TNF‐α) served roles in cell‐transplantation–induced hepatic inflammation, we used the TNF‐α antagonist, etanercept (ETN), for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas ETN before cell transplantation essentially normalized these responses. Moreover, ETN down‐regulated cell‐transplantation–induced intrahepatic release of secretory cytokines, such as high‐mobility group box 1. These effects of ETN decreased cell‐transplantation–induced activation of neutrophils, but not of KCs. Transplanted cell engraftment improved by several‐fold in ETN‐treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with ETN before multiple cell transplantation sessions. Transplanted cell numbers did not change over time, indicating absence of cell proliferation after ETN alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after ETN pretreatment significantly accelerated liver repopulation, compared to control rats. Conclusion: TNF‐α plays a major role in orchestrating cell‐transplantation–induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. Because TNF‐α antagonism by ETN decreased transplanted cell clearance, improved cell engraftment, and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy. (Hepatology 2014;60:1378–1388)

Endothelin-1 receptor A blocker darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats.

Cell transplantation‐induced hepatic ischemia and recruitment of vasoconstrictors (e.g., endothelin‐1; Edn1) leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan (DAR), which potently blocks Edn1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without DAR in dipeptidyl peptidase IV–deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells (KCs), neutrophils, or hepatic stellate cells (HSCs). The retrorsine‐partial hepatectomy model was used for liver repopulation studies. Whether DAR was directly cytoprotective was examined in cultured rat hepatocytes or CFSC‐8B rat HSCs. We found that DAR induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage, versus drug‐untreated controls. Moreover, in DAR‐treated animals, cell transplantation‐induced activation of KCs, albeit not of neutrophils, decreased, and fewer HSCs expressed desmin. In DAR‐treated rats, improvements in cell engraftment led to greater extent of liver repopulation, compared to drug‐untreated controls. In cell‐culture assays, DAR did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from HSCs. Moreover, DAR did not protect hepatocytes from tumor necrosis factor alpha– or oxidative stress–induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. Conclusion: Systemic administration of DAR decreases hepatic ischemia‐related events and thus indirectly improves cell engraftment and liver repopulation. This vascular mechanism may permit the development of combinatorial drug‐based regimens to help optimize cell therapy. (Hepatology 2014;59:1107–1117)

Thromboelastographic evaluation of coagulation in patients with extrahepatic portal vein thrombosis and non-cirrhotic portal fibrosis: A pilot study

Background and Aims:  Non‐cirrhotic portal hypertension due to extrahepatic portal vein thrombosis (EHO) and non‐cirrhotic portal fibrosis (NCPF) is a major cause of upper gastrointestinal hemorrhage in India. Hypercoagulability has been proposed to explain the thrombosis in the portal vein in EHO and intrahepatic portal vein radicals in NCPF. However, some authors have reported hypocoagulability in these patients. Thromboelastography (TEG), which gives a dynamic assessment of coagulation, has potential for evaluating coagulation in these patients but has not been used so far. It was the aim of this study to evaluate the coagulation status in patients of EHO and NCPF using TEG.

Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation.

Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications.