Viniyendra Pamecha

Effect of portal vein embolisation on the growth rate of colorectal liver metastases

Portal vein embolisation (PVE) is used to increase the remnant liver volume before major liver resection for colorectal metastases. The resection rate after PVE is 60–70%, mainly limited by disease progression. The effect of PVE on tumour growth rate has not been investigated. The objective of this study was to compare the growth characteristics of resected colorectal liver metastases in patients undergoing pre-operative PVE with those of matched controls who had not undergone PVE. There were 22 patients who had undergone preoperative PVE and 20 matched controls. Tumour growth rate was calculated by the change in tumour volume (CT/MRI volumetric assessment) from diagnosis to resection. Resected histological specimens were examined by two histopathologists independently for cell differentiation, percentage tumour cell necrosis and mitotic rate. Immunochemical staining with Ki67 was carried out using the MIB-1 monoclonal antibody and quantified using a Glasgow cell-counting graticule. The groups were comparable in demographics, stage of primary disease, volume of liver metastases at presentation and chemotherapy received. The tumour growth rate calculated from imaging was more rapid in the PVE group compared with that in controls (control: 0.05±0.25 ml day−1, PVE: 0.36±0.68 ml day−1, P=0.06). Histology showed no difference in the degree of differentiation, extent of necrosis or apoptosis between the two groups. However, mitotic rate was higher post PVE, as was the proliferation index Ki67 (P=0.04). This study has confirmed that tumour growth rate increased following PVE and that this is related to increased tumour cell division.

Techniques for liver parenchymal transection: a meta-analysis of randomized controlled trials

BACKGROUND Different techniques of liver parenchymal transection have been described, including the finger fracture, sharp dissection, clamp-crush methods and, more recently, the Cavitron ultrasonic surgical aspirator (CUSA), the hydrojet and the radiofrequency dissection sealer (RFDS). This review assesses the benefits and risks associated with the various techniques. METHODS Randomized clinical trials were identified from the Cochrane Library Trials Register, MEDLINE, EMBASE, Science Citation Index Expanded and reference lists. Odds ratio (ORs), mean difference (MDs) and standardized mean differences (SMDs) were calculated with 95% confidence intervals based on intention-to-treat analysis or available-case analysis. RESULTS We identified seven trials including a total of 556 patients. Blood transfusion requirements were lower with the clamp-crush technique than with the CUSA or hydrojet. The clamp-crush technique was quicker than the CUSA, hydrojet or RFDS. Infective complications and transection blood loss were greater with the RFDS than with the clamp-crush method. There was no significant difference between techniques in mortality, morbidity, liver dysfunction or intensive therapy unit and hospital stay. CONCLUSIONS The clamp-crush technique is more rapid and is associated with lower rates of blood loss and otherwise similar outcomes when compared with other methods of parenchymal transection. It represents the reference standard against which new methods may be compared.

Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.

Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End‐Stage Liver Disease (ρ = ‐0.582, P < 0.001) and Childs scores (P < 0.038). BMs of cirrhosis patients with higher Model of End‐Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin‐1β (P = 0.004), tumor necrosis factor‐α (P = 0.040), and interferon‐γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell‐derived factor 1 (P = 0.03) compared to those with lower Model of End‐Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. Conclusions: Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273‐1288)

Serial changes of cytokines and growth factors in peripheral circulation after right lobe donor hepatectomy.

Cytokines and growth factors have prominent roles in liver regeneration. The aim of this study was to evaluate the biological markers of liver regeneration in healthy donors undergoing right lobe donor hepatectomy for living donor liver transplantation. Twenty‐five voluntary liver donors were enrolled. Peripheral blood samples were taken a day before the operation and on postoperative days (PODs) 1, 3, 7, 14, and 42. Levels of hepatocyte growth factor (HGF), interleukin (IL) 6, tumor necrosis factor α (TNF‐α), thrombopoietin (TPO), transforming growth factor β1 (TGF‐β1), interferon (IFN) α, and IFNγ were monitored. The remnant liver volume (RLV) before surgery and regeneration liver volume (RgV) on POD 14 were calculated on computed tomography (CT). RgV/RLV ratio was correlated with the remnant‐liver‐volume‐to‐body‐weight ratio (RLVBWR). Inverse correlation was observed between RgV/RLV and RLVBWR (r2 = 0.61; P < 0.001). There was a significant rise of HGF on POD 1 (P = 0.001), POD 7 (P = 0.049), and POD 14 (P = 0.04). TNF‐α was elevated on POD 1 (P = 0.004). The levels of IL 6 (P < 0.001) and TPO (P < 0.001) were higher from POD 1 to POD 42. IFNα was higher on POD 14 (P = 0.003) and POD 42 (P = 0.001). There was a significant fall of IFNγ on POD 1 (P = 0.01) and increase on POD 14 (P = 0.04). The levels of TGF‐β1 were higher on POD 14 (P = 0.008) and on POD 42 (P = 0.002). In conclusion, HGF, IL 6, TNF‐α, and TPO are involved in the early phase, whereas TGF‐β1 and IFN are involved in the termination phase of liver regeneration. Liver regeneration was observed to be higher in donors with low RLVBWR. Liver Transpl 22:344–351, 2016.

Liver transplantation in acute on chronic liver failure: challenges and an algorithm for patient selection and management

Acute on chronic liver failure is an entity distinct from acute liver failure and acute decompensation of chronic liver disease. Despite best medical therapy, it is associated with high short-term mortality due to infection and organ failure. Liver transplantation is a potentially curative treatment option that has been shown to have good outcomes in this setting. As there are no reliable ways of predicting which subset of patients will recover spontaneously, early transplantation before establishment of full blown sepsis or organ failure is expected to have favorable outcomes with an acceptable risk. This article reviews current literature on liver transplantation for acute on chronic liver failure, discusses challenges in patient selection, and proposes an algorithm for management.

Biliary complications after living donor hepatectomy: A first report from India

Biliary complications after donor hepatectomy can result in significant morbidity. We herein present our experience of donor hepatectomy, highlighting surgical techniques that prevent complications. Data were reviewed from a prospectively maintained database of all donors who underwent hepatectomy from April 2011 to April 2015. Standard operative technique as described was followed in all patients. Biliary complications and morbidity were recorded and stratified as per Clavien‐Dindo classification. Results were compared with published literature. During the study period, 160 donors underwent hepatectomy. The majority of the graft types were right hemiliver without the middle hepatic vein (71.9%). Major complications (grade III and above) occurred in 5.6% of the donors. There was no donor mortality. Only 1 out of the 160 donors (0.6%) has had a grade III biliary complication requiring endoscopic retrograde cholangiography and papillotomy. There were 3 grade II biliary complications, all occurring after left lateral sectionectomy, necessitating prolonged retention of the intra‐abdominal drain. The median duration of hospital stay was 11 days (range, 5‐67 days), and the duration of follow‐up was 16 months (range, 3‐52 months). There was no loss to follow‐up, and no donor required readmission or outpatient procedures for any biliary complication. In conclusion, with careful donor selection and a standardized surgical technique, biliary complications can be minimized. Liver Transplantation 22 607‐614 2016 AASLD.

Imaging panorama in postoperative complications after liver transplantation.

The liver is the second most-often transplanted solid organ after the kidney, so it is clear that liver disease is a common and serious problem around the globe. With the advancements in surgical, oncological and imaging techniques, orthotopic liver transplantation has become the first-line treatment for many patients with end-stage liver disease. Ultrasound, and Doppler are the most economical and cost-effective imaging modalities for evaluating postoperative fluid collections and vascular complications. Computed tomography (CT) is used to confirm the findings of ultrasound and look for pulmonary complications. Magnetic resonance imaging (MRI) is used for the diagnosis of biliary complications, bile leaks and neurological complications. This article illustrates the imaging options for diagnosing the various complications that can be encountered in the postoperative period after liver transplantation.

Liver Transplantation After Bone Marrow Transplantation for End Stage Liver Disease with Severe Hepatopulmonary Syndrome in Dyskeratosis Congenita: A Literature First

Dyskeratosis congenita is a multisystem genetic disorder. Although hepatic involvement is reported in about 7% of patients with dyskeratosis congenita, it is not well characterized and often attributed to hemochromatosis from frequent blood transfusions. A few case reports describe cirrhosis and hepatic cell necrosis in affected individuals in autosomal dominant pedigrees. Bone marrow failure and malignancies are the principal causes of death in dyskeratosis congenita. We describe the first case of living donor liver transplantation, in dyskeratosis congenita for decompensated cirrhosis with portal hypertension. The patient also had associated severe hepatopulmonary syndrome, interstitial lung disease, bilateral hip replacement for avascular necrosis of the head of femur, and a past history of bone marrow transplantation for bone marrow failure.

EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients

Hepatocellular carcinoma (HCC) is believed to originate from cancer stem cells (CSCs). While epithelial cell adhesion molecule (EpCAM) is a marker of normal hepatic stem cells (HSCs), EpCAM+ cells from HCC behave like CSCs. Since HCC mostly develops on a cirrhotic background, we sought to determine whether CSC‐like EpCAM+ cells exist in patients with advanced cirrhosis. Both flow cytometry and immunohistochemistry showed that frequency of EpCAM+ cells in advanced cirrhosis was increased as compared to control. To determine whether increased EpCAM population in advanced cirrhosis harbors any CSC‐like cells, we compared molecular and functional features of EpCAM+ cells from advanced cirrhosis (Ep+CIR; n = 20) with EpCAM+ cells from both HCC (Ep+HCC; n = 20) and noncancerous/noncirrhotic (control) (Ep+NSC; n = 7) liver tissues. Ep+CIRs displayed similarity with Ep+HCC cells including upregulated expression of stemness and Notch pathway genes, enhanced self‐renewal in serial spheroid assay and generation of subcutaneous tumors in nonobese diabetic/severe combined immunodeficiency mice. Moreover, transcriptome and miRNome of Ep+CIRs appeared closer to that of Ep+HCC cells than Ep+NSCs. Interestingly, more than 50% micro RNAs (miRNAs) and transcripts specifically expressed in Ep+HCCs were also expressed in Ep+CIRs. However, none of Ep+NSC specific miRNAs and only 7% Ep+NSC specific transcripts were expressed in Ep+CIRs. Further, according to gene expression and in vitro Wnt inhibition analysis, autocrine Wnt signaling appeared to be a distinct feature of Ep+CIR and Ep+HCC cells, which was absent from Ep+NSCs. EpCAM+ cells in advanced cirrhosis possibly include a population of CSC‐like cells which can be explored for early diagnosis of HCC development. Stem Cells Translational Medicine 2017;6:807–818

Two-tier regenerative response in liver failure in humans.

Acute and chronic liver failure is associated with high mortality. The enormous regenerative potential of the liver has generated a lot of attention. We undertook this work to assess the two-tier regenerative response in liver failure by immunohistochemistry and to correlate such response with liver histology in acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis (CHD). Histological examination and immunohistochemical analysis of proliferating hepatocytes and activated hepatic progenitor cells (HPCs) were performed on the liver tissue of patients with ALF (25), ACLF (70), and CHD (70). Comparative analysis of regenerative markers and correlation with histological parameters were done in ALF, ACLF, and CHD. Hepatocytes proliferated significantly more in ALF in comparison to ACLF (p < 0.001) and CHD (p < 0.001). HPC proliferation was significantly higher in ACLF (p < 0.001) and CHD (p < 0.001) than in ALF. ACLF patients showed the highest HPC proliferation and differentiation. Significantly more intermediate hepatocytes were found in ACLF than in ALF and CHD (p < 0.001). Marked parenchymal replacement by fibrosis and/or necrosis correlated significantly with activation of HPC in ACLF (p = 0.01, odds ratio (OR) 4.95) and in CHD (p = 0.05, OR 4.19). The study of liver regeneration in human acute and chronic liver failure suggests that hepatocyte proliferation, providing the first line of regeneration response, is most active in ALF whereas HPC activation, the second line of defense, is more prominent in ACLF. More HPC differentiate to hepatocytes in ACLF than in CHD, reflecting better regenerative potential in ACLF.